01- Kinins and their B1 and B2 receptors as potential therapeutic targets for pain relief

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<p>Life Sciences 314 (2023) 121302</p><p>Available online 17 December 2022</p><p>0024-3205/© 2022 Elsevier Inc. All rights reserved.</p><p>Review article</p><p>Kinins and their B1 and B2 receptors as potential therapeutic targets for</p><p>pain relief</p><p>Indiara Brusco a, Maria Fernanda Pessano Fialho a, Gabriela Becker a, Evelyne Silva Brum a,</p><p>Amanda Favarin b, Lara Panazzolo Marquezin b, Patrick Tuzi Serafini b, Sara</p><p>Marchesan Oliveira a,*</p><p>a Graduate Program in Biological Sciences: Biochemistry Toxicology, Federal University of Santa Maria, Santa Maria, RS, Brazil</p><p>b Laboratory of Neurotoxicity and Psychopharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil</p><p>A R T I C L E I N F O</p><p>Keywords:</p><p>Neuropathic pain</p><p>Fibromyalgia</p><p>Bradykinin</p><p>Cancer</p><p>Inflammatory pain</p><p>Nociplastic pain</p><p>A B S T R A C T</p><p>Kinins are endogenous peptides that belong to the kallikrein-kinin system, which has been extensively studied for</p><p>over a century. Their essential role in multiple physiological and pathological processes is demonstrated by</p><p>activating two transmembrane G-protein-coupled receptors, the kinin B1 and B2 receptors. The attention is</p><p>mainly given to the pathological role of kinins in pain transduction mechanisms. In the past years, a wide range</p><p>of preclinical studies has amounted to the literature reinforcing the need for an updated review about the</p><p>participation of kinins and their receptors in pain disorders. Here, we performed an extensive literature search</p><p>since 2004, describing the historical progress and the current understanding of the kinin receptors’ participation</p><p>and its potential therapeutic in several acute and chronic painful conditions. These include inflammatory (mainly</p><p>arthritis), neuropathic (caused by different aetiologies, such as cancer, multiple sclerosis, antineoplastic toxicity</p><p>and diabetes) and nociplastic (mainly fibromyalgia) pain. Moreover, we highlighted the pharmacological actions</p><p>and possible clinical applications of the kinin B1 and B2 receptor antagonists, kallikrein inhibitors or kallikrein-</p><p>kinin system signalling pathways-target molecules in these different painful conditions. Notably, recent findings</p><p>sought to elucidate mechanisms for guiding new and better drug design targeting kinin B1 and B2 receptors to</p><p>treat a disease diversity. Since the kinin B2 receptor antagonist, Icatibant, is clinically used and well-tolerated by</p><p>patients with hereditary angioedema gives us hope kinin receptors antagonists could be more robustly tested for</p><p>a possible clinical application in the treatment of pathological pains, which present limited pharmacology</p><p>management.</p><p>List of abbreviations</p><p>ACE angiotensin-converting enzyme</p><p>BPA brachial plexus avulsion</p><p>CGRP calcitonin gene-related peptide</p><p>CNS central nervous system</p><p>CIPN chemotherapy-induced peripheral neuropathy</p><p>CRPS chronic post-ischaemic pain syndrome</p><p>CRPS complex regional pain syndrome</p><p>COX cyclooxygenase</p><p>CXCL- C-X-C motif chemokine ligand</p><p>DABk des-Arg9-bradykinin</p><p>DAG diacylglycerol</p><p>DAKd (des-Arg10-kallidin)</p><p>(continued on next column)</p><p>(continued )</p><p>DALBk des-Arg9[Leu8]-bradykinin</p><p>DRG dorsal root ganglia</p><p>EAE experimental autoimmune encephalomyelitis</p><p>ERK extracellular signal-regulated kinase</p><p>NF-κB factor nuclear kappa B</p><p>CFA Freund’s complete adjuvant</p><p>IASP International Association for the Study of Pain</p><p>INF-γ interferon-γ</p><p>IP3 inositol triphosphate-3</p><p>IL- interleukin</p><p>KC keratinocytes-derived chemokine</p><p>B1R kinin B1 receptor</p><p>B2R kinin B2 receptor</p><p>(continued on next page)</p><p>* Corresponding author at: Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, 97105-900 Santa</p><p>Maria, RS, Brazil.</p><p>E-mail address: saramarchesan@ufsm.br (S.M. Oliveira).</p><p>Contents lists available at ScienceDirect</p><p>Life Sciences</p><p>journal homepage: www.elsevier.com/locate/lifescie</p><p>https://doi.org/10.1016/j.lfs.2022.121302</p><p>Received 24 August 2022; Received in revised form 7 December 2022; Accepted 13 December 2022</p><p>Life Sciences 314 (2023) 121302</p><p>2</p><p>(continued )</p><p>NO nitric oxide</p><p>NOS nitric oxide synthase</p><p>NOD non-obese diabetic</p><p>NSAIDs nonsteroidal anti-inflammatory drugs</p><p>PSNL partial sciatic nerve ligation</p><p>PNS peripheral nervous system</p><p>PMA phorbol myristate acetate</p><p>PLC phospholipase C</p><p>PIP2 phosphatidylinositol 4,5-bisphosphate</p><p>PKC protein kinase C</p><p>PAR2 proteinase-activated receptor-2</p><p>PAR4 proteinase-activated receptor-4</p><p>SNRIs serotonin and noradrenaline reuptake inhibitors</p><p>SCN9A sodium voltage-gated channel alpha subunit 9</p><p>STZ streptozotocin</p><p>TRPV1 transient receptor potential vanilloid type 1 channel</p><p>TRPV4 transient receptor potential vanilloid type 4 channel</p><p>TNFα tumour necrosis factor α</p><p>UVB ultraviolet B</p><p>Nav voltage-gated sodium channels</p><p>1. Introduction</p><p>Pain is a subjective individual experience that involves the percep-</p><p>tion of an aversive stimulus and implies sensory, affective, cognitive,</p><p>and social components [1,2]. In 2020, the International Association for</p><p>the Study of Pain (IASP) redefined the pain concept as “An unpleasant</p><p>sensory and emotional experience associated with or resembling that</p><p>associated with, actual or potential tissue damage” [3]. Physiological</p><p>pain acts as an alert and adaptive response. However, in pathological</p><p>conditions such as chronic inflammatory, neuropathic, and nociplastic</p><p>pain, the pain becomes debilitating and one of the most frequent reasons</p><p>patients seek medical care [4–7].</p><p>Clinically available analgesic agents to treat these pathological pains</p><p>generally have poor efficacy and may present adverse effects [6]. Opi-</p><p>oids and nonsteroidal anti-inflammatory drugs (NSAIDs) are used to</p><p>treat inflammatory pain [6,8]. First-line drugs recommended to treat</p><p>neuropathic pain are tricyclic antidepressants, gabapentin, pregabalin,</p><p>and serotonin and noradrenaline reuptake inhibitors (SNRIs) (dulox-</p><p>etine and venlafaxine) [9,10]. For cancer pain treatment, the World</p><p>Health Organization guidelines (2018) also recommend NSAIDs, para-</p><p>cetamol, and opioids alone or in combination, depending on pain</p><p>severity [11]. Pregabalin and SNRIs (duloxetine and milnacipran) are</p><p>drugs approved by Food and Drug Administration to treat patients with</p><p>fibromyalgia [12,13]. However, these drugs fail to provide sustained</p><p>pain relief at doses tolerated by patients and cause class-specific adverse</p><p>effects, such as constipation, tolerance, gastrointestinal toxicity, som-</p><p>nolence, dizziness, sedation, nausea, palpitations, and others, which</p><p>limit their use [6,8–14].</p><p>Evidence indicates the involvement of the kallikrein-kinin system</p><p>and its receptors in physiological processes [15,16] and acute and</p><p>chronic painful conditions, such as inflammatory pain [17–23], neuro-</p><p>pathic pain [24–30], and nociplastic pain [30–32]. Thus, kinin receptor</p><p>antagonists could be promising pharmacological tools in treating these</p><p>pathological conditions since preclinical studies have already demon-</p><p>strated their involvement in different pain pathologies.</p><p>A considerable number of peptide and non-peptide kinin receptor</p><p>antagonists have been synthesized and could be clinically tested for pain</p><p>relief [33–39]. The fact that a kinin B2 receptor (B2R) antagonist, Ica-</p><p>tibant (Firazyr®), is clinically available for the treatment of hereditary</p><p>angioedema since 2010 [40,41], with good patient tolerability, should</p><p>encourage the development of clinical trials with kinin receptor antag-</p><p>onists for pain relief. Icatibant, for example, was clinically tested only in</p><p>osteoarthritis pain, but unfortunately, results are unavailable [42].</p><p>Therefore, we aimed to review the involvement of kinins in painful</p><p>pathological conditions and the therapeutic potential of kinin B1 (B1R)</p><p>and B2 (B2R) receptor antagonists in pain control and relief.</p><p>2. Pain and nociception</p><p>Pain is a sensory experience divided into distinct categories ac-</p><p>cording to the course of duration and pathophysiological mechanisms.</p><p>Concerning time, pain can be classified as</p><p>development of thermal hyperalgesia.</p><p>DALBk or Icatibant systemically administered also reversed the</p><p>infraorbital nerve constriction-induced mechanical and heat hyper-</p><p>algesia [28,160]. Corroborating with this result, knockout mice for B1R,</p><p>B2R, or B1R/B2R did not develop heat or mechanical hyperalgesia after</p><p>infraorbital nerve constriction [28]. Interestingly, dynorphin A, an</p><p>endogenous opioid peptide, seems to contribute to maintaining hyper-</p><p>algesia after spinal nerve lesions by activating kinin receptors</p><p>[161,162]. In this sense, subarachnoid dynorphin A (1–17) delivery</p><p>provoked orofacial heat hyperalgesia in mice, which DALBk but not</p><p>Icatibant reversed. Thus, dynorphin A could stimulate kinin receptors,</p><p>especially B1R, contributing to the maintenance of trigeminal neuro-</p><p>pathic pain [28]. These results indicate that B1R and B2R direct or in-</p><p>direct activation contribute to trigeminal neuropathic pain.</p><p>Consequently, not only kinin receptor antagonists but also intracellular</p><p>signalling pathways that lead to the activation of these receptors could</p><p>be promising pharmacological targets for the control of neuropathic</p><p>pain.</p><p>4.2.4. Chronic cancer pain</p><p>Cancer-associated chronic pain is caused by primary cancer and its</p><p>metastases (chronic cancer pain) or its treatment (chronic postcancer</p><p>treatment pain). Chronic cancer pain presents inflammatory and</p><p>neuropathic mechanisms due to the direct effect of tissue response to the</p><p>primary tumour or metastases. This is because tumour expansion in-</p><p>duces tissue damage and release of inflammatory mediators and can also</p><p>compress and destroy a sensory nerve resulting in neuropathic changes</p><p>[163]. Although cancer pain can be considered a type of mixed noci-</p><p>ceptive and neuropathic pain, increasing evidence suggests additional</p><p>unique elements indicating that it could be regarded as a separate pain</p><p>state [163,164]. Notably, neuropathic mechanisms are associated with</p><p>poorer prognoses in cancer pain [163].</p><p>The involvement of kinins in chronic cancer pain has been little</p><p>explored. Sevcik and colleagues [165] found the first finding in a pri-</p><p>mary bone cancer pain model induced by injecting osteolytic sarcoma</p><p>cells into the femurs of mice. The authors suggested that tumour</p><p>metastasis to the bone could cause kinins release due to bone remodel-</p><p>ling and tissue injury. In this model, B1R antagonists (LF22-0542 and</p><p>B6769) reduced ongoing and movement-evoked nociceptive behav-</p><p>iours. In 2010, Fujita and colleagues suggested that kinins released from</p><p>melanoma cells may cause painful symptoms. In this study, the cancer</p><p>pain model was induced in mice by intraplantar injection of B16–BL6</p><p>murine melanoma cells, which present B1R and B2R and low molecular</p><p>weight kininogen. Bradykinin-related peptide levels increased in the</p><p>melanoma area, and B1R mRNA expression, but not B2R, increased in the</p><p>L4/L5 DRG after model induction. The intraplantar administration of</p><p>B1R (DABk) and B2R (bradykinin or [Tyr8]-bradykinin) agonists</p><p>increased licking behaviour in melanoma-bearing mice. Additionally,</p><p>local injections of antagonists of these receptors (DALBk and Icatibant)</p><p>inhibited the spontaneous pain of melanoma-bearing mice. However,</p><p>mechanical allodynia was briefly attenuated by the B2R antagonist but</p><p>not by the B1R antagonist. Both antagonists were ineffective in reducing</p><p>thermal hyperalgesia [166]. Given the role that kinins and their re-</p><p>ceptors play in the proliferation of different types of cancer [117],</p><p>investigating their involvement in cancer pain could be further explored.</p><p>4.2.5. Chemotherapy-induced neuropathic pain</p><p>Chemotherapy-induced peripheral neuropathy (CIPN) arises from</p><p>treatment with antineoplastic agents. The increased incidence of cancer,</p><p>with higher cure rates and improved survival of patients, contributes to</p><p>CIPN-increased prevalence. The CIPN can interfere with the chemo-</p><p>therapy regimen since it can require a reduction in the dose of chemo-</p><p>therapy or even stop before completing the planned course. Indeed, this</p><p>may cause implications for the efficacy of oncological treatment and</p><p>patients’ survival. Although the acute CIPN can be resolved after fin-</p><p>ishing chemotherapy, in many cases, it can persist, resulting in chronic</p><p>symptoms months or even years later [167]. Thus, studying new phar-</p><p>macological targets is essential to find an adequate treatment for CIPN.</p><p>Preclinical studies demonstrated that kinin receptors are promising</p><p>targets in reducing CIPN, as described below.</p><p>B1R (des-Arg10Hoe140) and B2R (Icatibant) antagonists alleviated</p><p>mechanical hyperalgesia in a vincristine-induced neuropathy model.</p><p>Indomethacin or celecoxib also abolished the vincristine-induced me-</p><p>chanical hyperalgesia and enhanced the analgesic effect of des-</p><p>Arg10Hoe140 and Icatibant. Thus, the authors suggested that kinins</p><p>receptors can be potential targets for treating vincristine-caused neu-</p><p>ropathy. Moreover, COX inhibitors (indomethacin and celecoxib) could</p><p>be associated with B1R and B2R antagonists to treat this painful condi-</p><p>tion [150].</p><p>In paclitaxel-induced neuropathy, repeated systemic administration</p><p>of B1R (DALBk) and B2R (Icatibant) antagonists reduced the mechanical</p><p>hyperalgesia, while only Icatibant alleviated the thermal hyperalgesia.</p><p>Similarly, a single treatment with DALBk and Icatibant attenuated</p><p>paclitaxel-induced mechanical and thermal hyperalgesia. The intra-</p><p>cerebroventricular administration of these antagonists also reduced the</p><p>mechanical hyperalgesia of mice. Moreover, paclitaxel-induced thermal</p><p>and mechanical hyperalgesia was abolished in B1R, B2R, or B1R/B2R</p><p>knockout mice. An increase in B1R mRNA was observed in the thalamus</p><p>and parietal and pre-frontal cortex of paclitaxel-treated mice [29].</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>12</p><p>Another study confirmed the involvement of kinins and their re-</p><p>ceptors in paclitaxel-induced neuropathy extending the findings to the</p><p>acute phase of this pathology. B1R (DALBk and SSR240612) or B2R</p><p>(Icatibant and FR173657) antagonists reduced the mechanical allodynia</p><p>induced by paclitaxel single (acute) or repeated administration. Intra-</p><p>plantar administration of subnociceptive doses of the B1R (DABk) or B2R</p><p>(bradykinin) agonists caused nociceptive behaviour in paclitaxel-treated</p><p>mice. DALBk and Icatibant attenuated this behaviour. Single (acute) or</p><p>repeated paclitaxel treatment increased the B1R and B2R protein</p><p>expression in the sciatic nerve and kinin levels in the mice’s paw tissue</p><p>[30].</p><p>Brusco et al. [30] also demonstrated that the ACE inhibitor enalapril</p><p>enhanced the mechanical allodynia induced by a low dose of paclitaxel</p><p>(0.001 mg/kg; single or repeated injection), which were reversed by B1R</p><p>(DALBk) and B2R (Icatibant) antagonists treatment. Even at low doses,</p><p>single or repeated paclitaxel administration increased the B1R and B2R</p><p>protein expression in the sciatic nerve of mice. Enalapril plus paclitaxel</p><p>association inhibited the ACE activity in the serum, sciatic nerve, and</p><p>paw tissue of animals and increased the kinin levels in the mice’s paw</p><p>tissue [30]. Notably, hypertension is a frequent comorbidity in cancer</p><p>patients [168] and is commonly treated with ACE inhibitors, drugs</p><p>associated with breast cancer recurrence, and increased risk for gout</p><p>pain and sensory axonal neuropathy [93,130,169,170]. Results rein-</p><p>force the involvement of kinin receptors in paclitaxel-induced acute and</p><p>neuropathic pain. Moreover, they also raise an essential issue that hy-</p><p>pertensive patients on ACE inhibitors and paclitaxel treatment may</p><p>enhance the pain experience. This could occur since ACE is responsible</p><p>for bradykinin degradation, and ACE inhibitors show allosteric effects</p><p>on kinin receptors, enhancing its action</p><p>[83].</p><p>Zanata et al. [95] also demonstrated the involvement of B1R and B2R</p><p>in paclitaxel-associated acute pain syndrome in mice. However, in</p><p>contrast to Brusco et al. [30], these authors found that ACE inhibitors</p><p>attenuated the paclitaxel-induced mechanical and cold allodynia. The</p><p>authors discussed these discrepancies probably due to different pacli-</p><p>taxel doses used in both studies since the prior study used 4- to 4000-fold</p><p>lower doses of paclitaxel [30,95]. Importantly, Brusco et al. observed</p><p>increased expression of B1R and B2R in the sciatic nerve of mice even</p><p>using these low paclitaxel doses [30]. Furthermore, ACE inhibitor was</p><p>administered after pain caused by paclitaxel was established [30],</p><p>whereas Zanata and colleagues used ACE inhibitors as preventive</p><p>treatment 1 h before paclitaxel injections [95]. This treatment scheme</p><p>could also influence the discrepancies between the studies since ACE</p><p>inhibitors do not affect the onset of the neuro-inflammatory response,</p><p>but they facilitate its progression towards a point that becomes patho-</p><p>logical, enhancing a condition that has already been initiated by a</p><p>previous trigger [93]. However, given the role of ACE in the kallikrein-</p><p>kinin system and the renin-angiotensin system, their potential cross-talk</p><p>in the context of pain remain to be explored.</p><p>Additionally, Costa et al. [106] showed that kinins sensitize TRPV4</p><p>channels via PKCε activation to maintain paclitaxel-induced peripheral</p><p>neuropathy in mice. They observed that the B1R (DALBk) and B2R</p><p>(Icatibant) antagonists reduced the paclitaxel-induced mechanical</p><p>hyperalgesia, similar to the TRPV4 antagonist (HC-067047). HC-067047</p><p>inhibited the mechanical hyperalgesia induced by B2R (bradykinin) or</p><p>B1R (DABk) agonist. Additionally, bradykinin sensitized the TRPV4</p><p>channel, contributing to mechanical hyperalgesia dependent on PLC/</p><p>PKC activation. Furthermore, in paclitaxel-injected animals, Icatibant</p><p>and DALBk inhibited the overt nociception induced by hypotonic solu-</p><p>tion, a TRPV4 channels activator. The PKCε inhibition reduced the</p><p>hypotonicity-induced overt nociception in paclitaxel-treated mice,</p><p>similar to kinin receptor antagonists. Together, these findings</p><p>[29,30,95,106] suggest that peripheral and central B1R and B2R seem to</p><p>play a crucial role in paclitaxel chemotherapy-induced neuropathy.</p><p>Thus, they could be promising pharmacological targets to attenuate</p><p>neuropathic pain from this aetiology.</p><p>4.2.6. Multiple sclerosis-associated pain</p><p>Multiple sclerosis is a demyelinating inflammatory disease of the</p><p>CNS whose chronic pain symptoms significantly impact patients’ lives</p><p>[25,171]. Multiple sclerosis pain is associated with active inflammation</p><p>from the disease itself (central neuropathic pain) or complications</p><p>(headaches, tonic spasms, and musculoskeletal problems such as posture</p><p>and gait anomalies). Thus, pain tends to increase over time due to the</p><p>disease process and its complications [171].</p><p>Prat et al. [172] showed that B1R mRNA expression in peripheral</p><p>blood-derived mononuclear cells of patients with multiple sclerosis</p><p>positively correlated with the expanded disability status scale index and</p><p>the occurrence of clinical relapse. These authors suggested that the B1R</p><p>expression can serve as an index of disease activity in multiple sclerosis</p><p>due to the correlation of B1R mRNA levels with dynamic clinical and</p><p>magnetic resonance imaging measures [172]. Moreover, in the experi-</p><p>mental autoimmune encephalomyelitis (EAE), a model of multiple</p><p>sclerosis that includes induction, acute and chronic phases, B1R genetic</p><p>deletion or antagonism (DALBk) during induction and chronic phases</p><p>reduced disease progression through the modulation of TH1 and TH17-</p><p>myelin-specific lymphocytes and glial cell-dependent pathways. How-</p><p>ever, the blockade of the B1R in the acute phase of EAE had a slight</p><p>effect. Curiously, B1R agonist DABk reduced disease severity in the acute</p><p>phase by inhibiting increased blood-brain barrier permeability and cell</p><p>migration leading to blockage of CNS inflammation. In contrast, DABk</p><p>did not alter the EAE progression in the induction and chronic phases.</p><p>The blockade of the B2R (antagonism and genetic deletion) only showed</p><p>a moderate impact on the EAE progression. These results found by Dutra</p><p>et al. [173] suggested that the B1R plays a dual role in EAE progression</p><p>depending on the phase of treatment. In the acute phase of immuniza-</p><p>tion, B1R activation seems to be beneficial, while in the induction and</p><p>chronic stages, the best therapeutic strategy is B1R inhibition.</p><p>The same research group [25] found that genetic deletion or antag-</p><p>onism of kinin receptors, especially the B1R, inhibited tactile and ther-</p><p>mal hypersensitivity in the EAE model. In contrast, animals with EAE</p><p>treated with a B1R agonist present increased tactile hypersensitivity.</p><p>Moreover, B1R mRNA and protein levels increased in the spinal cord of</p><p>mice with EAE. The blockade of this receptor reduced the mRNA levels</p><p>of inflammatory molecules (IL-17, IFN-γ, IL-6, CXCL-1/KC, COX-2, and</p><p>NOS2) and glial activation in the spinal cord. The B1R antagonism also</p><p>prevented the IFN-γ-induced up-regulation of TNF-α, IL-6, CXCL-1, COX-</p><p>2, and NOS2 in astrocyte culture, while B2R antagonism was effective in</p><p>preventing only the COX-2 and NOS2 expression up-regulation. Finally,</p><p>the B1R was co-localized with astrocytes in the spinal cord of mice with</p><p>EAE. Thus, the B1R seems to play a critical role in the persistent hy-</p><p>persensitivity in the EAE model through the central inflammatory pro-</p><p>cess, possibly acting on astrocytes. The authors suggested that B1R</p><p>antagonists or drugs that reduce kinins release may be a potential</p><p>treatment for neuropathic pain in multiple sclerosis patients [25].</p><p>Gobel et al. also showed the kinins’ involvement in the pathology of</p><p>multiple sclerosis [174]. In this study, plasma prekallikrein levels, the</p><p>precursor of kallikrein, was markedly enhanced in active CNS lesions of</p><p>multiple sclerosis patients. Deficiency or pharmacologic blockade using</p><p>an antibody to prekallikrein rendered mice less susceptible to EAE. This</p><p>effect was accompanied by a reduction of blood-brain barrier disruption</p><p>and CNS inflammation. Thus, kallikrein inhibition during neuro-</p><p>inflammation could treat multiple sclerosis [174].</p><p>4.3. Nociplastic pain</p><p>Nociplastic pain is mechanistically distinct from pain caused by</p><p>inflammation or damage of tissues and neuropathic pain caused by</p><p>nerve damage. Although the underlying mechanisms of this pain cate-</p><p>gory are not entirely understood, there are augmented pain and sensory</p><p>processing and altered pain modulation in the CNS [57]. The term</p><p>nociplastic pain includes painful conditions driven by maladaptive</p><p>plasticity within the CNS previously identified as dysfunctional pain or</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>13</p><p>Table 1</p><p>Drugs that target the kallikrein-kinin system and their effects on experimental pain models.</p><p>Kinin receptor agonists</p><p>Compounds Targets Experimental models Observed effects References</p><p>DABk (des-arg9-</p><p>bradykinin)</p><p>B1R</p><p>agonist</p><p>Complex regional pain syndrome type-I Increased the mechanical and cold allodynia Gonçalves et al. [23]</p><p>Ultraviolet B radiation-induced pain Increased the pain sensation and local vasodilation Eisenbarth et al. [17]</p><p>Freund’s complete adjuvant Mechanical hyperalgesia after intraplantar injection Fox et al. [34]</p><p>Phorbol myristate acetate Enhanced the nociceptive response Ferreira et al. [100]</p><p>Streptozotocin-induced diabetic</p><p>neuropathy</p><p>Potentiated the heat hyperalgesia Gabra and Sirois</p><p>[139], Gabra et al.</p><p>[141]</p><p>Non-obese diabetic neuropathy Gabra and Sirois [143]</p><p>Streptozotocin-induced diabetic</p><p>neuropathy</p><p>Enhanced the tactile</p><p>allodynia Talbot et al. [145]</p><p>Lumbar spinal nerves ligation-induced</p><p>neuropathic pain</p><p>Caused overt nociception Werner et al. [107]</p><p>Neuropathic pain model in the brachial</p><p>plexus</p><p>Induced mechanical hypersensitivity when administered</p><p>intraneural or into the lower trunk of the brachial plexus</p><p>Quintão et al. [27]</p><p>Cancer pain induced by intraplantar</p><p>B16-BL6 murine melanoma cells</p><p>Enhanced the licking behaviour Fujita et al. [166]</p><p>Paclitaxel-induced acute and</p><p>neuropathic pain</p><p>Caused the overt nociceptive behaviour Brusco et al. [30]</p><p>Experimental autoimmune</p><p>encephalomyelitis-induced multiple</p><p>sclerosis</p><p>Reduced disease severity in the acute phase Dutra et al. [173]</p><p>Experimental autoimmune</p><p>encephalomyelitis-induced multiple</p><p>sclerosis</p><p>Enhanced the tactile hypersensitivity Dutra et al. [25]</p><p>Reserpine-induced fibromyalgia Caused the overt nociceptive behaviour Brusco et al. [183]</p><p>DAKd (des-Arg10-kallidin</p><p>or Lys-des-Arg9-</p><p>bradykinin)</p><p>B1R</p><p>agonist</p><p>Ultraviolet B radiation-induced pain Increased pain sensation and axon reflex Eisenbarth et al. [17]</p><p>Freund’s complete adjuvant Caused mechanical hyperalgesia Fox et al. [34]</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Produced a nociceptive response and activated the extracellular</p><p>signal-regulated kinase</p><p>Rashid et al. [24]</p><p>Bradykinin B2R</p><p>agonist</p><p>Ultraviolet B radiation-induced pain Increased pain sensation and axon reflex Eisenbarth et al. [17]</p><p>Acute nociception Produced Ca2+ signals and inhibited M currents in small</p><p>nociceptive dorsal root ganglion neurons</p><p>Liu et al. [134]</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Pronounced nociceptive responses and extracellular signal-</p><p>regulated kinase activation in myelinated dorsal root ganglion</p><p>neurons and satellite cells</p><p>Rashid et al. [24]</p><p>Lumbar spinal nerves ligation-induced</p><p>neuropathic pain</p><p>Caused overt nociception Werner et al. [107]</p><p>Neuropathic pain in the brachial plexus Induced mechanical hypersensitivity when administered</p><p>intraneural or into the lower trunk of the brachial plexus</p><p>Quintão et al. [27]</p><p>Cancer pain induced by intraplantar</p><p>B16-BL6 murine melanoma cells</p><p>Enhanced the paw-licking behaviour Fujita et al. [166]</p><p>Paclitaxel-induced acute and</p><p>neuropathic pain</p><p>Caused the overt nociceptive behaviour Brusco et al. [30]</p><p>Reserpine-induced fibromyalgia Caused the overt nociceptive behaviour and enhanced mechanical</p><p>allodynia</p><p>Brusco et al. [183],</p><p>Brusco et al. [31]</p><p>[Tyr8]-bradykinin B2R</p><p>agonist</p><p>Complex regional pain syndrome type-I Increased the mechanical and cold allodynia Gonçalves et al. [23]</p><p>Cancer pain induced by intraplantar</p><p>B16-BL6 murine melanoma cells</p><p>Enhanced the paw-licking behaviour Fujita et al. [166]</p><p>Kinin receptor antagonists</p><p>Compounds Targets Experimental models Observed effects References</p><p>DALBk B1R</p><p>antagonist</p><p>Monosodium urate crystals intra-articular</p><p>injection-induced gouty arthritis</p><p>Reduced the overt nociception behaviour, touch</p><p>allodynia, and inflammatory signs of gouty arthritis</p><p>Silva et al. [21]</p><p>Complex regional pain syndrome type-I Reduced the mechanical allodynia and paw oedema Gonçalves et al. [23]</p><p>Phorbol myristate acetate Reduced the spontaneous nociceptive behaviour Ferreira et al. [100]</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Reversed the mechanical allodynia Ferreira et al. [112]</p><p>Lumbar L5 and L6 spinal nerves ligation-</p><p>induced neuropathic pain</p><p>Reduced overt nociception, cold and mechanical</p><p>allodynia, and heat hyperalgesia</p><p>Werner et al. [107]</p><p>Neuropathic pain in the brachial plexus Reduced the mechanical hypersensitivity Quintão et al. [27]</p><p>Infraorbital nerve constriction Reduced the mechanical and heat hyperalgesia Luiz et al. [28]</p><p>Subarachnoid dynorphin A (1–17)-</p><p>induced orofacial pain</p><p>Reversed the heat hyperalgesia Lai et al. [161], Lai et al.</p><p>[162]</p><p>Cancer pain induced by intraplantar B16-</p><p>BL6 murine melanoma cells</p><p>Inhibited the spontaneous pain Fujita et al. [166]</p><p>Paclitaxel-induced neuropathy Reduced mechanical hyperalgesia and heat</p><p>hyperalgesia</p><p>Costa et al. [29]</p><p>Paclitaxel-induced acute and neuropathic</p><p>pain</p><p>Reduced the mechanical allodynia and overt</p><p>nociception behaviour</p><p>Brusco et al. [30]</p><p>Paclitaxel-induced neuropathy Reduced the mechanical hyperalgesia and overt</p><p>nociception behaviour</p><p>Costa et al. [106]</p><p>Reduced the disease progression Dutra et al. [173]</p><p>(continued on next page)</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>14</p><p>Table 1 (continued )</p><p>Kinin receptor antagonists</p><p>Compounds Targets Experimental models Observed effects References</p><p>Experimental autoimmune</p><p>encephalomyelitis-induced multiple</p><p>sclerosis</p><p>Experimental autoimmune</p><p>encephalomyelitis-induced multiple</p><p>sclerosis</p><p>Inhibited tactile and heat hypersensitivity and</p><p>prevented the IFNγ-induced up-regulation of</p><p>inflammatory mediators</p><p>Dutra et al. [25]</p><p>Reserpine-induced fibromyalgia Reduced the mechanical allodynia, cold sensitivity,</p><p>overt nociceptive behaviour, and reverted burrowing</p><p>behaviour reduction</p><p>Brusco et al. [183]</p><p>Reserpine-induced fibromyalgia Reduced the mechanical allodynia Brusco et al. [31]</p><p>Formalin-induced orofacial pain Reduced the overt nociception behaviour Chichorro et al. [32]</p><p>SSR240612 B1R</p><p>antagonist</p><p>Monosodium urate crystals intra-articular</p><p>injection-induced gouty arthritis</p><p>Reduced the enhancement of touch allodynia, overt</p><p>pain-like behaviours, and oedema</p><p>Silva et al. [21]</p><p>Tibial post-fracture pain Reduced mechanical and heat hyperalgesia, and</p><p>subjective pain</p><p>Minville et al. [22]</p><p>Streptozotocin-induced diabetic</p><p>neuropathy</p><p>Reduced the tactile and cold allodynia Talbot et al. [145]</p><p>Chronic glucose consumption-induced</p><p>diabetic neuropathy</p><p>Reversed the tactile and cold allodynia and suppressed</p><p>the B1R expression and vascular oxidative stress</p><p>Lungu et al. [146], Dias</p><p>et al. [147], Dias et al.</p><p>[148]</p><p>Sciatic nerve constriction-induced</p><p>neuropathic pain</p><p>Reduced the heat hyperalgesia Gougat et al. [33]</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Reversed the upregulation of B1R protein and mRNA</p><p>Brachial plexus avulsion-induced</p><p>neuropathic pain</p><p>Alleviated the mechanical hyperalgesia Quintão et al. [156]</p><p>Paclitaxel-induced acute and neuropathic</p><p>pain</p><p>Reduced the mechanical allodynia Brusco et al. [30]</p><p>Reserpine-induced fibromyalgia Abolished the mechanical allodynia and cold</p><p>hypersensitivity</p><p>Brusco et al. [183]</p><p>R-715 B1R</p><p>antagonist</p><p>Bilateral ovariectomy Reduced mechanical allodynia and depressive-like</p><p>behaviours</p><p>Maciel et al. [133]</p><p>Streptozotocin-induced diabetic</p><p>neuropathy</p><p>Reduced the heat hyperalgesia Gabra and Sirois [139],</p><p>Gabra et al. [141]</p><p>Reduced the tactile and cold allodynia Talbot et al. [145]</p><p>Non-obese diabetic neuropathy Reduced the heat hyperalgesia Gabra and Sirois [143]</p><p>Chronic glucose consumption-induced</p><p>diabetic neuropathy</p><p>Reversed the tactile and cold allodynia and suppressed</p><p>the B1R expression and vascular oxidative stress</p><p>Lungu et al. [146], Dias</p><p>et al. [148]</p><p>Brachial plexus avulsion-induced</p><p>neuropathic pain</p><p>Alleviated the mechanical hyperalgesia Quintão et al. [156]</p><p>R-954 B1R</p><p>antagonist</p><p>Transection of the right anterior cruciate</p><p>ligament</p><p>Reduced radiomorphological and histomorphological</p><p>alterations, decreased nociception and accelerated</p><p>postoperative recovery</p><p>Kaufman et al. [129]</p><p>Tibial post-fracture pain Reduced the prolonged mechanical and heat</p><p>hyperalgesia and subjective pain</p><p>Minville et al. [22]</p><p>Streptozotocin-induced diabetic</p><p>neuropathy</p><p>Reduced the heat hyperalgesia Gabra and Sirois, [139],</p><p>Gabra et al. [141], Gabra</p><p>et al. [142]</p><p>Insulin-resistant type 2 diabetes Reduced the heat hyperalgesia Gabra et al.</p><p>[144]</p><p>Spontaneous BioBreeding/Worchester</p><p>diabetic-prone</p><p>Reduced the heat hyperalgesia Gabra et al. [142]</p><p>Non-obese diabetic neuropathy Reduced the heat hyperalgesia Gabra et al. [143]</p><p>LF22–0542 B1R</p><p>antagonist</p><p>Freund’s complete adjuvant Reduced the heat hyperalgesia Porreca et al. [35]</p><p>Chronic glucose consumption-induced</p><p>diabetic neuropathy</p><p>Reversed the tactile and cold allodynia Lungu et al. [146], Dias</p><p>et al. [148]</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Reversed the heat hyperalgesia Petcu et al. [153]</p><p>Primary bone cancer pain model induced</p><p>by osteolytic sarcoma cells into the femurs</p><p>of mice</p><p>Reduced ongoing and movement-evoked nociceptive</p><p>behaviours</p><p>Sevcik et al. [165]</p><p>des-Arg10-Hoe140 B1R</p><p>antagonist</p><p>Streptozotocin-induced diabetic</p><p>neuropathy</p><p>Attenuated the mechanical hyperalgesia Bujalska et al. [149],</p><p>Bujalska and Makulska-</p><p>Nowak [150]</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Attenuated the nociceptive behaviour Rashid et al. [24]</p><p>Vincristine-induced neuropathic pain Alleviated the mechanical hyperalgesia Bujalska and Makulska-</p><p>Nowak [150]</p><p>ELN441958 B1R</p><p>antagonist</p><p>Carrageenan-induced pain Presented higher selectivity for primates over rodent</p><p>B1R and showed good permeability and metabolic</p><p>stability in vitro</p><p>Hawkinson et al. [131]</p><p>BI113823 B1R</p><p>antagonist</p><p>Freund’s complete adjuvant Reduced the mechanical hyperalgesia and the</p><p>mechanosensitive of peripheral afferents and spinal</p><p>nociceptive-specific neurons</p><p>Schuelert et al. [39]</p><p>NVP-SAA164 Freund’s complete adjuvant Reduced the mechanical hyperalgesia Fox et al. [34]</p><p>(continued on next page)</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>15</p><p>Table 1 (continued )</p><p>Kinin receptor antagonists</p><p>Compounds Targets Experimental models Observed effects References</p><p>B1R</p><p>antagonist</p><p>B6769 B1R</p><p>antagonist</p><p>Primary bone cancer pain induced by</p><p>osteolytic sarcoma cells into the femurs of</p><p>mice</p><p>Reduced the ongoing and movement-evoked</p><p>nociceptive behaviours</p><p>Sevcik et al. [165]</p><p>Antisense</p><p>oligodeoxynucleotides for</p><p>B1R</p><p>B1R gene</p><p>silencing</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Attenuated the nociceptive behaviour Rashid et al. [24]</p><p>Complex regional pain syndrome type-I Attenuated the mechanical allodynia Gonçalves et al. [23]</p><p>Icatibant B2R</p><p>antagonist</p><p>Intra-articular monosodium iodoacetate-</p><p>induced osteoarthritis</p><p>Alleviated the nociceptive behaviour and reduced the</p><p>incapacitation</p><p>Cialdai et al. [19]</p><p>Knee non-noxious and noxious rotation Blocked the joint afferent firing during non-noxious</p><p>and noxious rotation of the knee</p><p>Russel et al. [127]</p><p>Tibial post-fracture pain Reduced mechanical and heat hyperalgesia and</p><p>subjective pain</p><p>Minville et al. [22]</p><p>Complex regional pain syndrome type-I Reduced the mechanical allodynia and paw oedema Gonçalves et al. [23]</p><p>Inflammatory pain Reduced mechanical allodynia and depressive-like</p><p>behaviours</p><p>Grastilleur et al. [132]</p><p>Acute nociception Abolished the bradykinin-induced M current</p><p>inhibition</p><p>Liu et al. [134]</p><p>Visceral hypersensitivity induced by</p><p>PAR2 agonist</p><p>Abolished the visceral hypersensitivity Kawabata et al. [128]</p><p>Formalin-induced orofacial pain Reduced the overt nociception behaviour Chichorro et al. [32]</p><p>Streptozotocin-induced diabetic</p><p>neuropathy</p><p>Attenuated the mechanical hyperalgesia Bujalska et al. [149],</p><p>Bujalska and Makulska-</p><p>Nowak [150]</p><p>Lumbar L5 and L6 spinal nerves ligation-</p><p>induced neuropathic pain</p><p>Reduced the overt nociception behaviour, cold and</p><p>mechanical allodynia, and heat hyperalgesia</p><p>Werner et al. [107]</p><p>Neuropathic pain in the brachial plexus Reduced the mechanical hypersensitivity Quintão et al. [27]</p><p>Infraorbital nerve constriction Reduced the mechanical and heat hyperalgesia Luiz et al. [28], Luiz et al.</p><p>[160]</p><p>Cancer pain induced by intraplantar B16-</p><p>BL6 murine melanoma cells</p><p>Reduced the spontaneous pain and mechanical</p><p>allodynia</p><p>Fujita et al. [166]</p><p>Vincristine-induced neuropathic pain Alleviated the mechanical hyperalgesia Bujalska and Makulska-</p><p>Nowak [150]</p><p>Paclitaxel-induced neuropathy Reduced the mechanical and heat hyperalgesia Costa et al. [29]</p><p>Paclitaxel-induced acute and neuropathic</p><p>pain</p><p>Reduced the mechanical allodynia and overt</p><p>nociception behaviour</p><p>Brusco et al. [30]</p><p>Paclitaxel-induced neuropathy Reduced the mechanical hyperalgesia and overt</p><p>nociception behaviour</p><p>Costa et al. [106]</p><p>Experimental autoimmune</p><p>encephalomyelitis-induced multiple</p><p>sclerosis</p><p>Moderate impact on the disease progression Dutra et al. [173]</p><p>Experimental autoimmune</p><p>encephalomyelitis-induced multiple</p><p>sclerosis</p><p>Inhibited tactile and heat hypersensitivity and</p><p>prevented the cyclooxygenase 2 and nitric oxide</p><p>synthase 2 up-regulation</p><p>Dutra et al. [25]</p><p>Reserpine-induced fibromyalgia Abolished the mechanical allodynia, cold sensitivity,</p><p>and overt nociceptive behaviour</p><p>Brusco et al. [31], Brusco</p><p>et al. [183]</p><p>FR173657 B2R</p><p>antagonist</p><p>Paclitaxel-induced acute and neuropathic</p><p>pain</p><p>Reduced the mechanical allodynia Brusco et al. [30]</p><p>Reserpine-induced fibromyalgia Abolished the mechanical allodynia and cold</p><p>sensitivity</p><p>Brusco et al. [183]</p><p>MEN16132 B2R</p><p>antagonist</p><p>Intra-articular monosodium iodoacetate-</p><p>induced osteoarthritis</p><p>Alleviated the nociception behaviour and reduced the</p><p>incapacitation</p><p>Cialdai et al. [19]</p><p>LF16–0687 B2R</p><p>antagonist</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Reversed the heat hyperalgesia Petcu et al. [153]</p><p>Antisense</p><p>oligodeoxynucleotides for</p><p>B2R</p><p>B2R gene</p><p>silencing</p><p>Partial sciatic nerve ligation-induced</p><p>neuropathic pain</p><p>Alleviated the nociceptive behaviour Rashid et al. [24]</p><p>Complex regional pain syndrome type-I Attenuated the mechanical allodynia Gonçalves et al. [23]</p><p>Enzyme inhibitors</p><p>Compound Target Experimental model Observed effect Reference</p><p>Enalapril Angiotensin I-converting</p><p>enzyme inhibitor</p><p>Monosodium urate crystals intra-articular</p><p>injection-induced gouty arthritis</p><p>Increased touch allodynia, overt pain-like behaviours,</p><p>oedema, kininase I activity, and DABk content</p><p>Silva et al. [21]</p><p>Paclitaxel-induced acute and neuropathic</p><p>pain</p><p>Enhanced the mechanical allodynia, inhibited the ACE</p><p>activity, and increased the kinin levels</p><p>Brusco et al.</p><p>[30]</p><p>Paclitaxel-induced acute and neuropathic</p><p>pain</p><p>Attenuated the mechanical and cold allodynia Zanata et al.</p><p>[95]</p><p>Reserpine-induced fibromyalgia Enhanced the mechanical allodynia and kinin levels, and</p><p>inhibited the ACE activity</p><p>Brusco et al.</p><p>[31]</p><p>Captopril Angiotensin I-converting</p><p>enzyme inhibitor</p><p>Complex regional pain syndrome type-I Reversed the DALBk and Icatibant anti-allodynic effect Gonçalves et al.</p><p>[23]</p><p>Formalin-induced orofacial pain Enhanced the overt nociception behaviour Chichorro et al.</p><p>[32]</p><p>(continued on next page)</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>16</p><p>medically unexplained somatic syndromes [57,175]. Nociplastic pain</p><p>can occur in conditions such as fibromyalgia, orofacial pain, tension-</p><p>type headache, chronic low back pain, irritable bowel syndrome,</p><p>chronic primary bladder pain syndrome, and others [57] (Fig. 4c). The</p><p>symptoms observed in this painful condition include spontaneous and</p><p>stimulus-dependent pain and multifocal pain, widespread and intense,</p><p>besides other CNS-derived symptoms, such as fatigue, sleep, memory,</p><p>and mood problems [44,57]. This type of pain has low responsiveness to</p><p>peripherally directed therapies such as anti-inflammatory drugs</p><p>and</p><p>opioids. Thus, an improved understanding of its mechanisms is crucial to</p><p>developing effective treatment strategies [57].</p><p>4.3.1. Fibromyalgia</p><p>Fibromyalgia is a nociplastic pain type with an unclear aetiology that</p><p>affects 2–3 % of the world population. It is characterized by chronic</p><p>widespread pain accompanied by comorbidities such as sleep distur-</p><p>bances, fatigue, anxiety, depression, and hypertension, among others</p><p>[13,14,176,177]. Fibromyalgia patients present spontaneous pain in the</p><p>muscles or joints, allodynia, hyperalgesia, thermal hypersensitivity to</p><p>both heat and cold, and higher sensitivity to external stimuli, such as</p><p>chemicals, odours, sounds, or light [12,13,176,178–181]. Moreover,</p><p>about one-third of fibromyalgia patients present neuropathic-like</p><p>symptoms, which include burning pain, sensations of pins and nee-</p><p>dles, and dysesthesia [180,182]. However, the fibromyalgia diagnostic</p><p>criteria, pathophysiological mechanisms, and therapies remain actively</p><p>debated. In this sense, treating fibromyalgia patients requires a combi-</p><p>nation of drugs with various action mechanisms. Until now, the Food</p><p>and Drug Administration approved the use of gabapentinoids (pre-</p><p>gabalin) and SNRIs (duloxetine and milnacipran) to treat fibromyalgia</p><p>patients [12,13].</p><p>In searching for new pharmacological targets involved in the pain of</p><p>patients with fibromyalgia, Brusco et al. [183] demonstrated the kinins</p><p>and their B1R and B2R involvement in a reserpine-induced experimental</p><p>fibromyalgia model in mice. The experimental fibromyalgia model</p><p>caused mechanical allodynia in wild-type but not in B1R or B2R</p><p>knockout mice. This model also increased protein expression of B1R and</p><p>B2R and the bradykinin-related peptide levels in peripheral and central</p><p>structures. The mechanical allodynia and cold sensitivity were abolished</p><p>by B1R (DALBk and SSR240612) and B2R (Icatibant and FR173657)</p><p>antagonists. DALBk reversed the burrowing behaviour reduction,</p><p>indicative of nociception and depression (a comorbidity symptom of</p><p>fibromyalgia). DALBk and Icatibant also avoid an overt nociceptive</p><p>behaviour induced by intraplantar injection of B1R (DABk) and B2R</p><p>(bradykinin) agonists in animals submitted to reserpine-induced fibro-</p><p>myalgia model [183].</p><p>Since a clinical study showed that the use of ACE inhibitors is asso-</p><p>ciated with increased muscle pain [184] and hypertension is a frequent</p><p>comorbidity of fibromyalgia, Brusco et al. [31] investigated if ACE in-</p><p>hibitors enalapril and captopril could negatively interfere in the exper-</p><p>imental fibromyalgia model. Enalapril and captopril enhanced</p><p>reserpine-induced mechanical allodynia, while B1R and B2R antago-</p><p>nists effectively reduced this increase. Enalapril or captopril increased</p><p>bradykinin-related peptide levels and inhibited the ACE activity in pain</p><p>modulation structures in the fibromyalgia model. Thus, Brusco et al.</p><p>[31,183] concluded that B1R and B2R might represent potential targets</p><p>for relieving pain symptoms of fibromyalgia patients. Moreover, they</p><p>alert that it is crucial to be attentive to the class of antihypertensive</p><p>drugs used to treat hypertensive patients with fibromyalgia because ACE</p><p>inhibitors could enhance the pain symptoms of these patients.</p><p>4.3.2. Orofacial pain</p><p>Chronic temporomandibular pain disorders and chronic primary</p><p>orofacial pain also can be categorized as nociplastic pain. Although</p><p>some treatments are suggested, the effectiveness of most of them is</p><p>unknown [57]. It was verified that kinins contribute to the peripheral</p><p>nociception elicited by formalin injection in the orofacial region of the</p><p>rat, which mimics human orofacial pain. The formalin injection into the</p><p>upper lip of rats caused a concentration-dependent and biphasic</p><p>behavioural nociceptive response that occurred during the first 3 min</p><p>(0–3 min; phase I) and between 12 and 30 min (phase II), characterized</p><p>by rubbing of the injected area. Both nociceptive phases I and II trig-</p><p>gered by formalin were blunted by the local administration of the B2R</p><p>antagonist Icatibant. On the other hand, B1R antagonist DALBk reduced</p><p>only the second phase of the nociceptive response. Interestingly,</p><p>captopril, an ACE inhibitor, enhanced both phases of the nociceptive</p><p>response caused by a formalin sub-nociceptive dose. These results sug-</p><p>gest that kinin antagonists could effectively prevent pain in the orofacial</p><p>region [32].</p><p>In nociplastic pain, kinins involvement has only been investigated in</p><p>the experimental fibromyalgia and orofacial pain models. More studies</p><p>could be explored in these and other nociplastic pain models, such as</p><p>tension headache and irritable bowel syndrome.</p><p>5. Conclusion</p><p>The hypothesis that kinins and their B1 and B2 receptors are impli-</p><p>cated in inflammatory [17–23], neuropathic [24–30], nociplastic</p><p>[31,32,183], and cancer pain [165,166] is robustly supported and all</p><p>compounds mentioned in our review that act on the kallikrein-kinin</p><p>system in experimental pain models are summarized in Table 1. Thus,</p><p>B1R and B2R need to be seen as pharmacological targets for the rational</p><p>development of novel analgesics. The fact that a well-tolerated B2R</p><p>antagonist, Icatibant, is available in the clinic for the treatment of he-</p><p>reditary angioedema gives us hope this antagonist could be redirected to</p><p>new use, including the treatment of pathological pain conditions, which</p><p>present limited pharmacological management.</p><p>Extensive efforts to develop new antagonists with higher potency</p><p>and selectivity were hampered by the lack of knowledge about the three-</p><p>dimensional structures of kinin receptors and their activation [98].</p><p>Given the role of the kallikrein-kinin system in inflammation, pain,</p><p>Table 1 (continued )</p><p>Enzyme inhibitors</p><p>Compound Target Experimental model Observed effect Reference</p><p>Paclitaxel-induced acute and neuropathic</p><p>pain</p><p>Attenuated the mechanical and cold allodynia Zanata et al.</p><p>[95]</p><p>Reserpine-induced fibromyalgia Enhanced the mechanical allodynia and kinin levels, and</p><p>inhibited the ACE activity</p><p>Brusco et al.</p><p>[31]</p><p>Mergepta Kininase I inhibitor Monosodium urate crystals intra-articular</p><p>injection-induced gouty arthritis</p><p>Reduced the touch allodynia, overt pain-like behaviours, and</p><p>oedema</p><p>Silva et al. [21]</p><p>Reserpine-induced fibromyalgia Reduced the mechanical and cold allodynia Brusco et al.</p><p>[31]</p><p>Aprotinin Serine protease inhibitor Inflammatory pain Attenuated the tactile and heat hypersensitivities Grastilleur et al.</p><p>[132]</p><p>Thiorphan Carboxypeptidase M inhibitor Neuropathic pain in the brachial plexus Reduced the mechanical hypersensitivity Quintão et al.</p><p>[27]</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>17</p><p>cardiovascular disorders, and COVID-19, recently, two studies sought to</p><p>elucidate the molecular mechanisms of ligand binding, specific activa-</p><p>tion, and G protein coupling of the human kinin receptors. These find-</p><p>ings provide a framework for guiding drug design targeting B1R and B2R</p><p>to treat these diseases [97,98].</p><p>Since B1R and B2R can be activated indirectly by intracellular sig-</p><p>nalling pathways and by interacting with other receptors</p><p>[100,106,114,115,128,134,154,155], further studies on the interrela-</p><p>tionship between pharmacological targets and kinin receptors should be</p><p>investigated. This could bring about a new form of treatment in which</p><p>direct inhibition of these receptors by antagonists or indirect inhibition</p><p>could reduce painful pathological conditions. In addition, the associated</p><p>use of B1R and B2R antagonists with other drugs, such as NSAIDs and</p><p>opioids, could be an alternative to be explored in the control of painful</p><p>conditions.</p><p>CRediT authorship contribution statement</p><p>Indiara Brusco: Conceptualization, Writing – review & editing.</p><p>Maria Fernanda</p><p>Pessano Fialho: Conceptualization, Writing – review</p><p>& editing. Gabriela Becker: Conceptualization, Writing – review &</p><p>editing. Evelyne Silva Brum: Conceptualization, Writing – review &</p><p>editing. Amanda Favarin: Conceptualization, Writing – review &</p><p>editing. Lara Panazzolo Marquezin: Conceptualization, Writing – re-</p><p>view & editing. Patrick Tuzi Serafini: Conceptualization, Writing –</p><p>review & editing. Sara Marchesan Oliveira: Conceptualization,</p><p>Writing – review & editing, Funding acquisition, Supervision.</p><p>Declaration of competing interest</p><p>The authors declare that there are no conflicts of interest.</p><p>Acknowledgement</p><p>We thank the Program in Biological Sciences: Toxicological</p><p>Biochemistry (Federal University of Santa Maria) and we thank the</p><p>Federal University of Santa Maria.</p><p>Funding support for this project was provided in part by the Coor-</p><p>denação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil</p><p>(CAPES) - Finance Code 001; by the Fundação de Amparo à Pesquisa do</p><p>Estado do Rio Grande do Sul-FAPERGS (Grant #21/2551-0001966-2)</p><p>(Brazil); and by the Conselho Nacional de Desenvolvimento Científico e</p><p>Tecnológico-CNPq. CAPES/PROEX (process #23038.002125/2021-85;</p><p>Grant: #0036/2021). SMO is recipient of fellowship from CNPq (process</p><p>#304985/2020-1) and I.B., M.F.P.F., E.S⋅B, and G.B are recipient of</p><p>fellowship from CAPES/PROEX (process #88882.182148/2018-01,</p><p>#88882.182170/2018-01, #88887.185973/2018-00 and</p><p>#88887.568915/2020-00, respectively.</p><p>References</p><p>[1] E. Navratilova, F. Porreca, Reward and motivation in pain and pain relief, Nat.</p><p>Neurosci. 17 (2014) 1304–1312, https://doi.org/10.1038/nn.3811.</p><p>[2] A.C.de C. Williams, K.D. Craig, Updating the definition of pain, Pain 157 (2016)</p><p>2420–2423, https://doi.org/10.1097/j.pain.0000000000000613.</p><p>[3] S.N. Raja, D.B. Carr, M. Cohen, N.B. Finnerup, H. Flor, S. Gibson, F.J. Keefe, J.</p><p>S. Mogil, M. Ringkamp, K.A. Sluka, X.-J. Song, B. Stevens, M.D. Sullivan, P.</p><p>R. Tutelman, T. Ushida, K. Vader, The revised International Association for the</p><p>Study of Pain definition of pain: concepts, challenges, and compromises, Pain 161</p><p>(2020) 1976–1982, https://doi.org/10.1097/j.pain.0000000000001939.</p><p>[4] C.J. Woolf, What is this thing called pain? J. Clin. Invest. 120 (2010) 10–12,</p><p>https://doi.org/10.1172/JCI45178.3742.</p><p>[5] A.S. Yekkirala, D.P. Roberson, B.P. Bean, C.J. Woolf, Breaking barriers to novel</p><p>analgesic drug development, Nat. Rev. Drug Discov. 16 (2017) 545–564, https://</p><p>doi.org/10.1038/nrd.2017.87.</p><p>[6] S. Jayakar, J. Shim, S. Jo, B.P. Bean, I. Singeç, C.J. Woolf, Developing nociceptor-</p><p>selective treatments for acute and chronic pain, Sci. Transl. Med. 13 (2021) 1–17,</p><p>https://doi.org/10.1126/scitranslmed.abj9837.</p><p>[7] P. Mäntyselkä, E. Kumpusalo, R. Ahonen, A. Kumpusalo, J. Kauhanen,</p><p>H. Viinamäki, P. Halonen, J. Takala, Pain as a reason to visit the doctor: a study in</p><p>Finnish primary health care, Pain 89 (2001) 175–180, https://doi.org/10.1016/</p><p>S0304-3959(00)00361-4.</p><p>[8] Q. Zhang, Y. Ren, Y. Mo, P. Guo, P. Liao, Y. Luo, J. Mu, Z. Chen, Y. Zhang, Y. Li,</p><p>L. Yang, D. Liao, J. Fu, J. Shen, W. Huang, X. Xu, Y. Guo, L. Mei, Y. Zuo, J. Liu,</p><p>H. Yang, R. Jiang, Inhibiting Hv1 channel in peripheral sensory neurons</p><p>attenuates chronic inflammatory pain and opioid side effects, Cell Res. 32 (2022)</p><p>461–476, https://doi.org/10.1038/s41422-022-00616-y.</p><p>[9] N.B. Finnerup, N. Attal, S. Haroutounian, E. McNicol, R. Baron, R.H. Dworkin,</p><p>I. Gilron, M. Haanpää, P. Hansson, T.S. Jensen, P.R. Kamerman, K. Lund,</p><p>A. Moore, S.N. Raja, A.S.C. Rice, M. Rowbotham, E. Sena, P. Siddall, B.H. Smith,</p><p>M. Wallace, Pharmacotherapy for neuropathic pain in adults: a systematic review</p><p>and meta-analysis, Lancet Neurol. 14 (2015) 162–173, https://doi.org/10.1016/</p><p>S1474-4422(14)70251-0.</p><p>[10] N.B. Finnerup, R. Kuner, T.S. Jensen, Neuropathic pain: frommechanisms to</p><p>treatment, Physiol. Rev. 101 (2021) 259–301, https://doi.org/10.1152/</p><p>physrev.00045.2019.</p><p>[11] WHO, WHO Guidelines for the Pharmacological and Radiotherapeutic</p><p>Management of Cancer Pain in Adults and Adolescents, World Health</p><p>Organization, Geneva, 2018, 2018. Licence: CC BY-NC-SA 3.0 IGO.</p><p>[12] D.J. Clauw, Fibromyalgia and related conditions, Mayo Clin. Proc. 90 (2015)</p><p>680–692, https://doi.org/10.1016/j.mayocp.2015.03.014.</p><p>[13] P. Sarzi-Puttini, V. Giorgi, D. Marotto, F. Atzeni, Fibromyalgia: an update on</p><p>clinical characteristics, aetiopathogenesis and treatment, Nat. Rev. Rheumatol. 16</p><p>(2020) 645–660, https://doi.org/10.1038/s41584-020-00506-w.</p><p>[14] L.M. Arnold, K.B. Gebke, E.H.S. Choy, Fibromyalgia: management strategies for</p><p>primary care providers, (n.d.) 99–112. doi:10.1111/ijcp.12757.</p><p>[15] F. Marceau, D. Regoli, Bradykinin receptor ligands: therapeutic perspectives, Nat.</p><p>Rev. Drug Discov. 3 (2004) 845–852, https://doi.org/10.1038/nrd1522.</p><p>[16] L.M.F. Leeb-Lundberg, F. Marceau, W. Müller-Esterl, D.J. Pettibone, B.L. Zuraw,</p><p>International Union of Pharmacology, XLV. Classification of the kinin receptor</p><p>family: from molecular mechanisms to pathophysiological consequences,</p><p>Pharmacol. Rev. 57 (2005) 27–77, https://doi.org/10.1124/pr.57.1.2.</p><p>[17] H. Eisenbarth, R. Rukwied, M. Petersen, M. Schmelz, Sensitization to bradykinin</p><p>B1 and B2 receptor activation in UV-B irradiated human skin, Pain 110 (2004)</p><p>197–204, https://doi.org/10.1016/j.pain.2004.03.031.</p><p>[18] P.A. Leonard, R. Arunkumar, T.J. Brennan, Bradykinin antagonists have no</p><p>analgesic effect on incisional pain, Anesth. Analg. 99 (2004) 1166–1172, https://</p><p>doi.org/10.1213/01.ANE.0000130348.85587.BE.</p><p>[19] C. Cialdai, S. Giuliani, C. Valenti, M. Tramontana, C.A. Maggi, Effect of intra-</p><p>articular 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-</p><p>quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}</p><p>piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride</p><p>(MEN16132), a kinin B2 receptor antagonist, on nociceptive response in</p><p>monosodium iodoacetate-induced experimental osteoarthritis in rats,</p><p>J. Pharmacol. Exp. Ther. 331 (2009) 1025–1032, https://doi.org/10.1124/</p><p>jpet.109.159657.</p><p>[20] C. Driscoll, A. Chanalaris, C. Knights, H. Ismail, P.K. Sacitharan, C. Gentry,</p><p>S. Bevan, T.L. Vincent, Nociceptive sensitizers are regulated in damaged joint</p><p>tissues, including articular cartilage, when osteoarthritic mice display pain</p><p>behavior, Arthritis Rheumatol. 68 (2016) 857–867, https://doi.org/10.1002/</p><p>art.39523.</p><p>[21] C.R. Silva, S.M. Oliveira, C. Hoffmeister, V. Funck, G.P. Guerra, G. Trevisan,</p><p>R. Tonello, M.F. Rossato, J.B. Pesquero, M. Bader, M.S. Oliveira, J.J. McDougall,</p><p>J. Ferreira, The role of kinin B 1 receptor and the effect of angiotensin I-</p><p>converting enzyme inhibition on acute gout attacks in rodents, Ann. Rheum. Dis.</p><p>75 (2016) 260–268, https://doi.org/10.1136/annrheumdis-2014-205739.</p><p>[22] V. Minville, L. Mouledous, A. Jaafar, R. Couture, A. Brouchet, B. Frances, I. Tack,</p><p>J.P. Girolami, Tibial post fracture pain is reduced in kinin receptors deficient mice</p><p>and blunted by kinin receptor antagonists, J. Transl. Med. 17 (2019) 1–12,</p><p>https://doi.org/10.1186/s12967-019-2095-9.</p><p>[23] E.C.D. Gonçalves, G. Vieira, T.R. Gonçalves, R.R. Simões, I. Brusco, S.M. Oliveira,</p><p>J.B. Calixto, M. Cola, A.R.S. Santos, R.C. Dutra, Bradykinin receptors play a</p><p>critical role in the chronic post-ischaemia pain model, Cell. Mol. Neurobiol. 41</p><p>(2021) 63–78, https://doi.org/10.1007/s10571-020-00832-3.</p><p>[24] H. Rashid, M. Inoue, M. Matsumoto, H. Ueda, Switching of bradykinin-mediated</p><p>nociception following partial sciatic nerve injury in mice, J. Pharmacol. Exp.</p><p>Ther. 308 (2004) 1158–1164, https://doi.org/10.1124/jpet.103.060335.</p><p>[25] R.C. Dutra, A.F. Bento, D.F.P. Leite, M.N. Manjavachi, R. Marcon, M.A. Bicca, J.</p><p>B. Pesquero, J.B. Calixto, The role of kinin B1 and B2 receptors in the persistent</p><p>pain induced by experimental autoimmune encephalomyelitis (EAE) in mice:</p><p>evidence for the involvement of astrocytes, Neurobiol. Dis. 54 (2013) 82–93,</p><p>https://doi.org/10.1016/j.nbd.2013.02.007.</p><p>[26] J.P. Dias, H.D.B. Gariépy, B. Ongali, R. Couture, Brain kinin B1 receptor is</p><p>upregulated by the oxidative stress and its activation leads to stereotypic</p><p>nociceptive behavior in insulin-resistant rats, Peptides 69 (2015) 118–126,</p><p>https://doi.org/10.1016/j.peptides.2015.04.022.</p><p>[27] N.L.M. Quintão, L.W. Rocha, G.F. da Silva, A.F. Paszcuk, M.N. Manjavachi, A.</p><p>F. Bento, K.A.B.S. da Silva, M.M. Campos, J.B. Calixto, The kinin B1 and B2</p><p>receptors and TNFR1/p55 axis on neuropathic pain in the mouse brachial plexus,</p><p>Inflammopharmacology 27 (2019) 573–586, https://doi.org/10.1007/s10787-</p><p>019-00578-5.</p><p>[28] A.P. Luiz, S.D. Schroeder, G.A. Rae, J.B. Calixto, J.G. Chichorro, Contribution and</p><p>interaction of kinin receptors and dynorphin a in a model of trigeminal</p><p>neuropathic pain in mice, Neuroscience 300 (2015) 189–200, https://doi.org/</p><p>10.1016/j.neuroscience.2015.05.015.</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>18</p><p>[29] R. Costa, E.M. Motta, R.C. Dutra, M.N. Manjavachi, A.F. Bento, F.R. Malinsky, J.</p><p>B. Pesquero, J.B. Calixto, Anti-nociceptive effect of kinin B 1 and B 2 receptor</p><p>antagonists on peripheral neuropathy induced by paclitaxel in mice, Br. J.</p><p>Pharmacol. 164 (2011) 681–693, https://doi.org/10.1111/j.1476-</p><p>5381.2011.01408.x.</p><p>[30] I. Brusco, C.R. Silva, G. Trevisan, C. de Campos Velho, F.K. Gewehr, L.La. Rigo, M.</p><p>F. Rocca Tamiozzo, R. Rossato, G.D. Tonello, D. de Dalmolin, M.V. Almeida</p><p>Cabrini, J. Gomez, S.M.Oliveira Ferreira, Potentiation of paclitaxel-induced pain</p><p>syndrome in mice by angiotensin I converting enzyme inhibition and involvement</p><p>of kinins, Mol. Neurobiol. 54 (2017) 7824–7837, https://doi.org/10.1007/</p><p>s12035-016-0275-7.</p><p>[31] I. Brusco, A.B. Justino, C.R. Silva, R. Scussel, R.A. Machado-de-Ávila, S.</p><p>M. Oliveira, Inhibitors of angiotensin I converting enzyme potentiate</p><p>fibromyalgia-like pain symptoms via kinin receptors in mice, Eur. J. Pharmacol.</p><p>895 (2021), 173870, https://doi.org/10.1016/j.ejphar.2021.173870.</p><p>[32] J.G. Chichorro, B.B. Lorenzetti, A.R. Zampronio, Involvement of bradykinin,</p><p>cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial</p><p>nociception in rats, Br. J. Pharmacol. 141 (2004) 1175–1184, https://doi.org/</p><p>10.1038/sj.bjp.0705724.</p><p>[33] J. Gougat, B. Ferrari, L. Sarran, C. Planchenault, M. Poncelet, J. Maruani,</p><p>R. Alonso, A. Cudennec, T. Croci, F. Guagnini, K. Urban-Szabo, J.-P. Martinolle,</p><p>P. Soubrié, O. Finance, G. Le Fur, SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-</p><p>5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-</p><p>[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-</p><p>methylpropanamide hydrochloride], a new nonpeptide antagonist of the</p><p>bradykinin B1 receptor: biochemical and pharmacological characterization,</p><p>J. Pharmacol. Exp. Ther. 309 (2004) 661–669, https://doi.org/10.1124/</p><p>jpet.103.059527.</p><p>[34] A. Fox, S. Kaur, B. Li, M. Panesar, U. Saha, C. Davis, I. Dragoni, S. Colley,</p><p>T. Ritchie, S. Bevan, G. Burgess, P. McIntyre, Antihyperalgesic activity of a novel</p><p>nonpeptide bradykinin B 1 receptor antagonist in transgenic mice expressing the</p><p>human B 1 receptor, Br. J. Pharmacol. 144 (2005) 889–899, https://doi.org/</p><p>10.1038/sj.bjp.0706139.</p><p>[35] F. Porreca, T.W. Vanderah, W. Guo, M. Barth, P. Dodey, V. Peyrou, J.</p><p>M. Luccarini, J.L. Junien, D. Pruneau, Antinociceptive pharmacology of N-[[4-</p><p>(4,5-dihydro-1H-imidazol-2-yl)phenyl] methyl]-2-[2-[[(4-methoxy-2,6-</p><p>dimethylphenyl)sulfonyl]methylamino]ethoxy] -N-methylacetamide, fumarate</p><p>(LF22-0542), a novel nonpeptidic bradykinin B 1 receptor antagonist,</p><p>J. Pharmacol. Exp. Ther. 318 (2006) 195–205, https://doi.org/10.1124/</p><p>jpet.105.098368.</p><p>[36] J.J. Chen, T. Nguyen, D.C. D’Amico, W. Qian, J. Human, T. Aya, K. Biswas,</p><p>C. Fotsch, N. Han, Q. Liu, N. Nishimura, T.A.N. Peterkin, K. Yang, J. Zhu, B.</p><p>B. Riahi, R.W. Hungate, N.G. Andersen, J.T. Colyer, M.M. Faul, A. Kamassah,</p><p>J. Wang, J. Jona, G. Kumar, E. Johnson, B.C. Askew, 3-Oxo-2-piperazinyl</p><p>acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain</p><p>and inflammation, Bioorg. Med. Chem. Lett. 21 (2011) 3384–3389, https://doi.</p><p>org/10.1016/j.bmcl.2011.03.115.</p><p>[37] K. Biswas, T.A.N. Peterkin, M.C. Bryan, L. Arik, S.G. Lehto, H. Sun, F.Y. Hsieh,</p><p>C. Xu, R.T. Fremeau, J.R. Allen, Discovery of potent, orally bioavailable</p><p>phthalazinone bradykinin B1 receptor antagonists, J. Med. Chem. 54 (2011)</p><p>7232–7246, https://doi.org/10.1021/jm200808v.</p><p>[38] C.T.T. Wong, D.K. Rowlands, C.H. Wong, T.W.C. Lo, G.K.T. Nguyen, H.Y. Li, J.</p><p>P. Tam, Orally active peptidic bradykinin B 1 receptor antagonists engineered</p><p>from a cyclotide scaffold for inflammatory pain treatment, Angew. Chem. Int. Ed.</p><p>51 (2012) 5620–5624, https://doi.org/10.1002/anie.201200984.</p><p>[39] N. Schuelert, S. Just, L. Corradini, R. Kuelzer, C. Bernloehr, H. Doods, The</p><p>bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia</p><p>by desensitization of peripheral and spinal neurons, Eur. J. Pain 19 (2015)</p><p>132–142, https://doi.org/10.1002/ejp.573.</p><p>[40] W.R. Lumry, H. Farkas, D. Moldovan, E. Toubi, J. Baptista, T. Craig, M. Riedl,</p><p>Icatibant for multiple hereditary angioedema attacks across the controlled and</p><p>open-label extension phases of FAST-3, Int. Arch. Allergy Immunol. 168 (2015)</p><p>44–55, https://doi.org/10.1159/000441060.</p><p>[41] M. Baş, Clinical efficacy of icatibant in the treatment of acute hereditary</p><p>angioedema during the FAST-3 trial, Expert Rev. Clin. Immunol. 8 (2012)</p><p>707–717, https://doi.org/10.1586/eci.12.67.</p><p>[42] J. Lau, J. Rousseau, D. Kwon, F. Bénard, K.S. Lin, A systematic review of</p><p>molecular imaging agents targeting bradykinin B1 and B2 receptors,</p><p>Pharmaceuticals 13 (2020) 1–20, https://doi.org/10.3390/ph13080199.</p><p>[43] J. Scholz, C.J. Woolf, Can we conquer pain? Nat. Neurosci. 5 (2002) 1062–1067,</p><p>https://doi.org/10.1038/nn942.</p><p>[44] M. Costigan, J. Scholz, C.J. Woolf, Neuropathic pain: a maladaptive response of</p><p>the nervous system to damage, Annu. Rev. Neurosci. 32 (2009) 1–32, https://doi.</p><p>org/10.1146/annurev.neuro.051508.135531.</p><p>[45] R. Kuner, H. Flor, Structural plasticity and reorganisation in chronic pain, Nat.</p><p>Rev. Neurosci. 18 (2017) 20–30, https://doi.org/10.1038/nrn.2016.162.</p><p>[46] S.M. Oliveira, C.R. Silva, J. Ferreira, Critical role of protease-activated receptor 2</p><p>activation by mast cell tryptase in the development of postoperative pain,</p><p>Anesthesiology 118 (2013) 679–690, https://doi.org/10.1097/</p><p>ALN.0B013E31827D415F.</p><p>[47] R. Kuner, Central mechanisms of pathological pain, Nat. Med. 16 (2010)</p><p>1258–1266, https://doi.org/10.1038/nm.2231.</p><p>[48] A.I. Basbaum, D.M. Bautista, G. Scherrer, D. Julius, Cellular and molecular</p><p>mechanisms of pain, Cell 139 (2009) 267–284, https://doi.org/10.1016/j.</p><p>cell.2009.09.028.</p><p>[49] R.-D. Treede, W. Rief, A. Barke, Q. Aziz, M.I. Bennett, R. Benoliel, M. Cohen,</p><p>S. Evers, N.B. Finnerup, M.B. First, M.A. Giamberardino, S. Kaasa, E. Kosek,</p><p>P. Lavandʼhomme, M. Nicholas, S. Perrot, J. Scholz, S. Schug, B.H. Smith,</p><p>P. Svensson, J.W.S. Vlaeyen, S.-J. Wang, A classification of chronic pain for ICD-</p><p>11, Pain 156 (2015) 1003–1007, https://doi.org/10.1097/j.</p><p>pain.0000000000000160.</p><p>[50] R.-D. Treede, W. Rief, A. Barke, Q. Aziz, M.I. Bennett, R. Benoliel, M. Cohen,</p><p>S. Evers, N.B. Finnerup, M.B. First, M.A. Giamberardino, S. Kaasa, B. Korwisi,</p><p>E. Kosek, P. Lavand’homme, M. Nicholas, S. Perrot, J. Scholz, S. Schug, B.</p><p>H. Smith, P. Svensson, J.W.S. Vlaeyen, S.-J. Wang, Chronic pain as a symptom or</p><p>a disease: the IASP Classification of Chronic Pain for the International</p><p>Classification of Diseases (ICD-11), Pain 160 (2019) 19–27, https://doi.org/</p><p>10.1097/j.pain.0000000000001384.</p><p>[51] D.L.H. Bennett, C.G. Woods, Painful and painless channelopathies, Lancet</p><p>Neurol.</p><p>13 (2014) 587–599, https://doi.org/10.1016/S1474-4422(14)70024-9.</p><p>[52] P.M. Grace, M.R. Hutchinson, S.F. Maier, L.R. Watkins, Pathological pain and the</p><p>neuroimmune interface, Nat. Rev. Immunol. 14 (2014) 217–231, https://doi.org/</p><p>10.1038/nri3621.</p><p>[53] K. Michaud, C. Bombardier, P. Emery, Quality of life in patients with rheumatoid</p><p>arthritis: does abatacept make a difference? Clin. Exp. Rheumatol. 25 (2007)</p><p>S35–S45.</p><p>[54] J. Scholz, N.B. Finnerup, N. Attal, Q. Aziz, R. Baron, M.I. Bennett, R. Benoliel,</p><p>M. Cohen, G. Cruccu, K.D. Davis, S. Evers, M. First, M.A. Giamberardino,</p><p>P. Hansson, S. Kaasa, B. Korwisi, E. Kosek, P. Lavand’homme, M. Nicholas,</p><p>T. Nurmikko, S. Perrot, S.N. Raja, A.S.C. Rice, M.C. Rowbotham, S. Schug, D.</p><p>M. Simpson, B.H. Smith, P. Svensson, J.W.S. Vlaeyen, S.-J. Wang, A. Barke,</p><p>W. Rief, R.-D. Treede, The IASP classification of chronic pain for ICD-11: chronic</p><p>neuropathic pain, Pain 160 (2019) 53–59, https://doi.org/10.1097/j.</p><p>pain.0000000000001365.</p><p>[55] E. Kosek, M. Cohen, R. Baron, G.F. Gebhart, J.A. Mico, A.S.C. Rice, W. Rief, A.</p><p>K. Sluka, Do we need a third mechanistic descriptor for chronic pain states? Pain</p><p>157 (2016) 1382–1386, https://doi.org/10.1097/j.pain.0000000000000507.</p><p>[56] L. Colloca, T. Ludman, D. Bouhassira, R. Baron, A.H. Dickenson, D. Yarnitsky,</p><p>R. Freeman, A. Truini, N. Attal, N.B. Finnerup, C. Eccleston, E. Kalso, D.</p><p>L. Bennett, R.H. Dworkin, S.N. Raja, Neuropathic pain, Nat. Rev. Dis. Prim. 3</p><p>(2017) 17002, https://doi.org/10.1038/nrdp.2017.2.</p><p>[57] M.-A. Fitzcharles, S.P. Cohen, D.J. Clauw, G. Littlejohn, C. Usui, W. Häuser,</p><p>Nociplastic pain: towards an understanding of prevalent pain conditions, Lancet</p><p>397 (2021) 2098–2110, https://doi.org/10.1016/S0140-6736(21)00392-5.</p><p>[58] J.E. Abelous, E. Bardier, Les substances hypotensives de lúrine humanine</p><p>normale, C. R. Hebd. Seances Mem. Soc. Biol. 61 (1909) 511–512.</p><p>[59] E. Habermann, On pH-related modifications of kinin-producing alpha-globulin</p><p>(kininogen) from bovine serum and the molecular weight of kininogen I,</p><p>Biochem. Z. 337 (1963) 440–448.</p><p>[60] D. Regoli, J. Barabe, W.K. Park, Receptors for bradykinin in rabbit aortae, Can. J.</p><p>Physiol. Pharmacol. 55 (1977) 855–867, https://doi.org/10.1139/y77-115.</p><p>[61] E.T. Whalley, C.D. Figueroa, L. Gera, K.D. Bhoola, Discovery and therapeutic</p><p>potential of kinin receptor antagonists, Expert Opin. Drug Discov. 7 (2012)</p><p>1129–1148, https://doi.org/10.1517/17460441.2012.729038.</p><p>[62] R.J. Vavrek, J.M. Stewart, Competitive antagonists of bradykinin, Peptides 6</p><p>(1985) 161–164.</p><p>[63] P.D. Negraes, C.A. Trujillo, M.M. Pillat, Y.D. Teng, H. Ulrich, Roles of kinins in the</p><p>nervous system, Cell Transplant. 24 (2015) 613–623, https://doi.org/10.3727/</p><p>096368915X687778.</p><p>[64] E. Frey, H. Kraut, Ein neues Kreislaufhormon und seine Wirkung, Naunyn</p><p>Schmiedebergs Arch. Exp. Path Pharmak. 133 (1928) 1–56.</p><p>[65] E. Kashuba, J. Bailey, D. Allsup, L. Cawkwell, The kinin–kallikrein system:</p><p>physiological roles, pathophysiology and its relationship to cancer biomarkers,</p><p>Biomarkers 18 (2013) 279–296, https://doi.org/10.3109/</p><p>1354750X.2013.787544.</p><p>[66] K.D. Bhoola, C.D. Figueroa, K. Worthy, Bioregulation of kinins: kallikreins,</p><p>kininogens, and kininases, Pharmacol. Rev. 44 (1992) 1–44.</p><p>[67] M. Rocha e Silva, W.T. Beraldo, G. Rosenfeld, Bradykinin, a hypotensive and</p><p>smooth muscle stimulating factor released from plasma globulin by snake venoms</p><p>and by trypsin, Am. J. Physiol. Content 156 (1949) 261–273, https://doi.org/</p><p>10.1152/ajplegacy.1949.156.2.261.</p><p>[68] R.C. Dutra, Kinin receptors: key regulators of autoimmunity, Autoimmun. Rev.</p><p>(2016), https://doi.org/10.1016/j.autrev.2016.12.011.</p><p>[69] E.G. Erdös, E.M. Sloane, An enzyme in human blood plasma that inactivates</p><p>bradykinin and kallidins, Biochem. Pharmacol. 11 (1962) 585–592, https://doi.</p><p>org/10.1016/0006-2952(62)90119-3.</p><p>[70] H.Y. Yang, E. Erdös, Second kininase in human blood plasma, Nature 215 (1967)</p><p>1402–1403.</p><p>[71] B. Cassim, G. Mody, K.D. Bhoola, Kallikrein cascade and cytokines in inflamed</p><p>joints, Pharmacol. Ther. 94 (2002) 1–34, https://doi.org/10.1016/S0163-7258</p><p>(02)00166-3.</p><p>[72] A.P. Kaplan, K. Joseph, M. Silverberg, Pathways for bradykinin formation and</p><p>inflammatory disease, J. Allergy Clin. Immunol. 109 (2002) 195–209, https://</p><p>doi.org/10.1067/mai.2002.121316.</p><p>[73] R. Igić, Four decades of ocular renin-angiotensin and kallikrein-kinin systems</p><p>(1977–2017), Exp. Eye Res. 166 (2018) 74–83, https://doi.org/10.1016/j.</p><p>exer.2017.05.007.</p><p>[74] A.H. Schmaier, The elusive physiologic role of factor XII, J. Clin. Invest. 118</p><p>(2008) 3006–3009, https://doi.org/10.1172/JCI36617.</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>19</p><p>[75] M.E. Moreau, N. Garbacki, G. Molinaro, N.J. Brown, F. Marceau, A. Adam, The</p><p>kallikrein-kinin system: current and future pharmacological targets,</p><p>J. Pharmacol. Sci. 99 (2005) 6–38, https://doi.org/10.1254/jphs.SRJ05001X.</p><p>[76] G.A. Yarovaya, A.E. Neshkova, Past and present research on the kallikrein-kinin</p><p>system (on the 90th anniversary of the discovery of the system), Russ. J. Bioorg.</p><p>Chem. 41 (2015) 245–259, https://doi.org/10.1134/S1068162015030115.</p><p>[77] G.M. Yousef, T. Kishi, E.P. Diamandis, Role of kallikrein enzymes in the central</p><p>nervous system, Clin. Chim. Acta 329 (2003) 1–8, https://doi.org/10.1016/</p><p>S0009-8981(03)00004-4.</p><p>[78] R.W. Colman, Regulation of angiogenesis by the kallikrein-kinin system, Curr.</p><p>Pharm. Des. 12 (2006) 2599–2607, https://doi.org/10.2741/998.</p><p>[79] J.A. Guimarães, D.R. Borges, E.S. Prado, J. Prado, Kinin-converting</p><p>aminopeptidase from human serum, Biochem. Pharmacol. 22 (1973) 3157–3172,</p><p>https://doi.org/10.1016/0006-2952(73)90090-7.</p><p>[80] X. Zhang, F. Tan, V. Brovkovych, Y. Zhang, J.L. Lowry, R.A. Skidgel,</p><p>Carboxypeptidase M augments kinin B1 receptor signaling by conformational</p><p>crosstalk and enhances endothelial nitric oxide output, Biol. Chem. 394 (2013)</p><p>335–345, https://doi.org/10.1515/hsz-2012-0290.</p><p>[81] X. Zhang, F. Tan, Y. Zhang, R.A. Skidgel, Carboxypeptidase M and kinin B1</p><p>receptors interact to facilitate efficient B1 signaling from B2 agonists, J. Biol.</p><p>Chem. 283 (2008) 7994–8004, https://doi.org/10.1074/jbc.M709837200.</p><p>[82] X. Zhang, F. Tan, V. Brovkovych, Y. Zhang, R.A. Skidgel, Cross-talk between</p><p>carboxypeptidase M and the kinin B1 receptor mediates a new mode of G protein-</p><p>coupled receptor signaling, J. Biol. Chem. 286 (2011) 18547–18561, https://doi.</p><p>org/10.1074/jbc.M110.214940.</p><p>[83] E.G. Erdös, F. Tan, R.A. Skidgel, Angiotensin I-converting enzyme inhibitors are</p><p>allosteric enhancers of kinin B1 and B2 receptor function, Hypertension 55</p><p>(2010) 214–220, https://doi.org/10.1161/HYPERTENSIONAHA.109.144600.</p><p>[84] F.G. Pelorosso, P.T. Brodsky, C.L. Zold, R.P. Rothlin, Potentiation of des-Arg 9</p><p>-kallidin-induced vasoconstrictor responses by metallopeptidase inhibition in</p><p>isolated human umbilical artery, J. Pharmacol. Exp. Ther. 313 (2005)</p><p>1355–1360, https://doi.org/10.1124/jpet.105.083063.</p><p>[85] I. Fleming, K. Kohlstedt, R. Busse, New fACEs to the renin-angiotensin system,</p><p>Physiology 20 (2005) 91–95, https://doi.org/10.1152/physiol.00003.2005.</p><p>[86] I.M. Souza-silva, C.A. De Paula, L. Bolais-ramos, F. Alex, A.K. Santos, V. Louise,</p><p>S. De Oliveira, I. Domingos, M. Mota, A. Lídia, P. Barbosa, C. Vanessa, P. Teixeira,</p><p>S. Ricardo, A. Scalzo, J. Adriana, C. Raabe, J. Magalh, M. Antônio, P. Fontes, G.</p><p>B. Menezes, T. Verano-braga, S. Guatimosim, R. Augusto, S. Santos, Peptide</p><p>fragments of bradykinin show unexpected biological activity not mediated by B 1</p><p>or B 2 receptors, Br. J. Pharmacol. 179 (2022) 3061–3077, https://doi.org/</p><p>10.1111/bph.15790.</p><p>[87] M.E. Marin-Castaño, J.P. Schanstra, E. Neau, F. Praddaude, C. Pecher,</p><p>J.L. Ader,</p><p>J.P. Girolami, J.L. Bascands, Induction of functional bradykinin B1-receptors in</p><p>normotensive rats and mice under chronic angiotensin-converting enzyme</p><p>inhibitor treatment, Circulation 105 (2002) 627–632, https://doi.org/10.1161/</p><p>hc0502.102965.</p><p>[88] B. Williams, G. Mancia, W. Spiering, E.Agabiti Rosei, M. Azizi, M. Burnier, D.</p><p>L. Clement, A. Coca, G. de Simone, A. Dominiczak, T. Kahan, F. Mahfoud,</p><p>J. Redon, L. Ruilope, A. Zanchetti, M. Kerins, S.E. Kjeldsen, R. Kreutz, S. Laurent,</p><p>G.Y.H. Lip, R. McManus, K. Narkiewicz, F. Ruschitzka, R.E. Schmieder,</p><p>E. Shlyakhto, C. Tsioufis, V. Aboyans, I. Desormais, E.S.D. Group, 2018 ESC/ESH</p><p>Guidelines for the management of arterial hypertension, Eur. Heart J. 39 (2018)</p><p>3021–3104, https://doi.org/10.1093/eurheartj/ehy339.</p><p>[89] P. Corvol, T.A. Williams, F. Soubrier, Peptidyl dipeptidase A: angiotensin I-</p><p>converting enzyme, Methods Enzym. (1995) 283–305, https://doi.org/10.1016/</p><p>0076-6879(95)48020-X.</p><p>[90] T. Ignjatovic, F. Tan, V. Brovkovych, R.A. Skidgel, E.G. Erdös, Novel mode of</p><p>action of angiotensin I converting enzyme inhibitors: DIRECT ACTIVATION OF</p><p>BRADYKININ B1 RECEPTOR, J. Biol. Chem. 277 (2002) 16847–16852, https://</p><p>doi.org/10.1074/jbc.M200355200.</p><p>[91] Z. Chen, P.A. Deddish, R.D. Minshall, R.P. Becker, E.G. Erdös, F. Tan, Human ACE</p><p>and bradykinin B 2 receptors form a complex at the plasma membrane, FASEB J.</p><p>20 (2006) 2261–2270, https://doi.org/10.1096/fj.06-6113com.</p><p>[92] D. Borsook, S. Sava, Pain: do ACE inhibitors exacerbate complex regional pain</p><p>syndrome? Nat. Rev. Neurol. 5 (2009) 306–308, https://doi.org/10.1038/</p><p>nrneurol.2009.73.</p><p>[93] M. De Mos, F.J.P.M. Huygen, B.H.C. Stricker, J.P. Dieleman, M.C.J.</p><p>M. Sturkenboom, The association between ACE inhibitors and the complex</p><p>regional pain syndrome: suggestions for a neuro-inflammatory pathogenesis of</p><p>CRPS, Pain 142 (2009) 218–224, https://doi.org/10.1016/j.pain.2008.12.032.</p><p>[94] J.G. Choi, S.R. Choi, D.W. Kang, J. Kim, J.B. Park, H.W. Kim, Inhibition of</p><p>angiotensin converting enzyme induces mechanical allodynia through increasing</p><p>substance P expression in mice, Neurochem. Int. 146 (2021), 105020, https://doi.</p><p>org/10.1016/j.neuint.2021.105020.</p><p>[95] G.C. Zanata, L.G. Pinto, N.R. Silva, A.H.P. Lopes, F.F.B. Oliveira, I.R.S. Schivo, F.</p><p>Q. Cunha, P. McNaughton, T.M. Cunha, R.L. Silva, Blockade of bradykinin</p><p>receptors or angiotensin II type 2 receptor prevents paclitaxel-associated acute</p><p>pain syndrome in mice, Eur. J. Pain 25 (2021) 189–198, https://doi.org/</p><p>10.1002/ejp.1660.</p><p>[96] A. Blaukat, Structure and signalling pathways of kinin receptors, Andrologia 35</p><p>(2003) 17–23, https://doi.org/10.1046/j.1439-0272.2003.00533.x.</p><p>[97] Y. Yin, C. Ye, F. Zhou, J. Wang, D. Yang, W. Yin, M. Wang, H.E. Xu, Y. Jiang,</p><p>Molecular basis for kinin selectivity and activation of the human bradykinin</p><p>receptors, Nat. Struct. Mol. Biol. 28 (2021) 755–761, https://doi.org/10.1038/</p><p>s41594-021-00645-y.</p><p>[98] J. Shen, D. Zhang, Y. Fu, A. Chen, X. Yang, H. Zhang, Cryo-EM structures of</p><p>human bradykinin receptor-Gq proteins complexes, Nat. Commun. 13 (2022)</p><p>714, https://doi.org/10.1038/s41467-022-28399-1.</p><p>[99] J.N. Sharma, Pharmacologic targets and prototype therapeutics in the kallikrein-</p><p>kinin system: bradykinin receptor agonists or antagonists, Sci. World J. 6 (2006)</p><p>1247–1261, https://doi.org/10.1100/tsw.2006.226.</p><p>[100] J. Ferreira, K.M. Trichês, R. Medeiros, D.A. Cabrini, M.A.S. Mori, J.B. Pesquero,</p><p>M. Bader, J.B. Calixto, The role of kinin B1 receptors in the nociception produced</p><p>by peripheral protein kinase C activation in mice, Neuropharmacology 54 (2008)</p><p>597–604, https://doi.org/10.1016/j.neuropharm.2007.11.008.</p><p>[101] J.B. Calixto, R. Medeiros, E.S. Fernandes, J. Ferreira, D.A. Cabrini, M.M. Campos,</p><p>Kinin B 1 receptors: key G-protein-coupled receptors and their role in</p><p>inflammatory and painful processes, Br. J. Pharmacol. 143 (2004) 803–818,</p><p>https://doi.org/10.1038/sj.bjp.0706012.</p><p>[102] Q. Ma, The expression of bradykinin B 1 receptors on primary sensory neurones</p><p>that give rise to small caliber sciatic nerve fibres in rats, Neuroscience 107 (2001)</p><p>665–673.</p><p>[103] Q.-P. Ma, R. Hill, D. Sirinathsinghji, Basal expression of bradykinin B1 receptor in</p><p>peripheral sensory ganglia in the rat, Neuroreport 11 (2000) 4003–4005, https://</p><p>doi.org/10.1097/00001756-200012180-00020.</p><p>[104] P. Ehrenfeld, C. Millan, C.E. Matus, J.E. Figueroa, R.A. Burgos, F. Nualart, K.</p><p>D. Bhoola, C.D. Figueroa, Activation of kinin B1 receptors induces chemotaxis of</p><p>human neutrophils, J. Leukoc. Biol. 80 (2006) 117–124, https://doi.org/</p><p>10.1189/jlb.1205744.</p><p>[105] P. Schaeffer, M. Laplace, P. Savi, J. Herbert, Detection of bradykinin B 1 receptors</p><p>in rat aortic smooth muscle cells, Biochem. Pharmacol. 61 (2001) 291–298.</p><p>[106] R. Costa, M.A. Bicca, M.N. Manjavachi, G.C. Segat, F.C. Dias, E.S. Fernandes, J.</p><p>B. Calixto, Kinin receptors sensitize TRPV4 channel and induce mechanical</p><p>hyperalgesia: relevance to paclitaxel-induced peripheral neuropathy in mice, Mol.</p><p>Neurobiol. 55 (2018) 2150–2161, https://doi.org/10.1007/s12035-017-0475-9.</p><p>[107] M.F.P. Werner, C.A.L. Kassuya, J. Ferreira, A.R. Zampronio, J.B. Calixto, G.</p><p>A. Rae, Peripheral kinin B1 and B2 receptor-operated mechanisms are implicated</p><p>in neuropathic nociception induced by spinal nerve ligation in rats,</p><p>Neuropharmacology 53 (2007) 48–57, https://doi.org/10.1016/j.</p><p>neuropharm.2007.04.013.</p><p>[108] B. Cassim, O.M. Shaw, M. Mazur, N.L. Misso, A. Naran, D.R. Langlands, P.</p><p>J. Thompson, K.D. Bhoola, Kallikreins, kininogens and kinin receptors on</p><p>circulating and synovial fluid neutrophils: role in kinin generation in rheumatoid</p><p>arthritis, Rheumatology 48 (2008) 490–496, https://doi.org/10.1093/</p><p>rheumatology/kep016.</p><p>[109] J.B. Calixto, D.A. Cabrini, J. Ferreira, M.M. Campos, Kinins in pain and</p><p>inflammation, Pain 87 (2000) 1–5, https://doi.org/10.1016/S0304-3959(00)</p><p>00335-3.</p><p>[110] F. Marceau, D.R. Bachvarov, Kinin receptors, Clin. Rev. Allergy Immunol. 16</p><p>(1998) 385–401.</p><p>[111] J.B. Calixto, D.A. Cabrini, J. Ferreira, M.M. Campos, Inflammatory pain: kinins</p><p>and antagonists, Curr. Opin. Anaesthesiol. 14 (2001) 519–526, https://doi.org/</p><p>10.1097/00001503-200110000-00010.</p><p>[112] J. Ferreira, A. Beirith, M.A.S. Mori, R.C. Araújo, M. Bader, J.B. Pesquero, J.</p><p>B. Calixto, Reduced nerve injury-induced neuropathic pain in kinin B1 receptor</p><p>knock-out mice, J. Neurosci. 25 (2005) 2405–2412, https://doi.org/10.1523/</p><p>JNEUROSCI.2466-04.2005.</p><p>[113] M. Gröger, D. Lebesgue, D. Pruneau, J. Relton, S. Kim, J. Nussberger, N. Plesnila,</p><p>Release of bradykinin and expression of kinin B 2 receptors in the brain: role for</p><p>cell death and brain edema formation after focal cerebral ischemia in mice,</p><p>J. Cereb. Blood Flow Metab. 25 (2005) 978–989, https://doi.org/10.1038/sj.</p><p>jcbfm.9600096.</p><p>[114] T. Kohno, H. Wang, F. Amaya, G.J. Brenner, J.K. Cheng, R.R. Ji, C.J. Woolf,</p><p>Bradykinin enhances AMPA and NMDA receptor activity in spinal cord dorsal</p><p>horn neurons by activating multiple kinases to produce pain hypersensitivity,</p><p>J. Neurosci. 28 (2008) 4533–4540, https://doi.org/10.1523/JNEUROSCI.5349-</p><p>07.2008.</p><p>[115] H. Wang, T. Kohno, F. Amaya, G.J. Brenner, N. Ito, A. Allchorne, R.R. Ji, C.</p><p>J. Woolf, Bradykinin produces pain hypersensitivity by potentiating spinal cord</p><p>glutamatergic synaptic transmission, J. Neurosci. 25 (2005) 7986–7992, https://</p><p>doi.org/10.1523/JNEUROSCI.2393-05.2005.</p><p>[116] P. Busse, S. Christiansen, Hereditary angioedema, N. Engl. J. Med. 382 (2020)</p><p>1136–1148, https://doi.org/10.1056/NEJMra1808012.</p><p>[117] P.L.N. da Costa, P. Sirois, I.F. Tannock, R. Chammas, The role of kinin receptors in</p><p>cancer and therapeutic opportunities, Cancer Lett. 345 (2014) 27–38, https://doi.</p><p>org/10.1016/j.canlet.2013.12.009.</p><p>[118] R. Ji, A. Chamessian, Y. Zhang, Pain regulation by non-neuronal cells and</p><p>inflammation, Pain Res. 354 (2016) 572–577.</p><p>[119] Y. Huh, R.R. Ji, G. Chen, Neuroinflammation, bone marrow</p><p>stem cells, and</p><p>chronic pain, Front. Immunol. 8 (2017) 1014, https://doi.org/10.3389/</p><p>fimmu.2017.01014.</p><p>[120] F.A. Pinho-Ribeiro, W.A. Verri, I.M. Chiu, Nociceptor sensory neuron-immune</p><p>interactions in pain and inflammation, Trends Immunol. 38 (2017) 5–19, https://</p><p>doi.org/10.1016/j.it.2016.10.001.</p><p>[121] S. Safiri, A.A. Kolahi, E. Smith, C. Hill, D. Bettampadi, M.A. Mansournia, D. Hoy,</p><p>A. Ashrafi-Asgarabad, M. Sepidarkish, A. Almasi-Hashiani, G. Collins, J. Kaufman,</p><p>M. Qorbani, M. Moradi-Lakeh, A.D. Woolf, F. Guillemin, L. March, M. Cross,</p><p>Global, regional and national burden of osteoarthritis 1990-2017: a systematic</p><p>analysis of the Global Burden of Disease Study 2017, Ann. Rheum. Dis. (2020)</p><p>819–828, https://doi.org/10.1136/annrheumdis-2019-216515.</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>20</p><p>[122] N.K. Arden, T.A. Perry, R.R. Bannuru, O. Bruyère, C. Cooper, I.K. Haugen, M.</p><p>C. Hochberg, T.E. McAlindon, A. Mobasheri, J.Y. Reginster, Non-surgical</p><p>management of knee osteoarthritis: comparison of ESCEO and OARSI 2019</p><p>guidelines, Nat. Rev. Rheumatol. 17 (2021) 59–66, https://doi.org/10.1038/</p><p>s41584-020-00523-9.</p><p>[123] D. Aletaha, J.S. Smolen, Diagnosis and management of rheumatoid arthritis: a</p><p>review, JAMA - J. Am. Med. Assoc. 320 (2018) 1360–1372, https://doi.org/</p><p>10.1001/jama.2018.13103.</p><p>[124] J.S. Smolen, R.B.M. Landewé, J.W.J. Bijlsma, G.R. Burmester, M. Dougados,</p><p>A. Kerschbaumer, I.B. McInnes, A. Sepriano, R.F.Van Vollenhoven, M.De Wit,</p><p>D. Aletaha, M. Aringer, J. Askling, A. Balsa, M. Boers, A.A.Den Broeder, M.</p><p>H. Buch, F. Buttgereit, R. Caporali, M.H. Cardiel, D.De Cock, C. Codreanu,</p><p>M. Cutolo, C.J. Edwards, Y.Van Eijk-Hustings, P. Emery, A. Finckh, L. Gossec, J.</p><p>E. Gottenberg, M.L. Hetland, T.W.J. Huizinga, M. Koloumas, Z. Li, X. Mariette,</p><p>U. Müller-Ladner, E.F. Mysler, J.A.P.Da Silva, G. Poór, J.E. Pope, A. Rubbert-Roth,</p><p>A. Ruyssen-Witrand, K.G. Saag, A. Strangfeld, T. Takeuchi, M. Voshaar,</p><p>R. Westhovens, D.Van Der Heijde, EULAR recommendations for the management</p><p>of rheumatoid arthritis with synthetic and biological disease-modifying</p><p>antirheumatic drugs: 2019 update, Ann. Rheum. Dis. 79 (2020) S685–S699,</p><p>https://doi.org/10.1136/annrheumdis-2019-216655.</p><p>[125] A.P. Bond, M. Lemon, P.A. Dieppe, K.D. Bhoola, Generation of kinins in synovial</p><p>fluid from patients with arthropathy, Immunopharmacology 36 (1997) 209–216,</p><p>https://doi.org/10.1016/S0162-3109(97)00023-4.</p><p>[126] P. Cucchi, S. Meini, A. Bressan, C. Catalani, F. Bellucci, P. Santicioli, A. Lecci,</p><p>A. Faiella, L. Rotondaro, S. Giuliani, A. Giolitti, L. Quartara, C.A. Maggi,</p><p>MEN16132, a novel potent and selective nonpeptide antagonist for the human</p><p>bradykinin B2 receptor. In vitro pharmacology and molecular characterization,</p><p>Eur. J. Pharmacol. 528 (2005) 7–16, https://doi.org/10.1016/j.</p><p>ejphar.2005.10.014.</p><p>[127] F.A. Russell, V.E. Veldhoen, D. Tchitchkan, J.J. McDougall, Proteinase-activated</p><p>receptor-4 (PAR4) activation leads to sensitization of rat joint primary afferents</p><p>via a bradykinin B2 receptor-dependent mechanism, J. Neurophysiol. 103 (2010)</p><p>155–163, https://doi.org/10.1152/jn.00486.2009.</p><p>[128] A. Kawabata, N. Kawao, T. Kitano, M. Matsunami, R. Satoh, T. Ishiki, T. Masuko,</p><p>T. Kanke, N. Saito, Colonic hyperalgesia triggered by proteinase-activated</p><p>receptor-2 in mice: involvement of endogenous bradykinin, Neurosci. Lett. 402</p><p>(2006) 167–172, https://doi.org/10.1016/j.neulet.2006.03.074.</p><p>[129] G.N. Kaufman, C. Zaouter, B. Valteau, P. Sirois, F. Moldovan, Nociceptive</p><p>tolerance is improved by bradykinin receptor B1 antagonism and joint</p><p>morphology is protected by both endothelin type a and bradykinin receptor B1</p><p>antagonism in a surgical model of osteoarthritis, Arthritis Res. Ther. 13 (2011),</p><p>https://doi.org/10.1186/ar3338.</p><p>[130] H.K. Choi, L.C. Soriano, Y. Zhang, L.A. Garciá Rodriǵuez, Antihypertensive drugs</p><p>and risk of incident gout among patients with hypertension: population based</p><p>case-control study, BMJ 344 (2012), https://doi.org/10.1136/bmj.d8190.</p><p>[131] J.E. Hawkinson, B.G. Szoke, A.W. Garofalo, D.S. Hom, H. Zhang, M. Dreyer, J.</p><p>Y. Fukuda, L. Chen, B. Samant, S. Simmonds, K.P. Zeitz, A. Wadsworth, A. Liao, R.</p><p>A. Chavez, W. Zmolek, L. Ruslim, M.P. Bova, R. Holcomb, E.R. Butelman, M.</p><p>C. Ko, A.B. Malmberg, Pharmacological, pharmacokinetic, and primate analgesic</p><p>efficacy profile of the novel bradykinin B1 receptor antagonist ELN441958,</p><p>J. Pharmacol. Exp. Ther. 322 (2007) 619–630, https://doi.org/10.1124/</p><p>jpet.107.120352.</p><p>[132] S. Grastilleur, L. Mouledous, J. Bedel, J. Etcheverry, M. Bader, J.P. Girolami,</p><p>O. Fourcade, B. Frances, V. Minville, Role of kinin B2 receptors in opioid-induced</p><p>hyperalgesia in inflammatory pain in mice, Biol. Chem. 394 (2013) 361–368,</p><p>https://doi.org/10.1515/hsz-2012-0305.</p><p>[133] I. de Souza Maciel, V.M. Azevedo, P. Oliboni, M.M. Campos, Blockade of the kinin</p><p>B1 receptor counteracts the depressive-like behaviour and mechanical allodynia</p><p>in ovariectomised mice, Behav. Brain Res. 412 (2021), 113439, https://doi.org/</p><p>10.1016/j.bbr.2021.113439.</p><p>[134] B. Liu, J.E. Linley, X. Du, X. Zhang, L. Ooi, H. Zhang, N. Gamper, The acute</p><p>nociceptive signals induced by bradykinin in rat sensory neurons are mediated by</p><p>inhibition of M-type K+ channels and activation of Ca2+-activated Cl- channels,</p><p>J. Clin. Invest. 120 (2010) 1240–1252, https://doi.org/10.1172/JCI41084.</p><p>[135] M. Modrak, M.A.H. Talukder, K. Gurgenashvili, M. Noble, J.C. Elfar, Peripheral</p><p>nerve injury and myelination: potential therapeutic strategies, J. Neurosci. Res.</p><p>98 (2020) 780–795, https://doi.org/10.1002/jnr.24538.</p><p>[136] R. Pop-Busui, A.J.M. Boulton, E.L. Feldman, V. Bril, R. Freeman, R.A. Malik, J.</p><p>M. Sosenko, D. Ziegler, Diabetic neuropathy: a position statement by the</p><p>American Diabetes Association, Diabetes Care 40 (2017) 136–154, https://doi.</p><p>org/10.2337/dc16-2042.</p><p>[137] T. Frank, P. Nawroth, R. Kuner, Structure–function relationships in peripheral</p><p>nerve contributions to diabetic peripheral neuropathy, Pain 160 (2019) S29–S36,</p><p>https://doi.org/10.1097/j.pain.0000000000001530.</p><p>[138] H.L. Hébert, A. Veluchamy, N. Torrance, B.H. Smith, Risk factors for neuropathic</p><p>pain in diabetes mellitus, Pain 158 (2017) 560–568, https://doi.org/10.1097/j.</p><p>pain.0000000000000785.</p><p>[139] B.H. Gabra, P. Sirois, Pathways for the bradykinin B1 receptor-mediated diabetic</p><p>hyperalgesia in mice, Inflamm. Res. 53 (2004) 653–657, https://doi.org/</p><p>10.1007/s00011-004-1310-0.</p><p>[140] B. Ongali, M.M. Campos, M. Petcu, D. Rodi, F. Cloutier, J.G. Chabot, G. Thibault,</p><p>R. Couture, Expression of kinin B1 receptors in the spinal cord of streptozotocin-</p><p>diabetic rat, Neuroreport 15 (2004) 2463–2466, https://doi.org/10.1097/</p><p>00001756-200411150-00006.</p><p>[141] B.H. Gabra, V.F. Merino, M. Bader, J.B. Pesquero, P. Sirois, Absence of diabetic</p><p>hyperalgesia in bradykinin B1 receptor-knockout mice, Regul. Pept. 127 (2005)</p><p>245–248, https://doi.org/10.1016/j.regpep.2004.12.003.</p><p>[142] B.H. Gabra, O. Benrezzak, L.-H. Pheng, D. Duta, P. Daull, P. Sirois, F. Nantel,</p><p>B. Battistini, Inhibition of type 1 diabetic hyperalgesia in streptozotocin-induced</p><p>wistar versus spontaneous gene-prone BB/Worchester rats: efficacy of a selective</p><p>bradykinin B 1 receptor antagonist, J. Neuropathol. Exp. Neurol. 64 (2005)</p><p>782–789, https://doi.org/10.1097/01.jnen.0000178448.79713.5f.</p><p>[143] B.H. Gabra, P. Sirois, Hyperalgesia in non-obese diabetic (NOD) mice: a role for</p><p>the inducible bradykinin B1 receptor, Eur. J. Pharmacol. 514 (2005) 61–67,</p><p>https://doi.org/10.1016/j.ejphar.2005.03.018.</p><p>[144] B.H. Gabra, N. Berthiaume, P. Sirois, F. Nantel, B. Battistini, The kinin system</p><p>mediates hyperalgesia through the inducible bradykinin B1 receptor subtype:</p><p>evidence in various experimental</p><p>acute or chronic. Regarding</p><p>mechanisms, nociceptive and acute inflammatory pain present physio-</p><p>logical characteristics, while chronic inflammatory, neuropathic and</p><p>nociplastic pain are considered pathological [4,6,43,44].</p><p>Acute pain is transient and is acutely associated with a nociceptive</p><p>stimulus [45]. It is generally a consequence of tissue injuries, such as a</p><p>surgical procedure, has a limited duration time, tends to reduce in in-</p><p>tensity over time, and is abolished after healing [46–48]. In contrast,</p><p>chronic pain persists or recurs for more than three months, is a signifi-</p><p>cant source of human suffering, interferes deeply with the life quality of</p><p>patients, and is a great challenge in clinical practice [49,50]. Often</p><p>chronic pain is associated with affective and cognitive impairments,</p><p>such as depression, anxiety, anhedonia, and learning deficits [1]. Acute</p><p>pain differs considerably from chronic pain in terms of mechanisms and</p><p>response to analgesics [6].</p><p>According to its pathophysiology, nociceptive pain serves as a</p><p>warning device and is essential to detect and minimize the contact of an</p><p>individual with damaging or noxious stimuli. Thus, the ability to detect</p><p>harmful stimuli is primordial for the survival and well-being of an or-</p><p>ganism [4–6]. This is dramatically illustrated in individuals who suffer</p><p>from congenital abnormalities such as mutations in the SCN9A gene that</p><p>encodes the voltage-gated sodium channel 1.7 (Nav1.7). These muta-</p><p>tions can inactivate the SCN9A gene making individuals incapable of</p><p>detecting painful stimuli such as the piercing pain from a sharp object,</p><p>flame heat, or even a broken bone. Thus, they do not engage in appro-</p><p>priate protective behaviours against these conditions, which can be life-</p><p>threatening [6,48,51]. On the other hand, multiple missense mutations</p><p>in SCN9A can delay channel inactivation leading to gain-of-function of</p><p>the gene and consequently the hyperexcitability and conditions such as</p><p>familial erythromelalgia or paroxysmal extreme pain disease [51].</p><p>The inflammatory pain occurs after tissue damage caused by me-</p><p>chanical trauma or infection, ischemia, tumour growth, or an autoim-</p><p>mune process. In this condition, various inflammatory mediators are</p><p>released by activated nociceptors or nonneural cells that reside within or</p><p>infiltrate into the injured area, including mast cells, basophils, platelets,</p><p>macrophages, neutrophils, endothelial cells, keratinocytes, and fibro-</p><p>blasts resulting in an ‘inflammatory soup’ [4,43,48]. This ‘inflammatory</p><p>soup’ is rich in serotonin, histamine, glutamate, adenosine, substance P,</p><p>calcitonin gene-related peptide (CGRP), bradykinin, prostaglandins,</p><p>thromboxane, leukotrienes, endocannabinoids, nerve growth factor,</p><p>tumour necrosis factor α (TNFα), interleukin-1β (IL1β), extracellular</p><p>proteases, and protons, which promote an increased sensory sensitivity,</p><p>and so, are critical to initiate and sustain pain. This pain occurs due to</p><p>changes in the nervous system, causing the development of spontaneous</p><p>and stimulus-dependent (allodynia and hyperalgesia) pain [44]. Acute</p><p>inflammatory pain is considered adaptive and protective since it assists</p><p>in healing the injured body part by creating a situation that discourages</p><p>physical contact and movement [4,43,48,52]. Usually, inflammatory</p><p>pain disappears after the resolution of the initial tissue injury. However,</p><p>in chronic disorders such as rheumatoid arthritis, the pain persists as</p><p>long as inflammation is active and may acquire pathological charac-</p><p>teristics [6,44,53].</p><p>In contrast to physiological pain, pathological pain is not protective</p><p>but maladaptive, resulting from abnormal functioning of the nervous</p><p>system. This pathological pain can also occur after a lesion or disease of</p><p>the somatosensory nervous system, as in neuropathic pain, in the</p><p>absence of noxious stimuli, active inflammation, or detectable damage</p><p>to the nervous system, as in nociplastic pain [6,52,54,55]. Lesions or</p><p>diseases involving the somatosensory nervous system may paradoxically</p><p>lead to a loss of function, cause spontaneous pain (present in many</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>3</p><p>clinical conditions, particularly neuropathic pain), or be evoked by</p><p>sensory stimuli (hyperalgesia and allodynia). Neuropathic pain is usu-</p><p>ally a chronic disease that either can persist continuously or manifests</p><p>with recurrent painful episodes. It can occur in neurological conditions</p><p>of unknown aetiology, such as idiopathic neuropathies or known aeti-</p><p>ologies causing chronic peripheral or central neuropathic pain, which is</p><p>based on the location of the lesion or disease in the peripheral or central</p><p>somatosensory nervous system, respectively [6,44,50,54,56].</p><p>Nociplastic pain is characterized by substantial pain in the absence of</p><p>noxious stimulus and no, or minimal, peripheral inflammatory pathol-</p><p>ogy but in whom clinical and psychophysical findings suggest altered</p><p>nociceptive function [4,6,55]. Notably, nociplastic pain includes pain</p><p>complaints previously identified by stigmatising terms such as</p><p>dysfunctional pain or medically unexplained somatic syndromes [57].</p><p>3. Kallikrein-kinin system</p><p>The kallikrein-kinin system includes an endogenous multiprotein</p><p>cascade evidenced between 1909 and 1980 (Fig. 1) [16,58–70]. Its</p><p>activation triggers the intrinsic coagulation pathway and enzymatic</p><p>hydrolysis of kininogen, with the consequent formation of bradykinin-</p><p>related peptides. The kallikrein-kinin system has an essential role in</p><p>physiological and pathological processes such as inflammation, vaso-</p><p>dilation, smooth muscle contraction, cardioprotection, vascular</p><p>permeability, blood pressure control, coagulation, and pain [65].</p><p>The kallikrein-kinin system is constituted by complex interactions</p><p>between its various components: kallikreins (tissue and plasma enzymes</p><p>involved in the synthesis of kinins), kininogens (glycoproteins pre-</p><p>cursors of kinins), kininases (enzymes that metabolize kinins), kinins</p><p>itself and their receptors (B1R and B2R) [15,68] (Fig. 2).</p><p>Bradykinin peptide is released from the high molecular weight</p><p>kininogen after activation of plasma kallikrein. Plasma kallikrein is</p><p>formed from the pre-kallikrein, which is predominantly synthesized in</p><p>the liver, and other organs, cells, and tissues [71–73]. Plasma pre-</p><p>kallikrein activation occurs in pathological (dependent of factor XIIa</p><p>or via contact) or physiological conditions (independent of factor XII)</p><p>[65,68,72,74,75]. On the other hand, kallidin peptide (lys-bradykinin)</p><p>is released from the low molecular weight kininogen by proteolytic</p><p>cleavage after activating tissue kallikrein, a serine protease and acid</p><p>glycoprotein secreted by various organs and cells [65,68,76–78]. Tissue</p><p>kallikrein is synthesized as an inactive enzyme (pro-kallikrein) that is</p><p>converted into an active form by the proteolytic cleavage of an amino-</p><p>terminal peptide by local proteases [65,75]. Additionally, kallidin can</p><p>be converted to bradykinin through cleavage of its N-terminal lysine</p><p>residue by plasma aminopeptidases (Fig. 2) [79].</p><p>Kinins bradykinin and kallidin are rapidly metabolized by kininases I</p><p>and II [75]. Kininases I are represented by carboxypeptidase M and</p><p>carboxypeptidase N. Carboxypeptidase M is a peptidase found mainly</p><p>anchored in the plasma membrane and acts preferentially on peptides</p><p>containing arginine residues in the C-terminal portion (such as</p><p>bradykinin) [65,71,75,80]. Carboxypeptidase N is a plasma enzyme that</p><p>acts preferentially on peptides containing lysine in the C-terminal</p><p>portion (such as kallidin) [65,71,75]. In this way, they can remove the</p><p>terminal amino acids of bradykinin and kallidin molecules, forming the</p><p>active metabolites des-Arg9-bradykinin</p><p>animal models of type 1 and type 2 diabetic</p><p>neuropathy, Biol. Chem. 387 (2006) 127–143, https://doi.org/10.1515/</p><p>BC.2006.018.</p><p>[145] S. Talbot, E. Chahmi, J.P. Dias, R. Couture, Key role for spinal dorsal horn</p><p>microglial kinin B1receptor in early diabetic pain neuropathy,</p><p>J. Neuroinflammation 7 (2010) 1–16, https://doi.org/10.1186/1742-2094-7-36.</p><p>[146] C. Lungu, J.P. Dias, C.E. de França, B. Ongali, D. Regoli, F. Moldovan, R. Couture,</p><p>Involvement of kinin B1 receptor and oxidative stress in sensory abnormalities</p><p>and arterial hypertension in an experimental rat model of insulin resistance,</p><p>Neuropeptides 41 (2007) 375–387, https://doi.org/10.1016/j.npep.2007.09.005.</p><p>[147] J.P. Dias, S. Talbot, J. Sénécal, P. Carayon, R. Couture, Kinin B1 receptor</p><p>enhances the oxidative stress in a rat model of insulin resistance: outcome in</p><p>hypertension, allodynia and metabolic complications, PLoS One 5 (2010) 1–14,</p><p>https://doi.org/10.1371/journal.pone.0012622.</p><p>[148] J.P. Dias, M.A. Ismael, M. Pilon, J. De Champlain, B. Ferrari, P. Carayon,</p><p>R. Couture, The kinin B 1 receptor antagonist SSR240612 reverses tactile and cold</p><p>allodynia in an experimental rat model of insulin resistance, Br. J. Pharmacol. 152</p><p>(2007) 280–287, https://doi.org/10.1038/sj.bjp.0707388.</p><p>[149] M. Bujalska, J. Tatarkiewicz, S.W. Gumułka, Effect of bradykinin receptor</p><p>antagonists on vincristine- and streptozotocin-induced hyperalgesia in a rat model</p><p>of chemotherapy-induced and diabetic neuropathy, Pharmacology 81 (2008)</p><p>158–163, https://doi.org/10.1159/000110788.</p><p>[150] M. Bujalska, H. Makulska-Nowak, Bradykinin receptor antagonists and</p><p>cyclooxygenase inhibitors in vincristine-and streptozotocin-induced hyperalgesia,</p><p>Pharmacol. Rep. 61 (2009) 631–640, https://doi.org/10.1016/S1734-1140(09)</p><p>70115-X.</p><p>[151] D. Burke, B.M. Fullen, D. Stokes, O. Lennon, Neuropathic pain prevalence</p><p>following spinal cord injury: a systematic review and meta-analysis, Eur. J. Pain</p><p>21 (2017) 29–44, https://doi.org/10.1002/ejp.905.</p><p>[152] M.J. Teixeira, M.G.da S. da Paz, M.T. Bina, S.N. Santos, I. Raicher, R. Galhardoni,</p><p>D.T. Fernandes, L.T. Yeng, A.F. Baptista, D.C. de Andrade, Neuropathic pain after</p><p>brachial plexus avulsion - central and peripheral mechanisms, BMC Neurol. 15</p><p>(2015) 1–9, https://doi.org/10.1186/s12883-015-0329-x.</p><p>[153] M. Petcu, J.P. Dias, B. Ongali, G. Thibault, W. Neugebauer, R. Couture, Role of</p><p>kinin B1 and B2 receptors in a rat model of neuropathic pain, Int.</p><p>Immunopharmacol. 8 (2008) 188–196, https://doi.org/10.1016/j.</p><p>intimp.2007.09.009.</p><p>[154] V. Cernit, J. Sénécal, R. Othman, R. Couture, Reciprocal regulatory interaction</p><p>between TRPV1 and kinin B1 receptor in a rat neuropathic pain model, Int. J.</p><p>Mol. Sci. 21 (2020) 821, https://doi.org/10.3390/ijms21030821.</p><p>[155] J. Ferreira, G.L. Da Silva, J.B. Calixto, Contribution of vanilloid receptors to the</p><p>overt nociception induced by B 2 kinin receptor activation in mice, Br. J.</p><p>Pharmacol. 141 (2004) 787–794, https://doi.org/10.1038/sj.bjp.0705546.</p><p>[156] N.L.M. Quintão, G.F. Passos, R. Medeiros, A.F. Paszcuk, F.L. Motta, J.B. Pesquero,</p><p>M.M. Campos, J.B. Calixto, Neuropathic pain-like behavior after brachial plexus</p><p>avulsion in mice: the relevance of kinin B1 and B2 receptors, J. Neurosci. 28</p><p>(2008) 2856–2863, https://doi.org/10.1523/JNEUROSCI.4389-07.2008.</p><p>[157] N.L.M. Quintão, D. Balz, A.R.S. Santos, M.M. Campos, J.B. Calixto, Long-lasting</p><p>neuropathic pain induced by brachial plexus injury in mice: role triggered by the</p><p>pro-inflammatory cytokine, tumour necrosis factor α, Neuropharmacology 50</p><p>(2006) 614–620, https://doi.org/10.1016/j.neuropharm.2005.11.007.</p><p>[158] G. Cruccu, G. Di Stefano, A. Truini, Trigeminal neuralgia, N. Engl. J. Med. 383</p><p>(2020) 754–762, https://doi.org/10.1056/NEJMra1914484.</p><p>[159] G. Di Stefano, S. Maarbjerg, T. Nurmikko, A. Truini, G. Cruccu, Triggering</p><p>trigeminal neuralgia, Cephalalgia 38 (2018) 1049–1056, https://doi.org/</p><p>10.1177/0333102417721677.</p><p>[160] A.P. Luiz, S.D. Schroeder, J.G. Chichorro, J.B. Calixto, A.R. Zampronio, G.A. Rae,</p><p>Kinin B1 and B2 receptors contribute to orofacial heat hyperalgesia induced by</p><p>infraorbital nerve constriction injury in mice and rats, Neuropeptides 44 (2010)</p><p>87–92, https://doi.org/10.1016/j.npep.2009.10.005.</p><p>[161] J. Lai, M. Luo, Q. Chen, S. Ma, L.R. Gardell, M.H. Ossipov, F. Porreca, in:</p><p>Dynorphin A Activates Bradykinin Receptors to Maintain Neuropathic Pain 9,</p><p>2006, pp. 1534–1540, https://doi.org/10.1038/nn1804.</p><p>[162] J. Lai, M.Chyi Luo, Q. Chen, F. Porreca, Pronociceptive actions of dynorphin via</p><p>bradykinin receptors, Neurosci. Lett. 437 (2008) 175–179, https://doi.org/</p><p>10.1016/j.neulet.2008.03.088.</p><p>[163] M.I. Bennett, S. Kaasa, A. Barke, B. Korwisi, W. Rief, R.-D. Treede, The IASP</p><p>classification of chronic pain for ICD-11: chronic cancer-related pain, Pain 160</p><p>(2019) 38–44, https://doi.org/10.1097/j.pain.0000000000001363.</p><p>[164] S. Falk, A.H. Dickenson, Pain and nociception: mechanisms of cancer-induced</p><p>bone pain, J. Clin. Oncol. 32 (2014) 1647–1654, https://doi.org/10.1200/</p><p>JCO.2013.51.7219.</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>21</p><p>[165] M.A. Sevcik, J.R. Ghilardi, K.G. Halvorson, T.H. Lindsay, K. Kubota, P.W. Mantyh,</p><p>Analgesic efficacy of bradykinin B1 antagonists in a murine bone cancer pain</p><p>model, J. Pain 6 (2005) 771–775, https://doi.org/10.1016/j.jpain.2005.06.010.</p><p>[166] M. Fujita, T. Andoh, K. Ohashi, A. Akira, I. Saiki, Y. Kuraishi, Roles of kinin B1</p><p>and B2 receptors in skin cancer pain produced by orthotopic melanoma</p><p>inoculation in mice, Eur. J. Pain 14 (2010) 588–594, https://doi.org/10.1016/j.</p><p>ejpain.2009.10.010.</p><p>[167] L.A. Colvin, Chemotherapy-induced peripheral neuropathy: where are we now?</p><p>Pain 160 (2019) S1–S10, https://doi.org/10.1097/j.pain.0000000000001540.</p><p>[168] C.C. Reyes-Gibby, P.K. Morrow, A. Buzdar, S. Shete, Chemotherapy-induced</p><p>peripheral neuropathy as a predictor of neuropathic pain in breast cancer patients</p><p>previously treated with paclitaxel, J. Pain 10 (2009) 1146–1150, https://doi.org/</p><p>10.1016/j.jpain.2009.04.006.</p><p>[169] P.A. Ganz, L.A. Habel, E.K. Weltzien, B.J. Caan, S.W. Cole, Examining the</p><p>influence of beta blockers and ACE inhibitors on the risk for breast cancer</p><p>recurrence: results from the LACE cohort, Breast Cancer Res. Treat. 129 (2011)</p><p>549–556, https://doi.org/10.1007/s10549-011-1505-3.</p><p>[170] Y.K. Chae, E.N. Brown, X. Lei, A. Melhem-Bertrandt, S.H. Giordano, J.K. Litton, G.</p><p>N. Hortobagyi, A.M. Gonzalez-Angulo, M. Chavez-MacGregor, Use of ACE</p><p>inhibitors and angiotensin receptor blockers and primary breast cancer outcomes,</p><p>J. Cancer 4 (2013) 549–556, https://doi.org/10.7150/jca.6888.</p><p>[171] B. Amatya, J. Young, F. Khan, Non-pharmacological interventions for chronic</p><p>pain in multiple sclerosis, Cochrane Database Syst. Rev. (2018), https://doi.org/</p><p>10.1002/14651858.CD012622.pub2.</p><p>[172] A. Prat, K. Biernacki, T. Saroli, J.E. Orav, C.R.G. Guttmann, H.L. Weiner, S.</p><p>J. Khoury, J.P. Antel, Kinin B1 receptor expression on multiple sclerosis</p><p>mononuclear cells, Arch. Neurol. 62 (2005) 795, https://doi.org/10.1001/</p><p>archneur.62.5.795.</p><p>[173] R.C. Dutra, D.F.P. Leite, A.F. Bento, M.N. Manjavachi, E.S. Patrício, C.</p><p>P. Figueiredo, J.B. Pesquero, J.B. Calixto, The role of kinin receptors in preventing</p><p>neuroinflammation and its clinical severity during experimental autoimmune</p><p>encephalomyelitis in mice, PLoS One 6 (2011), e27875, https://doi.org/10.1371/</p><p>journal.pone.0027875.</p><p>[174] K. Göbel, C.-M. Asaridou, M. Merker, S. Eichler, A.M. Herrmann, E. Geuß, T. Ruck,</p><p>L. Schüngel, L. Groeneweg, V. Narayanan, T. Schneider-Hohendorf, C.C. Gross,</p><p>H. Wiendl, B.E. Kehrel, C. Kleinschnitz, S.G. Meuth, Plasma kallikrein modulates</p><p>immune cell trafficking during neuroinflammation</p><p>via PAR2 and bradykinin</p><p>release, Proc. Natl. Acad. Sci. 116 (2019) 271–276, https://doi.org/10.1073/</p><p>pnas.1810020116.</p><p>[175] C.J. Woolf, Capturing novel non-opioid pain targets, Biol. Psychiatry (2019) 1–8,</p><p>https://doi.org/10.1016/j.biopsych.2019.06.017.</p><p>[176] E.da S. Brum, G. Becker, M.F.P. Fialho, S.M. Oliveira, Animal models of</p><p>fibromyalgia: what is the best choice?, Pharmacol. Ther. 230 (2021) 107959, doi:</p><p>10.1016/j.pharmthera.2021.107959.</p><p>[177] E.H.S. Choy, The role of sleep in pain and fibromyalgia, Nat. Rev. Rheumatol. 11</p><p>(2015) 513–520, https://doi.org/10.1038/nrrheum.2015.56.</p><p>[178] D.J. Clauw, Fibromyalgia, JAMA 311 (2014) 1547, https://doi.org/10.1001/</p><p>jama.2014.3266.</p><p>[179] A.A. Larson, J.V. Pardo, J.D. Pasley, Review of overlap between thermoregulation</p><p>and pain modulation in fibromyalgia, Clin. J. Pain 30 (2014) 544–555, https://</p><p>doi.org/10.1097/AJP.0b013e3182a0e383.</p><p>[180] G. Littlejohn, E. Guymer, Neurogenic inflammation in fibromyalgia, Semin.</p><p>Immunopathol. 40 (2018) 291–300, https://doi.org/10.1007/s00281-018-0672-</p><p>2.</p><p>[181] V. Napadow, L. LaCount, K. Park, S. As-Sanie, D.J. Clauw, R.E. Harris, Intrinsic</p><p>brain connectivity in fibromyalgia is associated with chronic pain intensity,</p><p>Arthritis Rheum. 62 (2010) 2545–2555, https://doi.org/10.1002/art.27497.</p><p>[182] W. Häuser, S. Perrot, C. Sommer, Y. Shir, M.-A. Fitzcharles, Diagnostic</p><p>confounders of chronic widespread pain: not always fibromyalgia, PAIN Rep. 2</p><p>(2017) 598, https://doi.org/10.1097/PR9.0000000000000598.</p><p>[183] I. Brusco, A.B. Justino, C.R. Silva, S. Fischer, T.M. Cunha, R. Scussel, R.</p><p>A. Machado-de-Ávila, J. Ferreira, S.M. Oliveira, Kinins and their B1 and B2</p><p>receptors are involved in fibromyalgia-like pain symptoms in mice, Biochem.</p><p>Pharmacol. 168 (2019) 119–132, https://doi.org/10.1016/j.bcp.2019.06.023.</p><p>[184] F. Boix, C. Røe, L. Rosenborg, S. Knardahl, Kinin peptides in human trapezius</p><p>muscle during sustained isometric contraction and their relation to pain, J. Appl.</p><p>Physiol. 98 (2005) 534–540, https://doi.org/10.1152/japplphysiol.01340.2003.</p><p>I. Brusco et al.</p><p>(Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-</p><p>Pro7-Phe8, DABk) and des-Arg10-kallidin (Lys1-Arg2-Pro3-Pro4-Gly5-</p><p>Phe6-Ser7-Pro8-Phe9, DAKd), respectively [65,71]. Both DABk and DAKd</p><p>activate the B1R, while bradykinin and kallidin act through the activa-</p><p>tion of B2R [16,68]. Carboxypeptidase M also allosterically potentiates</p><p>the affinity between the B1R and its des-Arg-kinins agonists. In addition,</p><p>bradykinin or kallidin can bind to carboxypeptidase M, causing a</p><p>conformational change that is transmitted to the B1R on the plasma</p><p>membrane by protein-protein interaction, leading to this receptor acti-</p><p>vation [80–82] (Fig. 3a). In humans, the collective term “kinins” refers</p><p>to the polypeptides bradykinin, kallidin, and the two metabolites, DABk</p><p>and DAKd, which constitute the four biologically active kinins [15,65].</p><p>Kininase II, angiotensin I-converting enzyme (ACE), besides amino-</p><p>peptidase P and neutral endopeptidase (neprilysin), are metal-</p><p>lopeptidases that cleave kinins into inactive metabolites (Fig. 2) [65,75].</p><p>The ACE, for example, inactivates the bradykinin by removing the C-</p><p>terminal dipeptide Phe8-Arg9 (1-7) and cleaves the Phe5-Ser6 bond to</p><p>generate the second dipeptide Ser6-Pro7, transforming bradykinin into</p><p>its inactive final bradykinin (1-5) product [71,83]. ACE can also cleave</p><p>the kallidin and DABk leading to inactive fragments [15,42,75,84,85].</p><p>Interestingly, a recent study demonstrated that peptide fragments of</p><p>bradykinin (bradykinin (1-5) and (1-7)), firstly regarded as biologically</p><p>inert, presented biological activity not mediated by B1R or B2R [86].</p><p>The ACE links the kallikrein-kinin system and the renin-angiotensin</p><p>system since it inactivates the vasodilator bradykinin and activates</p><p>vasopressor angiotensin II (from angiotensin I) [63,87]. Thus, ACE in-</p><p>hibitors are commonly used to treat hypertension [88] and cardiovas-</p><p>cular and renal alterations [15]. Since ACE inhibitors prevent the</p><p>degradation of bradykinin by ACE, they can increase the levels of this</p><p>peptide [80,83] besides increasing the signalling of kinin receptors [83].</p><p>In ACE, the canonical sequence (HEXXH) containing zinc-binding resi-</p><p>dues in the active sites of the N and C domains is essential for inhibitor</p><p>binding [89]. Notably, the second extracellular loop of the human B1R</p><p>has the same consensus sequence (HEAWH) required for ACE inhibitors</p><p>to activate the B1R. Thus, some ACE inhibitors can directly activate the</p><p>B1R, even without ACE expression, acting as direct allosteric agonists of</p><p>this receptor (Fig. 3b) [83,90].</p><p>ACE inhibitors can also act as indirect allosteric potentiators of kinins</p><p>activity at the B2R by interactions with ACE. ACE inhibitors bind to the</p><p>enzyme, causing a conformational change, which is then transmitted to</p><p>the B2R via heterodimerization of ACE with the cell surface receptor,</p><p>where both are co-localized [83,91]. ACE inhibitors also resensitise</p><p>kinin receptors and reduce their internalization. In this sense, ACE in-</p><p>hibitor drugs have been associated with an increased risk of developing</p><p>pain conditions [92–94], although there are controversial data [95]</p><p>(Fig. 3b).</p><p>Fig. 1. Timeline on main dates relating to the discovery of the kallikrein-kinin system. Kinin B1 receptor (B1R); kinin B2 receptor (B2R).</p><p>Parts of the figure were drawn using pictures from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 unported license.</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>4</p><p>Both physiological and pathological processes triggered by kinins</p><p>occur via the B1R and B2R [15,16]. Signals mediated by the B2R are</p><p>generally more transient, whereas the stimulation of B1R causes pro-</p><p>longed responses [96]. Kinin receptors are members of a superfamily of</p><p>Gq-type G protein-coupled membrane receptors with seven trans-</p><p>membrane domains, an extracellular N-terminal, and an intracellular C-</p><p>terminal portion [97,98]. The stimulation of these receptors triggers the</p><p>activation of multiple signalling pathways through second messengers,</p><p>especially the phospholipase C (PLC) pathway, with consequent for-</p><p>mation of inositol triphosphate-3 (IP3) and diacylglycerol (DAG),</p><p>intracellular calcium mobilization, and activation of protein kinase C</p><p>(PKC) [16,99]. When stimulated, kinin receptors can also activate</p><p>calcium-sensitive potassium channels, adenylate cyclase, phospholipase</p><p>A2, nitric oxide synthase (NOS), NF-κB, and several protein kinases. In</p><p>addition, they promote the release of prostaglandins, arachidonic acid,</p><p>interleukins, and the production of endothelium-derived relaxing fac-</p><p>tors, including nitric oxide (NO), which in turn increases vascular</p><p>permeability and cause vasodilation (Fig. 2) [15,16,66,96,100].</p><p>The B2R is constitutively expressed on the cell surface of various</p><p>tissues mediating physiological actions of kinins in nociception and in-</p><p>flammatory response. It has been identified in the gastrointestinal,</p><p>cardiovascular, respiratory, genitourinary, peripheral (PNS) and central</p><p>(CNS) nervous systems [75]. This receptor exhibits a high affinity for</p><p>bradykinin and kallidin [68]. On the other hand, the B1R has a greater</p><p>Fig. 2. Kallikrein-kinin system. The conversion of factor XII to factor XIIa mediates the activation of pre-kallikrein to plasm kallikrein, while pro-kallikrein is</p><p>converted in tissue kallikrein by proteolytic cleavage initiating the production of kinins. Kininogens are the precursors of kinins and consist of two isoforms: high</p><p>molecular weight kininogen (6 domains, D1-D6) and low molecular weight kininogen (5 domains, D1-D5). The domains are formed by heavy and light chains linked</p><p>by a domain that includes the bradykinin or kallidin (lys-bradykinin) sequence (D4). Plasma kallikrein acts on high molecular weight kininogen forming bradykinin,</p><p>while tissue kallikrein acts on low molecular weight kininogen forming kallidin. After cleavage of high and low molecular weight kininogen by plasma and tissue</p><p>kallikrein, bradykinin and kallidin are released, respectively. Bradykinin and kallidin can be converted to inactive peptides by kininases II [angiotensin I-converting</p><p>enzyme (ACE)]. On the other hand, kininases I [carboxypeptidases M and N (CPM and CPN)] convert bradykinin and kallidin into active metabolites des-Arg9-</p><p>bradykinin (DABk) and des-Arg10-kallidin (DAKd), respectively. Kallidin can also be converted to bradykinin through aminopeptidases. Bradykinin and kallidin exert</p><p>their effects by activating the kinin B2 receptor (B2R), while their active metabolites (DABk and DAKd) activate the kinin B1 receptor (B1R). B1R and B2R are coupled</p><p>to Gq protein, and their activation involves the phospholipase C (PLC) pathway, with consequent formation of inositol 1,4,5-triphosphate (IP3) and diacylglycerol</p><p>(DAG), which are responsible for calcium mobilization (Ca2+) and by translocation of protein kinase C (PKC), respectively. Ca2+ mediates the activation of nitric</p><p>oxide synthase (NOS), the production of NO and the stimulation of phospholipase A2 (PLA2) with consequent release of arachidonic acid (AA) and production of</p><p>prostaglandins (PG). Endoplasmic reticulum (ER); Mitogen-activated protein kinase (MAPK).</p><p>Adapted from Kashuba et al. [65]. Parts of the figure were drawn using pictures from Servier Medical Art by Servier, licensed under a Creative Commons Attribution</p><p>3.0 unported license.</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>5</p><p>affinity for the active metabolites of kinins, DABk and DAKd</p><p>[16,100,101]. The B1R also appears to interact with the carboxypepti-</p><p>dase M, leading to intracellular signalling of the receptor, as mentioned</p><p>above [82]. It is usually absent or under-expressed on physiological</p><p>conditions but can be up-regulated in acute or persistent inflammatory</p><p>and nociceptive processes [16,100,101]. Cytokines can regulate the</p><p>expression of the B1R gene via mitogen-activated kinase protein (MAPK)</p><p>and transcription factors, such as NF-κB [75]. There is evidence that the</p><p>B1R can be expressed constitutively in small and medium-diameter</p><p>neurons and peptidergic and non-peptidergic C fibres [102,103]. In</p><p>addition, non-neuronal constitutive expression includes cells of the im-</p><p>mune system (macrophages, fibroblasts, neutrophils) and endothelial</p><p>cells [104,105].</p><p>Physiologically, the kinins’ action on endothelial cells leads to classic</p><p>symptoms of inflammation, vascular response, and pain in injured tissue</p><p>[15,16]. Pathologically, activation of kinin receptors triggers sponta-</p><p>neous nociception, allodynia, and mechanical and thermal hyperalgesia</p><p>[30,106,107] in humans and experimental animals [101]. Thus, kinins</p><p>are involved in acute and chronic painful conditions</p><p>[21,30,100,107,108]. The effects of kinins can be direct or indirect,</p><p>associated with secondary mediators, including prostanoids, tachyki-</p><p>nins, cytokines, products derived from mast cells, and NO [109,110].</p><p>Additionally, B1R and B2R are expressed in important structures for pain</p><p>modulation in the PNS and CNS, such as nociceptors, dorsal root ganglia</p><p>(DRG), neurons, sciatic nerve, spinal cord, thalamus, cerebral cortex,</p><p>hypothalamus, satellite cells, sympathetic ganglia, glial cells (astrocyte</p><p>and microglia) [15,21,29,30,63,101,102,111–113]. Bradykinin is also</p><p>released in the spinal cord in response to nociceptor inputs and acts as a</p><p>neuromodulator in postsynaptic B2R, potentiating glutamatergic syn-</p><p>aptic transmission to produce pain hypersensitivity [114,115]. Together</p><p>these data show the ability of kinins to cause pain directly [15].</p><p>Therefore, B1R and B2R antagonists may be helpful in the treatment</p><p>of acute and persistent pain conditions. This hypothesis has been</p><p>explored in several preclinical studies, and it is interesting since the</p><p>kallikrein-kinin system is targeted in some clinical studies. In addition to</p><p>Icatibant, a B2R antagonist, the Food and Drug Administration has</p><p>approved using two monoclonal antibodies that inhibit plasma kalli-</p><p>krein, the Lanadelumab for prevention and the Ecallantide for acute</p><p>attacks in patients with hereditary angioedema. Inhibitors of C1 (a</p><p>subunit of the complement cascade), which inhibit plasma kallikrein,</p><p>coagulation factors, and complement pathway, also have approved</p><p>indications for hereditary angioedema [116]. Although these kallikrein</p><p>inhibitors are being clinically tested for conditions such as COVID-19,</p><p>prostate cancer, hereditary autoinflammatory disease, lung injury, and</p><p>others (http://www.clinicaltrials.gov), there are no clinical studies on</p><p>their role in pain control.</p><p>A clinical study of Phase II evaluated the intra-articular doses effect</p><p>of Icatibant on painful knee osteoarthritis, but unfortunately, results are</p><p>not available (NCT00303056, completed). In two Phase II studies, the</p><p>intra-articular administration of MEN16132 (Fasitibant), a B2R antag-</p><p>onist, was also investigated in knee pain in osteoarthritis (NCT01091116</p><p>and NCT02205814), and although treated patients used less rescue</p><p>medication, there was no direct evidence of its efficacy. The MK-0686, a</p><p>B1R antagonist, was investigated in Phase II to treat the postherpetic</p><p>neuralgia (halted development and undisclosed results), postoperative</p><p>dental pain, and osteoarthritis (NCT00533403 and NCT00296569, both</p><p>completed, but unpublished results). BI-113823, a B1R antagonist, was</p><p>tested in Phase I for osteoarthritis (NCT01207973, terminated, but re-</p><p>sults are unavailable). Finally, SSR-240612, a B1R antagonist, seems to</p><p>have been investigated in Phase II for inflammation and neuropathic</p><p>pain, but the study was halted for undisclosed reasons (http://www.</p><p>clinicaltrials.gov), [42].</p><p>The discontinuation of these studies may be associated with adverse</p><p>effects, lack of efficacy, possibly associated with animal models not</p><p>translated well to human disease, or methodological flaws. Notably,</p><p>Icatibant causes only discomfort at the injection site as a common</p><p>adverse effect, while kallikrein inhibitors are commonly related to</p><p>prolonged partial thromboplastin time, mild injection-site reaction, and</p><p>dizziness [116]. In this sense, Icatibant seems to be a promising alter-</p><p>native to pain control, although more clinical studies are still needed.</p><p>Given the physiological roles of the B2R, its prolonged blockade may</p><p>produce possible adverse effects [117]. Thus, a dosage adjustment and</p><p>treatment duration may be required when B2R antagonists are tested to</p><p>ensure their clinical applicability. Moreover, the inducible expression of</p><p>B1R suggests that its inhibition would interfere less with the physio-</p><p>logical functions of healthy individuals [117]. Therefore, studies using</p><p>B1R antagonists to treat painful pathological conditions continue to be</p><p>encouraged.</p><p>Fig. 3. Interaction between kinins and their receptors with kininase I (CPM) and kininase II (ACE). (a) Three ways carboxypeptidase M (CPM) interacts with the kinin</p><p>B1 receptor (B1R). 1) Carboxypeptidase M allosterically potentiates the affinity of the B1R for its agonists, the des-Arg-kinins. 2) Binding of the CPM substrate</p><p>(bradykinin) to the enzyme’s active site causes a conformational change in the enzyme, which is transmitted via protein-protein interaction to the B1R, resulting in</p><p>the coupling of the G protein (Gq) and receptor activation. 3) The cleavage of C-terminal residues of bradykinin by CPM generates B1R agonists (des-Arg-kinins) that</p><p>can further activate the associated B1R or additional B1R. (b) Potentiation of B1R and kinin B2 receptor (B2R) signalling by angiotensin I-converting enzyme (ACE)</p><p>inhibitors. 1) ACE inhibitors are indirect allosteric potentiators of kinins activity at the B2R through interactions with ACE (C domain) since both are co-located in the</p><p>membrane. 2) ACE inhibitors prevent the degradation of bradykinin which is an agonist of the B2R and serves as a substrate for kininase I to form the B1R agonists,</p><p>the des-Arg-kinins. 3) ACE inhibitors are direct allosteric agonists of the B1R at a site that differs from the agonist binding site, the des-Arg-kinins. In ACE, the</p><p>sequence HEXXH containing zinc-binding residues in the active sites of the N and C domain is essential for inhibitor binding. The second extracellular loop of the B1R</p><p>has the same consensus sequence (HEAWH) required for ACE inhibitors to activate the B1R.</p><p>Adapted from Erdös et al. [83] and Zhang et al. [80]. Parts of the figure were drawn using pictures from Servier Medical Art by Servier, licensed under a Creative</p><p>Commons Attribution 3.0 unported license.</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>6</p><p>4. Kinins and their B1 and B2 receptors as potential therapeutic</p><p>targets for pain relief of different aetiologies</p><p>In the present review, we performed an extensive literature search</p><p>since 2004 on the involvement of kinins and their receptors in pain</p><p>disorders. We emphasized their participation in several painful condi-</p><p>tions, such as arthritis, cancer, multiple sclerosis, fibromyalgia,</p><p>antineoplastic toxicity, diabetes, among others. All evidence from pre-</p><p>clinical studies indicates that antagonists of B1R and B2R have a relevant</p><p>therapeutic potential for treating pathological pains such as chronic</p><p>inflammatory, neuropathic, and nociplastic (Fig. 4). Considering that</p><p>the B2R antagonist, Icatibant, is clinically used for treating hereditary</p><p>angioedema</p><p>and is well tolerated by patients, this antagonist could be</p><p>interesting for treating these pathological pains, which are difficult to</p><p>Fig. 4. Kinins and their B1 (B1R) and B2 (B2R) receptors are targets to alleviate inflammatory (a), neuropathic (b), and nociplastic (c). Kinin levels and the B1R and</p><p>B2R expression are increased in peripheral and central regions involved in pain modulation in different inflammatory, neuropathic and nociplastic pain models. On</p><p>the other hand, B1R and B2R antagonists or knockout mice, as well as kininase I and kallikrein inhibitors, reduce pain symptoms associated with these models.</p><p>Freund’s complete adjuvant (CFA); Phorbol myristate acetate (PMA); Ultraviolet B (UVB).</p><p>Adapted Parts of the figure were drawn using pictures from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 unported license.</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>7</p><p>treat and clinically available analgesic drugs generally have low efficacy</p><p>and may cause adverse effects.</p><p>4.1. Inflammatory pain</p><p>The inflammation is characterized by five cardinal signs: redness,</p><p>increased heat, swelling, pain, and loss of function. Acute inflammation</p><p>has a protective role and involves immune cells, blood vessels, inflam-</p><p>matory and specialized pro-resolution mediators, aiming to eliminate</p><p>the initial cause of cell injury and initiate tissue repair. Acute pain is a</p><p>cardinal feature that occurs when inflammatory mediators bind to their</p><p>receptors on primary sensory neurons that innervate injured skin,</p><p>muscle, and joint tissues [118]. In contrast to acute inflammation,</p><p>chronic inflammation does not play an active role in wound healing and</p><p>is often detrimental, contributing to diseases like osteoarthritis and</p><p>rheumatoid arthritis. While acute inflammation is essential for acute</p><p>pain, it is unclear whether chronic inflammation also is critical for</p><p>driving chronic pain [6,118]. However, it is known that pro-</p><p>inflammatory mediators modulate pain sensitivity through nociceptors</p><p>activation, leading to the development of peripheral and central sensi-</p><p>tization and induction of chronic pain conditions. Moreover, peripheral</p><p>sensitization in nociceptors is essential for developing chronic pain and</p><p>transitioning from acute to chronic pain [6,118–120].</p><p>Current treatments for chronic inflammatory pain are insufficient</p><p>and cause severe adverse effects. Thus, deepening the understanding of</p><p>the mechanisms of this pain and stimulating the search for new therapies</p><p>are urgently needed. Notably, kinins contribute to inflammatory pain</p><p>conditions such as tibial fracture-induced pain, chronic post-ischaemic</p><p>pain syndrome (CRPSI and CRPS), and arthritic pain [17–23] (Fig. 4a).</p><p>4.1.1. Arthritic pain</p><p>Among inflammatory pains, kinins involvement is more well-</p><p>founded in arthritic pain. Osteoarthritis, for example, is a common</p><p>chronic joint disorder characterized by local inflammation and joint</p><p>structural change. It is accompanied by painful symptoms and loss of</p><p>function leading to considerable impairment of patients’ life quality,</p><p>associated with problematic clinical management [121,122]. Topical</p><p>NSAIDs are used as first-line treatments for osteoarthritis, while oral</p><p>NSAIDs and intra-articular injections treat persistent pain. Further, oral</p><p>NSAIDs should be controlled due to their known cardiovascular, hepatic,</p><p>and renal adverse effects [122].</p><p>Rheumatoid arthritis is a systemic autoimmune disease that involves</p><p>chronic inflammation of the synovial membrane, which can destroy</p><p>articular cartilage and juxta-articular bone, with a worldwide preva-</p><p>lence of about 5 per 1000 adults. Its cause is unknown, although genetic</p><p>and environmental factors are involved. Rheumatoid arthritis can lead</p><p>to disability, inability to work, and increased mortality [123]. Some</p><p>treatment strategies are available, such as synthetic disease-modifying</p><p>antirheumatic drugs, methotrexate, leflunomide, sulfasalazine, and</p><p>short-term glucocorticoids, administered alone or combined. However,</p><p>disease-modifying antirheumatic drugs can have insufficient efficacy or</p><p>cause adverse effects in up to 50 % of patients. Methotrexate and glu-</p><p>cocorticoids also cause adverse effects that limit their use. Moreover,</p><p>about 20–30 % of patients are refractory to all current treatment options</p><p>[124]. Thus, the development of new therapies is still necessary.</p><p>In 1997, Bond et al. [125] showed for the first time that synovial</p><p>fluid from rheumatoid arthritis and osteoarthritis patients has the</p><p>necessary machinery to produce kinins. A few years later, Cassim et al.</p><p>[108] investigated the participation of kallikreins, kininogens, and kinin</p><p>receptors in circulating and synovial fluid neutrophils of rheumatoid</p><p>arthritis patients. There was a decrease in fluorescence immunolabelling</p><p>of tissue kallikrein in circulating and synovial fluid neutrophils from</p><p>rheumatoid arthritis patients compared with circulating neutrophils</p><p>from healthy volunteers. These findings suggested that neutrophils were</p><p>activated in synovial fluid, releasing the kallikrein by secretion or</p><p>degranulation. Similarly, there was a decrease in the immunolabelling of</p><p>kininogen (loss of the kinin moiety) in this same group compared with</p><p>circulating neutrophils from healthy volunteers, indicating consumption</p><p>of substrate for forming and releasing kinins. Immunolabelling of B1R</p><p>and B2R on circulating and synovial fluid neutrophils was increased in</p><p>rheumatoid arthritis patients compared with healthy volunteers. More-</p><p>over, the synovial fluid of rheumatoid arthritis patients generated large</p><p>amounts of kinins that correlated significantly with measures of disease</p><p>activity (swollen joint count). Possibly, generated kinins in the synovial</p><p>fluid from rheumatoid arthritis patients have many pathophysiological</p><p>effects that enhance and perpetuate rheumatic joint inflammation. The</p><p>results presented by Cassim et al. [108] suggest the involvement of the</p><p>kallikrein-kinin cascade proteins in the pathophysiology of rheumatoid</p><p>arthritis, supporting the potential clinical application of kallikrein in-</p><p>hibitors and kinin receptor antagonists as therapies for inflamed joints.</p><p>In this same year, Cialdai et al. [19] investigated the participation of</p><p>bradykinin in knee joint osteoarthritis induced by intra-articular</p><p>administration of monosodium iodoacetate in rats. The amount of bra-</p><p>dykinin in synovial fluid of monosodium iodoacetate-treated rats was</p><p>higher than the control group and relatively constant up to 21 days from</p><p>monosodium iodoacetate treatment. In this osteoarthritis model, Icati-</p><p>bant and MEN16132, B2R antagonists, alleviated the animals’ pain.</p><p>MEN16132 reduced the animals’ incapacitation produced by intra-</p><p>articular monosodium iodoacetate with inhibition of pain around 50</p><p>%, and its analgesic effect was more potent and longer-lasting than</p><p>Icatibant [19,126]. Thus, these results appoint an essential role for</p><p>bradykinin in osteoarthritic pain.</p><p>An interaction between the kinins and the proteinase-activated re-</p><p>ceptor-4 (PAR4) was found in the knee joint. The PAR4 activation</p><p>increased joint afferent firing during non-noxious and noxious rotation</p><p>of the knee, and PAR4 and B2R antagonists inhibited this effect. PAR4-</p><p>induced sensitization was associated with B2R activation, suggesting</p><p>the involvement of kinins in this process [127]. Notably, Kawabata et al.</p><p>[128] showed a role of PAR2 in visceral hypersensitivity and suggested</p><p>the involvement of the bradykinin-B2R pathway in this process.</p><p>In an experimental osteoarthritis model induced by transection of the</p><p>right anterior cruciate ligament in rats, the local treatment with antag-</p><p>onists of endothelin receptor type A and B1R was able to slow</p><p>or stabilize</p><p>the development of radiomorphological and histomorphological alter-</p><p>ations that occur in osteoarthritis pathogenesis. B1R antagonist dimin-</p><p>ished hind limb nociception and accelerated postoperative recovery in</p><p>this osteoarthritis model [129]. Additionally, mice submitted to partial</p><p>meniscectomy or surgical destabilization of the medial meniscus</p><p>developed pain-related behaviour in mechanical and cold sensitivity</p><p>tests, analgesiometry, incapacitance, and forced flexion tests. B1R and</p><p>B2R genes and others were upregulated in joint tissues of mice dis-</p><p>playing pain-related behaviour, especially in articular cartilage. The</p><p>results of this study reinforce the involvement of B1R and B2R in</p><p>damaged joint tissues [20].</p><p>In 2016, Silva et al. [21] elegantly demonstrated the participation of</p><p>the B1R in an acute gout model induced by monosodium urate crystals</p><p>intra-articular injection in rodents’ right ankle joint. They observed an</p><p>increase in B1R expression, DABk content (B1R agonist), and kininase I</p><p>activity (enzyme forming of B1R agonist) in the joint region in this</p><p>model. Furthermore, the B1R antagonism or genetic deletion reduced all</p><p>painful (overt pain-like behaviour and touch allodynia) and inflamma-</p><p>tory (oedema ankle joint, IL1β levels, myeloperoxidase activity, total</p><p>leukocyte number, and leukocyte rolling and adherence) signs of gouty</p><p>arthritis. The kininase I inhibitor intra-articular administration, Mer-</p><p>gepta, reduced the touch allodynia, overt pain-like behaviours, and</p><p>oedema induced by monosodium urate intra-articular injections.</p><p>In a comparative study in humans, Choi et al. [130] indicated that</p><p>ACE inhibitors are associated with an increased risk of gout. In this</p><p>sense, Silva et al. [21] investigated if ACE inhibitors could facilitate</p><p>acute gouty attacks in mice. The ACE inhibitor enalapril reduced the</p><p>ACE activity in the articular tissue of animals after an intra-articular</p><p>injection of low-dose monosodium urate. Enalapril also enhanced the</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>8</p><p>touch allodynia, overt pain-like behaviours, and oedema in this model.</p><p>Both kininase I inhibitor and the B1R antagonist reduced the enhance-</p><p>ment induced by enalapril. Furthermore, enalapril increased the kini-</p><p>nase I activity and DABk content. Altogether, these results demonstrate</p><p>the critical role of the B1R in acute gouty attacks and also provide an</p><p>essential warning to physicians and patients about the use of ACE in-</p><p>hibitors by hypertensive patients with gouty arthritis.</p><p>4.1.2. Post-fracture pain and postsurgical pain</p><p>B1R and B2R antagonists appear as potential therapeutic targets to</p><p>alleviate post-fracture pain [22], which is associated with an inflam-</p><p>matory process leading to intense pain. Tibial fracture of wild-type mice</p><p>increased the B1R and B2R mRNA and protein levels at the fracture site.</p><p>Similarly, the tibial fracture also increased the c-Fos expression in the</p><p>superficial layers in the ipsilateral L3–L5 dorsal horn of the spinal cord</p><p>in wild-type but not in B2R knockout mice. The tibial fracture caused</p><p>prolonged mechanical and thermal hyperalgesia and subjective pain</p><p>without causing locomotor alterations. These painful symptoms were</p><p>attenuated in B1R and B2R knockout mice and by B1R (SSR 240612 and</p><p>R954) and B2R (Icatibant) antagonists. Ketoprofen, a dual cyclo-</p><p>oxygenase 1 and 2 (COX) inhibitor, also presented an analgesic effect</p><p>after tibial fracture, which was abolished in B1R and B2R knockout mice.</p><p>Thus, B1R and B2R activation contribute to tibial fracture-induced pain</p><p>through a downstream COX-1/COX-2 mechanism [22].</p><p>In contrast to post-fracture pain, B1R and B2R did not seem involved</p><p>in the inflammatory pain induced by plantar incision in rats since pep-</p><p>tide B1R (des-Arg9[Leu8]-bradykinin — DALBk) and B2R (Icatibant)</p><p>antagonists did not reduce the mechanical or thermal hypersensitivity</p><p>after the surgical procedure. Despite postsurgical pain being a common</p><p>type of inflammatory pain, the etiology and role of inflammation seem</p><p>different than in other models, suggesting that there may be unique</p><p>inflammatory mechanisms in postsurgical pain [18].</p><p>The findings of Minville and colleagues [22] in post-fracture pain</p><p>seem to be more robust than those found in postsurgical pain since they:</p><p>used knockout B1R and B2R animals; evaluated the mRNA and protein of</p><p>B1R and B2R; investigated the c-Fos expression and tissue alterations in</p><p>knockout mice by immunohistochemistry and histology, respectively;</p><p>and evaluated the effect of peptide and non-peptide kinin receptor an-</p><p>tagonists treatment. In contrast, the studies of Leonard and colleagues</p><p>[18] in postsurgical pain were limited only to the use of peptide kinin</p><p>receptor antagonists whose post-treatment was performed at 2 h or 2</p><p>days after the surgical incision; and pre-treatment occurred 1 h before</p><p>the incision, but the behavioural tests in 2 h after incision, i.e., 3 h after</p><p>treatment on day 1. The peptidic nature of these antagonists usually</p><p>makes them more effective in the first 2 h after their administration.</p><p>Thus, the use of non-peptide kinin receptor antagonists, knockout ani-</p><p>mals, and kinin receptors expression could better confirm the role of</p><p>kinins in the postsurgical pain model. Moreover, differences between</p><p>these studies may also be related to the chosen model, which one con-</p><p>sisted of a closed tibial fracture model [22], while the other exposed the</p><p>plantar skin and fascia by surgical incision [18].</p><p>4.1.3. Chronic post-ischaemic pain</p><p>B1R and B2R also seem involved in chronic post-ischaemic pain, a</p><p>syndrome CRPS type-I model. Mice submitted to an ischaemia-</p><p>reperfusion process developed mechanical and cold allodynia and paw</p><p>oedema. Systemic, local, and spinal administration of B1R (DALBk) and</p><p>B2R (Icatibant) antagonists reduced the mechanical allodynia and paw</p><p>oedema, but not cold allodynia. In contrast, B1R (DABk) and B2R (Tyr-</p><p>bradykinin) agonists enhanced the mechanical and cold allodynia after</p><p>ischaemia-reperfusion. The anti-allodynic effect of DALBk and Icatibant</p><p>was reversed by ACE inhibitor captopril. The genetic inhibition with</p><p>antisense oligonucleotides targeting B1R and B2R also attenuated the</p><p>mechanical allodynia caused by ischaemia-reperfusion. Thus, B1R and</p><p>B2R seem promising pharmacological targets for treating CRPS type-I</p><p>[23].</p><p>4.1.4. Ultraviolet B radiation-induced pain</p><p>A clinical study demonstrated that B1R (DAKd) and B2R (bradykinin)</p><p>agonists dose-dependently evoked pain, vasodilatation, and protein</p><p>extravasation in normal human skin. Additionally, the pain sensation</p><p>and axon reflex in the human skin submitted to ultraviolet B (UVB) ra-</p><p>diation was enhanced by B1R and B2R agonists, whereas local vasodi-</p><p>latation was increased only following B1R activation. On the other hand,</p><p>UVB radiation did not enhance B1R and B2R agonists-induced protein</p><p>extravasation. Thus, these results demonstrate a differential sensitiza-</p><p>tion of neuronal and vascular B1R and B2R in UVB-irradiated human skin</p><p>[17]. Neuronal B1R and B2R seem to contribute to the pain symptoms</p><p>caused by UVB radiation. In contrast, only the vascular B1R was</p><p>involved in local vasodilation in this model, suggesting a possible</p><p>upregulation of vascular B1R in the pathological radiation process. This</p><p>hypothesis would need to be confirmed by evaluating B1R expression in</p><p>endothelial cells.</p><p>4.1.5. Other inflammatory pain models</p><p>Kinin receptors are also involved in pain signalling pathways in</p><p>response to tissue damage and inflammation in other inflammatory pain</p><p>models. The NVP-SAA164, a non-peptide B1R antagonist with a high</p><p>affinity for the human B1R, presented an antinociceptive effect in an</p><p>inflammatory pain model induced by intraplantar</p><p>Freund’s complete</p><p>adjuvant (CFA) injection. CFA caused similar mechanical hyperalgesia</p><p>in wild-type and transgenic mice in which the native B1R was deleted,</p><p>and the gene encoding the human B1R was inserted (hB1 knockin). On</p><p>the other hand, mechanical hyperalgesia was reduced in B1R knockout</p><p>mice compared to wild-type mice. Furthermore, the B1R agonist DAKd</p><p>injected into the contralateral paw at 24 h following CFA injection</p><p>caused mechanical hyperalgesia that was similar in wild-type and hB1-</p><p>knockin mice but was absent in B1R knockout mice. NVP-SAA164</p><p>reversed the CFA- or DAKd-induced mechanical hyperalgesia in hB1-</p><p>knockin mice but not in wild-type mice, supporting its utility in treating</p><p>inflammatory pain in a clinical setting [34].</p><p>Later, another study demonstrated that the intraplantar CFA</p><p>increased the B1R mRNA expression in the skin tissue, DRG, and spinal</p><p>cord at 24 h after its injection into the rat’s right hind paw and caused</p><p>mechanical hyperalgesia. BI113823, a B1R antagonist, reduced the CFA-</p><p>induced mechanical hyperalgesia when administered orally or intra-</p><p>thecally. BI113823 also reduced the mechanosensitive (firing rate) of</p><p>peripheral afferents and spinal nociceptive-specific neurons but did not</p><p>affect wide dynamic range neurons [39].</p><p>Kinins and their receptors also contribute to inflammatory pain</p><p>caused by intraplantar carrageenan administration. A B1R antagonist,</p><p>the benzamide ELN441958, presented higher selectivity for primates</p><p>over rodent B1R (human > rhesus monkey > rat > mouse) in an in vitro</p><p>assay. ELN441958 showed good permeability and metabolic stability in</p><p>vitro, consistent with high oral exposure and moderate plasma half-lives</p><p>in rats and rhesus monkeys. ELN441958 dose-dependently reduced the</p><p>thermal hyperalgesia elicited by carrageenan injected into the monkey’s</p><p>tail. Thus, ELN441958 could be a promising molecule in treating in-</p><p>flammatory pain because it exhibits high oral bioavailability and potent</p><p>systemic efficacy in inflammatory pain induced in rhesus monkeys</p><p>[131]. Additionally, LF22-0542, a B1R antagonist, alleviated thermal</p><p>hypersensitivity in both acute (carrageenan) and persistent (CFA) in-</p><p>flammatory pain models in rats [35].</p><p>In another carrageenan-induced inflammatory pain model, the</p><p>sufentanil infusion, a μ-opioid receptor agonist, in mice previously</p><p>treated with intraplantar carrageenan, caused sustained tactile and</p><p>thermal hypersensitivities, characterizing the development of opioid-</p><p>induced hyperalgesia. This hypersensitivity caused by sufentanil was</p><p>blunted in B2R knockout mice. Aprotinin, a protease inhibitor that in-</p><p>hibits the production of bradykinin, and the B2R (Icatibant) but not B1R</p><p>(R954) antagonist attenuated the tactile and thermal hypersensitivities</p><p>caused by sufentanil. B2R seems involved in developing opioid-induced</p><p>hyperalgesia during inflammatory pain in mice. Thus, the authors</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>9</p><p>suggested that B2R could be a promissory pharmacological target to</p><p>prevent opioid-induced hyperalgesia in painful inflammatory condi-</p><p>tions, such as postoperative pain [132]. However, as mentioned above,</p><p>the role of kinins in postoperative pain needs to be further explored in</p><p>the expression and genetic manipulation of receptors, although peptide</p><p>B1R and B2R antagonists did not reduce pain behaviours in a plantar</p><p>incision model [18].</p><p>Studies also showed that the inhibition of the B1R might be a phar-</p><p>macological tool for treating pain and depression symptoms in women</p><p>during the perimenopause/menopause period. The authors found that</p><p>the ovariectomized mice developed time-related mechanical allodynia</p><p>and depressive-like behaviours. Both of these changes were reduced by</p><p>the genetic deletion or antagonism of B1R, but not B2R [133]. The</p><p>decreasing ovarian hormones seem to increase the B1R activity, upre-</p><p>gulated in pathological conditions, via oxidative stress and pro-</p><p>inflammatory cytokines in peripheral and central structures related to</p><p>pain and depression. However, more investigations are needed on the</p><p>direct role of ovarian hormones on the kinin-kallikrein system [133].</p><p>The B1R stimulation also contributes to acute inflammatory pain</p><p>through PKC activation in peripheral tissues. In this study, the intra-</p><p>plantar injection of phorbol myristate acetate (PMA), a PKC activator,</p><p>caused a spontaneous nociceptive behaviour that was abolished by a B1R</p><p>genetic deletion or antagonism (DALBk). The intraplantar DABk injec-</p><p>tion, a B1R agonist, enhanced the nociceptive response caused by a PMA</p><p>sub-nociceptive dose without causing nociception in naive mice. DALBk</p><p>alleviated this enhancement. Furthermore, selective PKC or protein</p><p>synthesis inhibitors attenuated the DABk-induced nociceptive behav-</p><p>iour. Intraplantar PMA also increased the B1R protein levels in the mice</p><p>paw [100].</p><p>In 2010, Liu et al. [134] demonstrated that bradykinin-induced acute</p><p>nociceptive signals in small nociceptive neurons from rat DRG were</p><p>mediated by inhibition of M-type K+ channels and activation of Ca2+-</p><p>activated Cl− channels. This study suggested that PLC was activated, and</p><p>PIP2 was hydrolysed downstream of bradykinin stimulation in DRG</p><p>neurons. Bradykinin also produced Ca2+ signals and inhibited M cur-</p><p>rents in small nociceptive DRG neurons. Pre-treatment of neurons with a</p><p>B2R antagonist (Icatibant) or a PLC inhibitor (edelfosine) abolished M</p><p>current inhibition. In contrast, the disruption of intracellular Ca2+</p><p>reduced this inhibition, suggesting that bradykinin-induced M current</p><p>inhibition depends on the PLC- and IP3-mediated intracellular Ca2+</p><p>rises. Bradykinin-induced inhibition of M current was accompanied by</p><p>the simultaneous activation of an inward current conducted by Ca2+-</p><p>activated Cl− channels from the PLC/IP3/Ca2+ pathway, which can ac-</p><p>count for the excitatory effect of bradykinin. In vivo investigations</p><p>showed that retigabine, an M channel opener, attenuated intraplantar</p><p>bradykinin-induced nociceptive responses in rats. This result is accord-</p><p>ing to the patch-clamp experiment, where the application of retigabine</p><p>reversed the inhibitory effect of bradykinin on M-type current. Similarly,</p><p>Cl− channel blockers also alleviated the intraplantar bradykinin-induced</p><p>nociceptive behaviour [134]. This study clarified mechanisms involved</p><p>in spontaneous inflammatory pain, evidencing new pharmacological</p><p>targets, such as B1R and B2R, for treating painful conditions of inflam-</p><p>matory origin [134].</p><p>4.2. Neuropathic pain</p><p>Neuropathic pain is caused by a lesion or disease of the somatosen-</p><p>sory nervous system, affecting 7–10 % of the general population [56]</p><p>and represents a major clinical and public health problem that often</p><p>leads to significant functional impairment and permanent disability</p><p>[54,135]. Neuropathic pain can occur in neurological conditions of</p><p>unknown aetiology, such as idiopathic neuropathies, or known aetiol-</p><p>ogies. In the case of known aetiologies, are included the most common</p><p>conditions of peripheral (trigeminal neuralgia, peripheral nerve injury,</p><p>painful polyneuropathy, postherpetic neuralgia, and painful radiculop-</p><p>athy) and central (pain caused by spinal cord or brain injury, post-stroke</p><p>pain, and pain associated with multiple sclerosis) neuropathic pain</p><p>[6,44,50,54,56]. Since that neuropathic pain remains challenging to</p><p>treat and represents an urgent medical need, understanding the pe-</p><p>ripheral and central mechanisms that contribute to developing neuro-</p><p>pathic pain is essential to propose more effective treatments. Kinin</p><p>receptors seem to be promising targets for developing new analgesic</p><p>drugs to treat neuropathy pain (Fig. 4b).</p><p>4.2.1. Diabetes</p><p>Neuropathy is the most common complication of diabetes mellitus,</p><p>with approximately 20 % of patients with type 1 diabetes mellitus and</p><p>50 % with type 2 diabetes mellitus developing diabetic peripheral</p><p>neuropathy within 20 years after initial diagnosis [136,137]. Painful</p><p>diabetic peripheral neuropathy is associated with poor patients’ quality</p><p>of life, who often suffer from comorbidities such as depression and</p><p>anxiety, leading to reduced productivity and employability [138].</p><p>However, treatments used to control the pain of patients with painful</p><p>diabetic peripheral neuropathy are often insufficient and cause un-</p><p>pleasant adverse effects [136,137]. Thus, the study of new pharmaco-</p><p>logical targets is relevant to treat this pain, and kinin receptors seem</p><p>promising targets in reducing diabetic peripheral neuropathy.</p><p>In 2004, Gabra and Sirois [139] found evidence of B1R participation</p><p>and subsequent activation of the NO, substance P, and CGRP pathways</p><p>in the thermal hyperalgesia development in streptozotocin (STZ)-</p><p>induced diabetic mice. It was observed that STZ caused thermal</p><p>hyperalgesia in mice in both hot plate and tail immersion tests, which</p><p>was enhanced by a B1R agonist (DABk). Both thermal hyperalgesia and</p><p>its enhancement by DABk were attenuated by B1R antagonists, NOS</p><p>inhibitors, and substance P and CGRP antagonists [139]. This same year,</p><p>Ongali et al. [140] demonstrated a significant increase in specific B1R</p><p>binding sites and B1R mRNA levels in the dorsal horn of STZ-induced</p><p>diabetic rats.</p><p>The same research group [141] also observed that wild-type but not</p><p>B1R knockout mice developed thermal hyperalgesia in the STZ-induced</p><p>diabetes model. Furthermore, the B1R agonist (DABk) enhanced the</p><p>hyperalgesia in diabetic wild-type mice but did not alter the nociceptive</p><p>behaviour in B1R knockout mice. Another study by the same authors also</p><p>demonstrated that the B1R antagonist, R-954, attenuated the thermal</p><p>hyperalgesia in a time- and dose-dependent manner in STZ-induced</p><p>diabetic rats and spontaneous BioBreeding/Worchester diabetic-prone</p><p>rats [142]. The involvement of B1R in diabetic neuropathy was also</p><p>shown in a spontaneous type 1 diabetes mellitus model using female</p><p>non-obese diabetic (NOD) mice. DABk, a B1R agonist, enhanced the</p><p>hyperalgesia in NOD mice in both hot plate and tail immersion pain tests</p><p>after its acute and chronic administration. The diabetic hyperalgesia in</p><p>NOD mice was restored to values observed in control non-diabetic mice</p><p>in both thermal nociceptive tests by a B1R antagonist (R-715) and its</p><p>more potent and long-acting analogue (R-954) when acutely or chron-</p><p>ically administered [143]. Additionally, R-954 also attenuated the</p><p>thermal hyperalgesia in Zucker diabetic fatty rats, a spontaneous genetic</p><p>model of type 2 diabetes mellitus [144].</p><p>Talbot et al. [145] investigated the participation of microglial B1R in</p><p>STZ-induced diabetic neuropathy. The systemic or intrathecal adminis-</p><p>tration of B1R antagonists (SSR240612 and R-715) or microglia in-</p><p>hibitors (fluorocitrate and minocycline) reduced the tactile and cold</p><p>allodynia in STZ-induced diabetic rats. On the other hand, the intra-</p><p>thecal injection of the B1R agonist DABk enhanced the STZ-induced</p><p>tactile allodynia, which was prevented by SSR240612 and microglia</p><p>inhibitors. Microglia inhibitors also abolished heat thermal hyperalgesia</p><p>caused by DABk in STZ-induced diabetic rats. The authors also observed</p><p>an increase in mRNA levels of B1R, IL1β, and TNF-α in the thoracic spinal</p><p>cord of STZ-induced diabetic rats, which was markedly reduced by</p><p>microglia inhibitors. The STZ-induced diabetic neuropathy model also</p><p>increased the density of specific B1R binding sites in the spinal cord of</p><p>rats, which was reduced after microglia inhibition. Thus, Talbot et al.</p><p>[145] proposed that the upregulation of B1R in spinal dorsal horn</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>10</p><p>microglia by pro-inflammatory cytokines can be a crucial mechanism in</p><p>early neuropathic pain in STZ-induced diabetic rats.</p><p>B1R antagonists were also evaluated in an insulin resistance model</p><p>induced by chronic glucose consumption. B1R mRNA was markedly</p><p>increased in the liver, aorta, lung, kidney, gastrocnemius muscle, and</p><p>spinal cord of rats subjected to this model [146,147]. Acute treatment</p><p>with non-peptide B1R antagonists (SSR240612, LF22-0542) or a peptide</p><p>B1R antagonist (R-715) reversed in a dose-dependent manner the cold</p><p>and tactile allodynia in glucose-fed rats [146,148]. Additionally, chronic</p><p>blockade of B1R with SSR240612 caused a persistent inhibition of tactile</p><p>and cold allodynia, the suppression of B1R expression, and vascular</p><p>oxidative stress in this model [147]. These findings suggested a bene-</p><p>ficial effect of B1R antagonism in neuropathic pain associated with in-</p><p>sulin resistance.</p><p>In addition to the investigations on the role of the B1R in diabetic</p><p>neuropathy models, Bujalska et al. [149] also investigated the involve-</p><p>ment of B2R in the STZ-induced diabetic neuropathy model. STZ caused</p><p>mechanical hyperalgesia in diabetic mice, which was attenuated by B1R</p><p>(des-Arg10-Hoe140) and B2R (Icatibant) antagonists. After that, Bujalska</p><p>and Makulska-Nowak [150] showed that these B1R and B2R antagonists</p><p>and an inhibitor of inducible NOS alleviated the STZ-induced diabetic</p><p>hyperalgesia. The previous treatment of mice with inducible or consti-</p><p>tutive NOS inhibitor enhanced the antihyperalgesic effect of both Ica-</p><p>tibant and des-Arg10-Hoe140. Moreover, indomethacin or celecoxib,</p><p>COX-1 and COX-2 inhibitors, respectively, simultaneously administered</p><p>with low doses of B1R (des-Arg10-Hoe140) or B2R (Icatibant) antagonists</p><p>enhanced the antihyperalgesic action of these antagonists in the STZ-</p><p>induced neuropathy model [150]. These results are interesting</p><p>because COX inhibitors could increase the analgesic effect of B1R and</p><p>B2R antagonists in neuropathic pain settings, especially diabetic</p><p>neuropathy.</p><p>Together, these results point to the B1R as a potential pharmaco-</p><p>logical target for treating patients with painful diabetic neuropathy.</p><p>Similarly, B2R also seems to be involved in diabetic neuropathy.</p><p>4.2.2. Injury-induced neuropathic pain</p><p>Neuropathic pain can also be caused by injuries in the peripheral</p><p>nerve, spinal cord, and brain or brachial plexus avulsion (BPA) [54,135].</p><p>After a peripheral nerve lesion, neuropathic pain can occur in a manner</p><p>persistent or recurrent within the innervation territory of the affected</p><p>nerve [54]. The central neuropathic pain associated with spinal cord</p><p>injury is caused by a lesion or disease of the somatosensory pathways in</p><p>the spinal cord and is one of the most disabling consequences affecting</p><p>more than 50 % of patients [54,151]. Additionally, the chronic central</p><p>neuropathic pain associated with brain injury is caused by a lesion or</p><p>disease of the somatosensory cortex, connected brain regions, or asso-</p><p>ciated pathways in the brain [54]. After BPA, 95 % of patients present</p><p>persistent neuropathic pain involving peripheral and central compo-</p><p>nents negatively impacting their life quality [152].</p><p>In a neuropathic pain model induced by partial sciatic nerve ligation</p><p>(PSNL), Rashid et al. [24] observed that the intraplantar bradykinin</p><p>caused more pronounced nociceptive responses in nerve-injured than in</p><p>sham-operated mice. This study evaluated nociceptive behaviours by</p><p>the bradykinin-induced nociceptive flexion test performed in the right</p><p>hind limb connected to an isotonic transducer and recorder. B2R an-</p><p>tagonists (Icatibant and FR173657) dose-dependently blocked the</p><p>bradykinin-mediated nociception in sham-operated, but not nerve-</p><p>injured, mice. On the other hand, a B1R antagonist (des-Arg10-</p><p>Hoe140) attenuated bradykinin-mediated nociception in nerve-injured</p><p>but not sham-operated mice. The</p><p>antisense oligodeoxynucleotides for</p><p>B1R and B2R alleviated the bradykinin-caused nociception in nerve-</p><p>injured and sham-operated mice, respectively. The ERK activation was</p><p>also observed after intraplantar bradykinin in unmyelinated DRG neu-</p><p>rons of sham-operated mice and myelinated DRG neurons and satellite</p><p>cells of nerve-injured mice. The B1R agonist, lys-des-Arg9-bradykinin,</p><p>also produced a nociceptive response and activated ERK in nerve-</p><p>injured, but not in sham-operated, mice. The B2R were expressed in</p><p>unmyelinated DRG neurons with little presence of the B1R in sham-</p><p>operated mice. In nerve-injured mice, the B1R were expressed mainly</p><p>in myelinated DRG neurons and satellite cells, while the B2R expression</p><p>decreased. The authors concluded that seems to be a switch of receptor</p><p>and fibre subtype for kinins-mediated nociception after peripheral nerve</p><p>injury, which might contribute to the pathobiology of neuropathic pain</p><p>[24].</p><p>In the same neuropathic pain model, Ferreira et al. [112] demon-</p><p>strated that mice with ablation of the gene for the B1R presented a</p><p>reduction in the early stages of mechanical allodynia and thermal</p><p>hyperalgesia. Similarly, a B1R antagonist (DALBk) reversed the me-</p><p>chanical allodynia in nerve-injured mice. After nerve injury, an upre-</p><p>gulation in B1R mRNA was also observed in the ipsilateral paw, sciatic</p><p>nerve, and spinal cord of wild-type mice. The authors concluded that</p><p>B1R activation seems essential to neuropathic pain development and</p><p>suggested that an oral B1R antagonist might have therapeutic potential</p><p>in managing chronic pain [112]. Corroborating these results, increased</p><p>B1R and B2R binding sites were observed in superficial laminae of the</p><p>ipsi- and contralateral spinal cord and DRG of mice after PSNL. The kinin</p><p>B1R (LF22-0542) or B2R (LF16-0687) antagonist reversed the thermal</p><p>hyperalgesia but not mechanical and cold allodynia caused by nerve</p><p>ligation [153]. Additionally, in a sciatic nerve constriction-induced</p><p>neuropathic pain model, the SSR240612 oral administration, a B1R</p><p>antagonist, reduced the thermal hyperalgesia in rats [33].</p><p>Recently, Cernit et al. [154] demonstrated that B1R contributes to</p><p>thermal hyperalgesia in rats submitted to PSNL. B1R protein and mRNA</p><p>were increased in the ipsi- and contralateral spinal cord of rats after</p><p>PSNL, and the B1R antagonist (SSR240612) reversed this upregulation.</p><p>The B1R was immunodetected on nonpeptide sensory fibres and astro-</p><p>cytes but not on microglia of injured-nerve rats. The PSNL also enhanced</p><p>the B1R immunofluorescence in the spinal cord dorsal horn and DRG.</p><p>Similar results to B1R were found for the transient receptor potential</p><p>vanilloid type 1 (TRPV1), and else, B1R was colocalized with TRPV1 in</p><p>the spinal dorsal horn and DRG. This study again demonstrates the</p><p>involvement of the B1R in neuropathic pain induced by PSNL. Here, the</p><p>authors suggest a possible interaction between the B1R and TRPV1</p><p>channel in the superficial laminae of the spinal cord dorsal horn and on</p><p>the sensory fibres of rats submitted to PSNL [154]. Previously, Ferreira</p><p>et al. [155] showed that bradykinin could produce nociceptive effects by</p><p>sensitizing the TRPV1 receptor through the PLC pathway activation and</p><p>formation of lipoxygenase-derived products.</p><p>In another neuropathic pain model induced by the lumbar L5 and L6</p><p>spinal nerves ligation, the intraplantar injection of the B1R (DABk) and</p><p>B2R (bradykinin) agonists caused overt nociception compared to non-</p><p>operated rats. B1R (DALBk) and B2R (Icatibant) antagonists reduced</p><p>the overt nociception triggered by DABk and bradykinin and attenuated</p><p>the cold and mechanical allodynia and heat hyperalgesia. Moreover,</p><p>there was an increase in the B1R and B2R protein levels in ipsilateral</p><p>L4–L6 spinal nerve and hind paw skin after spinal nerve ligation. These</p><p>results reinforce the B1R participation and demonstrate the involvement</p><p>of B2R in a neuropathic pain model. Thus, peripheral and central B1R</p><p>and B2R may be pharmacological targets effective in reducing neuro-</p><p>pathic pain [107].</p><p>B1R also seems to contribute to the neuropathic pain induced by BPA</p><p>in a model where the lower trunk brachial plexus was exposed and</p><p>extorted by traction using forceps. Mice submitted to the BPA procedure</p><p>developed mechanical and thermal hyperalgesia, which are absent in</p><p>B1R knockout mice. B1R (R-715 or SSR240612) antagonists adminis-</p><p>tered by local, intraperitoneal, spinal, and supra-spinal routes alleviated</p><p>the BPA-caused mechanical hyperalgesia. B1R mRNA levels and B1R</p><p>protein expression increased in spinal and supraspinal structures. These</p><p>results evidenced the contribution of the B1R at peripheral and central</p><p>levels in the BPA-caused neuropathic pain model. On the other hand,</p><p>this study showed that genetic deletion of B2R produced only a slight</p><p>reduction in the hypernociception and the B2R antagonist was</p><p>I. Brusco et al.</p><p>Life Sciences 314 (2023) 121302</p><p>11</p><p>ineffective in this neuropathic pain model [156]. The authors attributed</p><p>this difference to B1R and B2R because B1R stimulation would be more</p><p>associated with long-lasting nociceptive alterations than B2R.</p><p>Since nociceptive responses caused by BPA in mice mainly depend on</p><p>the generation of TNFα [157], there may be an interaction between the</p><p>TNF1/p55 receptor and B1R and B2R in the long-lasting pain processes</p><p>associated with nerve injury. Here, the neuropathic pain model was</p><p>induced by an intraneural injection of TNF or kinin agonists into mice’s</p><p>lower trunk of the brachial plexus (without extortion), which may</p><p>explain the greater participation of B2R [27], different from the study</p><p>above [156]. TNFR1/p55 knockout mice presented reduced mechanical</p><p>hypersensitivity after intraneural injection of either B1R (DABk) or B2R</p><p>(bradykinin) agonists administered into the lower trunk of the brachial</p><p>plexus of mice. The co-treatment with B1R (DALBk) or B2R (Icatibant)</p><p>antagonists partially reduced this nociceptive response in wild-type</p><p>mice. Similarly, B1R and B2R knockout mice also demonstrated</p><p>reduced mechanical hypersensitivity after intraneural injection of the</p><p>recombinant mouse (rm)-TNF into the lower trunk of the brachial</p><p>plexus. Intraneural rm-TNF increased the B1R mRNA expression in the</p><p>spinal cord and DRG and B2R in the DRG, confirming the interaction</p><p>between TNF1/p55 and B1R and B2R. Intraneural bradykinin or DABk</p><p>caused mechanical hypersensitivity, inhibited by pre-treatment with</p><p>DALBk. However, Icatibant did not modify the hypersensitivity induced</p><p>by intraneural DABk. Thiorphan, a carboxypeptidase M inhibitor,</p><p>reduced the intraneural bradykinin-induced mechanical hypersensitiv-</p><p>ity suggesting that bradykinin does not only activate the B2R as an</p><p>orthosteric agonist but also seems to be converted into DABk that</p><p>consequently activates the B1R. Altogether, these results describe an</p><p>interaction between TNF and the kinins system on neuropathic pain in</p><p>brachial plexus, suggesting an essential role for B1R and B2R in the CNS</p><p>sensitisation by the cross-talk with carboxypeptidase M after intraneural</p><p>rm-TNF [27].</p><p>4.2.3. Trigeminal neuropathic pain</p><p>Trigeminal neuralgia is a type of orofacial pain that affects one or</p><p>more divisions of the trigeminal nerve. A proportion of 91–99 % of</p><p>patients with trigeminal neuralgia develop paroxysmal pain, which is</p><p>considered a pathognomonic feature of this disease [158]. Furthermore,</p><p>24–49 % of patients also report continuous or long-lasting pain between</p><p>paroxysmal attacks [158,159].</p><p>Both B1R and B2R seem relevant in trigeminal neuropathic pain</p><p>induced by infraorbital nerve constriction [28,160]. B1R (DALBk) or B2R</p><p>(Icatibant) antagonist applied to the infraorbital nerve of mice during</p><p>nerve constriction delayed the</p>