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<p>Neuropeptides 43 (2009) 341–353</p><p>Contents lists available at ScienceDirect</p><p>Neuropeptides</p><p>journal homepage: www.elsevier .com/locate /npep</p><p>The role of b-endorphin in the pathophysiology of major depression</p><p>K.M. Hegadoren a,*, T. O’Donnell b, R. Lanius d, N.J. Coupland b, N. Lacaze-Masmonteil c</p><p>a Faculty of Nursing, University of Alberta, Edmonton, AB, Canada T6G 2G3</p><p>b Department of Psychiatry, University of Alberta, Edmonton, AB, Canada T6G 2G3</p><p>c Campus Saint Jean, University of Alberta, Edmonton, AB, Canada T6G 2G3</p><p>d Department of Psychiatry, University of Western Ontario, Canada T6G 2G3</p><p>a r t i c l e i n f o</p><p>Article history:</p><p>Received 14 March 2009</p><p>Accepted 25 June 2009</p><p>Available online 3 August 2009</p><p>Keywords:</p><p>Depression</p><p>b-Endorphin</p><p>Stress response systems</p><p>HPA axis</p><p>Methodology</p><p>Review</p><p>0143-4179/$ - see front matter � 2009 Elsevier Ltd. A</p><p>doi:10.1016/j.npep.2009.06.004</p><p>* Corresponding author. Tel.: +1 780 492 4591; fax</p><p>E-mail address: kathy.hegadoren@ualberta.ca (K.M</p><p>a b s t r a c t</p><p>A role for b-endorphin (b-END) in the pathophysiology of major depressive disorder (MDD) is suggested by</p><p>both animal research and studies examining clinical populations. The major etiological theories of depression</p><p>include brain regions and neural systems that interact with opioid systems and b-END. Recent preclinical</p><p>data have demonstrated multiple roles for b-END in the regulation of complex homeostatic and behavioural</p><p>processes that are affected during a depressive episode. Additionally, b-END inputs to regulatory pathways</p><p>involving feeding behaviours, motivation, and specific types of motor activity have important implications</p><p>in defining the biological foundations for specific depressive symptoms. Early research linking b-END to</p><p>MDD did so in the context of the hypothalamic–pituitary–adrenal (HPA) axis activity, where it was suggested</p><p>that HPA axis dysregulation may account for depressive symptoms in some individuals. The primary aims of</p><p>this paper are to use both preclinical and clinical research (a) to critically review data that explores potential</p><p>roles for b-END in the pathophysiology of MDD and (b) to highlight gaps in the literature that limit further</p><p>development of etiological theories of depression and testable hypotheses. In addition to examining meth-</p><p>odological and theoretical challenges of past clinical studies, we summarize studies that have investigated</p><p>basal b-END levels in MDD and that have used challenge tests to examine b-END responses to a variety of</p><p>experimental paradigms. A brief description of the synthesis, location in the CNS and behavioural pharma-</p><p>cology of this neuropeptide is also provided to frame this discussion. Given the lack of clinical improvement</p><p>observed with currently available antidepressants in a significant proportion of depressed individuals, it is</p><p>imperative that novel mechanisms be investigated for antidepressant potential. We conclude that the</p><p>renewed interest in elucidating the role of b-END in the pathophysiology of MDD must be paralleled by con-</p><p>sensus building within the research community around the heterogeneity inherent in mood disorders, stan-</p><p>dardization of experimental protocols, improved discrimination of POMC products in analytical techniques</p><p>and consistent attention paid to important confounds like age and gender.</p><p>� 2009 Elsevier Ltd. All rights reserved.</p><p>Contents</p><p>1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342</p><p>2. Synthesis, location and pharmacology of b-endorphin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343</p><p>3. b-Endorphin and behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344</p><p>4. Methodological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345</p><p>5. Serotonin, depression and b-END . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346</p><p>6. The HPA axis, depression and b-END . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346</p><p>7. Studies examining baseline levels of b-endorphin in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346</p><p>8. Challenge studies of b-endorphin in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347</p><p>9. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349</p><p>10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350</p><p>References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350</p><p>ll rights reserved.</p><p>: +1 780 492 2551.</p><p>. Hegadoren).</p><p>http://dx.doi.org/10.1016/j.npep.2009.06.004</p><p>mailto:kathy.hegadoren@ualberta.ca</p><p>http://www.sciencedirect.com/science/journal/01434179</p><p>http://www.elsevier.com/locate/npep</p><p>342 K.M. Hegadoren et al. / Neuropeptides 43 (2009) 341–353</p><p>1. Introduction</p><p>Animal and human research support involvement of central</p><p>opioid systems in the pathophysiology of major depressive</p><p>disorder (MDD). However, the complexity of interdependent inter-</p><p>actions between opioid-releasing neurons and other neurotrans-</p><p>mitter and neuromodulatory systems has made it difficult to</p><p>delineate specific contributions that endogenous opioids make to</p><p>the development and persistence of depressive symptoms. Of the</p><p>endogenous opioids that have been identified as contributing to</p><p>the etiology of MDD, b-endorphin (b-END) has been the most</p><p>studied.</p><p>Initial studies regarding b-END focused on peripheral and cen-</p><p>tral transmission of pain stimuli and b-END’s role on attenuation</p><p>of nocioception signalling. Increasingly, pain has become recog-</p><p>nized as a very complex behaviour, encompassing sensory, affec-</p><p>tive and cognitive components (Zubieta et al., 2001). This led to</p><p>investigations of such phenomena as stress-induced analgesia, as</p><p>well as attempts to examine putative roles for endogenous opioids</p><p>in stress-related psychiatric disorders, such as MDD and posttrau-</p><p>matic stress disorder (PTSD), and physical health problems. For</p><p>example, increased production of b-END has been detected in</p><p>those with arthritis, viral and parasitic infections and atopic ecze-</p><p>ma (Slominski et al., 2000). Acute alcohol intake in animals in-</p><p>creases brain b-END levels (Olive et al., 2001), while habitual</p><p>alcohol consumption leads to lowered plasma b-END levels in hu-</p><p>mans (Vescovi et al., 1992). 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Neurosci. 22, 5100–5107.</p><p>The role of β-endorphin in the pathophysiology o</p><p>Introduction</p><p>Synthesis, location and pharmacology of β-endorp</p><p>β-Endorphin and behaviour</p><p>Methodological considerations</p><p>Serotonin, depression and β-END</p><p>The HPA axis, depression and β-END</p><p>Studies examining baseline levels of β-endorphin</p><p>Challenge studies of β-endorphin in depression</p><p>Discussion</p><p>Conclusion</p><p>References</p><p>energy and concentration, feeling of</p><p>worthlessness and guilt and impairment of occupational, social</p><p>and personal functioning (American Psychiatric Association,</p><p>1994). Several hypotheses have been explored to explain the onset</p><p>and persistence of MDD symptoms (for review see Belmaker and</p><p>Agam (2008)). One of the earliest hypotheses postulates a deficit</p><p>in serotonin (5-HT) and norepinephrine (NE) transmission in the</p><p>brain. Although this monamine hypothesis is supported by the</p><p>clinical efficacy of many antidepressants, the time lag between</p><p>the acute pharmacological effects and clinical improvement sug-</p><p>gest that a cascade of molecular events and changes in key neural</p><p>pathways within the CNS occurs in the presence of antidepressant</p><p>drugs.</p><p>In addition to the time lag for drug efficacy in terms of mono-</p><p>amine theory development, up to 1/3 of patients responding poorly</p><p>to 5-HT or NE reuptake inhibitors. This has led some researchers to</p><p>propose alternative hypotheses. Using both animal models and</p><p>clinical populations, multiple investigators have shown that envi-</p><p>ronmental stressors or stressful life events play an etiological role</p><p>in the development of MDD (Frank et al., 1994; Kendler et al., 1993,</p><p>2002; Meaney, 2001; Weiss and Post, 1998), especially in women</p><p>(Kendler et al., 2002). These strong relationships between stress</p><p>and depressive symptoms led researchers to investigate hormones</p><p>and neuropeptides involved in biological stress response systems</p><p>(Charmandari et al., 2005). A major focus of investigation has been</p><p>the hypothalamic–pituitary–adrenal (HPA) axis, which plays a</p><p>pivotal role in the mobilization of central and peripheral responses</p><p>to a stressor. Increases in levels of corticotropin releasing hormone</p><p>(CRH), adrenocorticotropic hormone (ACTH) and cortisol have been</p><p>observed in the majority (but not all) of those with MDD (Gutman</p><p>and Nemeroff, 2003; Heim et al., 2008; Pariante and Lightman,</p><p>2008; Reul and Holsboer, 2002; Strohle and Holsboer, 2003). HPA</p><p>axis challenge tests suggest dysregulation of control mechanisms</p><p>within the axis. Other avenues of exploration supported a role</p><p>for the hypersecretion of extra-hypothalamic CRH and led to the</p><p>CRH hypothesis of MDD (Makino et al., 2002; Nemeroff, 1996).</p><p>The multiplicity of regulatory inputs to the HPA axis and the iden-</p><p>tification of extra-hypothalamic CRH pathways led to investiga-</p><p>tions of other endogenous peptides including b-END that might</p><p>be involved in the regulation of the HPA as it relates to MDD</p><p>and/or to the overall behavioural responses to stress.</p><p>Another area of exploration related to MDD is within the field of</p><p>neuropsychoimmunology. Similarities between cytokine-induced</p><p>sickness and depression symptoms have led researchers to postu-</p><p>late that interactions between the brain and immune systems may</p><p>underlay the development of depression symptoms (for reviews</p><p>see Dantzer et al. (2008) and Khairova et al. (2009)). Indeed,</p><p>MDD may reflect exaggerated cytokine-mediated behaviour</p><p>(termed ‘‘sickness behaviour”) in response to prolonged inflamma-</p><p>tion and/or psychological stress. Evidence to support this neuro-</p><p>psychoimmunological model of MDD comes from data</p><p>associating MDD with increases in pro-inflammatory cytokines</p><p>such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour</p><p>necrosis factor alpha (TNF-a) (Maes et al., 2009). More recently,</p><p>levels of C-reactive protein (CRP), a peripheral marker of immune</p><p>activation, have also been shown to be increased in MDD (Raison</p><p>et al., 2006) and to normalize with antidepressant drug treatment</p><p>(O’Brien et al., 2006). Conversely, patients with chronic inflamma-</p><p>tory or neurodegenerative diseases often experience symptoms of</p><p>depression (Dantzer et al., 2008; Caballero et al., 2008). Pro-inflam-</p><p>matory cytokines are known to stimulate immune cells such as</p><p>lymphocytes, and natural killer (NK) cells, as well as acting as po-</p><p>tent stimulators of hypothalamic CRH release (Turnbull and Rivier,</p><p>1999). In turn, CRH is a known stimulator of peripheral b-END</p><p>release from many types of immune cells under inflammatory con-</p><p>ditions and thus, pro-inflammatory cytokines likely play an impor-</p><p>tant role in contributing to circulating levels of b-END. Animal data</p><p>that show anti-inflammatory and immunosuppressive properties</p><p>of b-END (Silberstein et al., 2009) may explain the positive benefits</p><p>of CRH-mediated increases in b-END levels under inflammatory</p><p>conditions are suggestive of a clinical role for anti-cytokine thera-</p><p>pies for MDD (Khairova et al., 2009).</p><p>Interest in b-END and MDD seemed to peak in the mid-1980s</p><p>and then waned, due in part to the equivocal results obtained</p><p>across studies and methodological challenges in quantification of</p><p>multiple neuropeptides arising from large precursor molecules.</p><p>Early reports suggested that b-END infusions had a temporary</p><p>mood elevating effect in very small numbers of depressed patients,</p><p>but results varied across the small studies that were completed</p><p>(Berger and Barchas, 1983). Much of the early research examining</p><p>basal b-END levels in depressed populations has been contradic-</p><p>tory, making hypotheses development and testing difficult. More</p><p>recent work, using neuroimaging paradigms (Gotlib and Hamilton,</p><p>2008) suggests a decrease in b-END neurotransmission during neg-</p><p>ative affect. These data together with post-mortem evidence for in-</p><p>creased density of mu (l)-opioid receptors in the brain of</p><p>depressed suicide victims (Gross-Isseroff et al., 1998; Gabilondo</p><p>et al., 1995), supports the hypothesis of b-END deficiency with a</p><p>compensatory up-regulation of l-opioid receptors in MDD (Pickar</p><p>et al., 1981). Recent advances in analytical methods and our under-</p><p>standing of the neural circuitry related to stress responses have</p><p>rekindled interest in investigating putative roles for b-END in</p><p>stress responses and mood disorders.</p><p>This review will summarize available data pertaining to the role</p><p>of b-END in MDD, provide some potential explanations for the dis-</p><p>crepancies across published studies and suggest new areas of re-</p><p>search that may lend insight to this field. The review will be</p><p>K.M. Hegadoren et al. / Neuropeptides 43 (2009) 341–353 343</p><p>framed by a brief description of the synthesis, CNS location and</p><p>behavioural pharmacology of b-END.</p><p>2. Synthesis, location and pharmacology of b-endorphin</p><p>b-END, a 31-amino acid C-terminal fragment (molecular</p><p>weight = 3464.98), is produced by posttranslational processing of</p><p>the large precursor, proopiomelanocortin (POMC). Differential pro-</p><p>cessing of POMC may generate several peptides: ACTH, pro-ACTH,</p><p>a- and b-melanocyte stimulating hormone (MSH), b-lipotropin, as</p><p>well as the endorphins (Akil et al., 1988). POMC neuropeptides</p><p>such as b-END and ACTH are produced in both the anterior and</p><p>intermediate lobes of the pituitary, as well as in a cluster of neu-</p><p>rons in the hypothalamic arcuate nucleus (Stengaard-Pedersen</p><p>and Larsson, 1981). Major b-END pathways in the CNS, as extrapo-</p><p>lated from both animal and human data, are illustrated in Fig. 1.</p><p>b-END-containing cell bodies of the arcuate nucleus project exten-</p><p>sively to multiple regions within the hypothalamus [medial preop-</p><p>tic area, periventricular nuclei (PVN), nucleus accumbens, bed</p><p>nucleus of the stria terminalis (BNST), periaqueductal gray (PAG),</p><p>amygdala, pontine nuclei, raphe nuclei, and locus coeruleus (LC)]</p><p>(Bugnon et al., 1979; Tsou et al., 1986; Watson et al., 1977). An-</p><p>other brain region with b-endorphin- and related POMC-releasing</p><p>cell bodies is the nucleus of the tractus solitarius (NTS) of the cau-</p><p>dal medulla, which innervates the brain stem and spinal cord</p><p>(Bronstein et al., 1992; Tsou et al., 1986). Peripherally, high con-</p><p>centrations of immunoreactivity for active b-END and a-melano-</p><p>tropin have been found in human adrenal medulla, but not in</p><p>other mammalian species (Evans et al., 1983). In response to</p><p>RN</p><p>A</p><p>Arc</p><p>Cortisol</p><p>CRH</p><p>MPOA</p><p>BNST</p><p>Acc</p><p>ACTH</p><p>+</p><p>-</p><p>PVN</p><p>pB-END</p><p>+</p><p>-</p><p>RN</p><p>A</p><p>Arc</p><p>Cortisol</p><p>CRH</p><p>MPOA</p><p>BNST</p><p>Acc</p><p>ACTH</p><p>+</p><p>-</p><p>PVN</p><p>pB-END</p><p>+</p><p>-</p><p>Fig. 1. Major b-END pathways in the</p><p>central nervous system. Solid black: location of POM</p><p>A: amygdala; ARC: arcuate nucleus; Acc: nucleus accumbens; BNST: bed nucleus of stria t</p><p>solitarius; PAG: periaqueductal grey matter; PVN: paraventricular nucleus; RN: raphe n</p><p>peripheral inflammation, leukocytes are the major source of</p><p>peripheral b-END (Machelska, 2007). There is evidence that periph-</p><p>erally administered b-END does enter the CNS; however, it is not</p><p>clear whether it can pass across the blood brain barrier or if the</p><p>transport occurs at the level of the spinal cord (Gerner et al., 1982).</p><p>In rats, much of the b-END within hypothalamic areas is in the</p><p>biologically active form (Emeson and Eipper, 1986). For this re-</p><p>view, ‘‘active” b-END interacts with opioid receptors both centrally</p><p>and peripherally. Proportions of active and inactive b-END vary</p><p>among projection regions (Castro and Morrison, 1997). In the hu-</p><p>man anterior pituitary, b-END is primarily in the active non-acety-</p><p>lated form (Smith et al., 1985). However, in the human</p><p>intermediate lobe of the pituitary, inactive N-acetylated b-endor-</p><p>phin is the predominant form (Chretien et al., 1979; Smith et al.,</p><p>1985). Although ACTH and AVP stimulate the intermediate lobe</p><p>of the pituitary to release inactive b-END, the physiological rele-</p><p>vance remains unclear (Eberwine et al., 1987; Saland et al., 1988,</p><p>1991; Chretien et al., 1979; Smith et al., 1985). While ‘‘inactive”</p><p>b-END does not interact with opioid receptors, it may be incorrect</p><p>to assume that it has no biological function.</p><p>CRH and AVP, from the PVN of the hypothalamus act as triggers</p><p>to initiate posttranslational processing of POMC in anterior pitui-</p><p>tary corticotrophs (Bao et al., 2008; Kato et al., 1980; Young,</p><p>1989), yielding ACTH, b-END, and various other peptides (Mor-</p><p>mede et al., 1986; Nikolarakis et al., 1986; Vale et al., 1978). In a</p><p>reciprocal fashion, the administration of low to moderate doses</p><p>of b-END or the intracerebroventricular injection of b-END in rats</p><p>appears to increase hypothalamic CRH synthesis and release</p><p>(Buckingham, 1986; Wang et al., 1996); whereas decreased</p><p>LC</p><p>PA</p><p>G</p><p>NTS</p><p>LC</p><p>PA</p><p>G</p><p>NTS</p><p>C-containing cells and projections. Dashed lines: HPA axis and regulatory pathways.</p><p>erminalis; LC: locus coeruleus; MPOA: medial preoptic area; NTS: nucleus of tractus</p><p>uclei; CRH: corticotrophin releasing hormone; p b-TND: plasma b-endorphin.</p><p>344 K.M. Hegadoren et al. / Neuropeptides 43 (2009) 341–353</p><p>synthesis and release of CRH is observed in response to high doses</p><p>of b-END (Buckingham, 1986; Plotsky, 1986; Suda et al., 1992;</p><p>Tsagarakis et al., 1990). Przewlocki (2002) suggests that this bimo-</p><p>dal response pattern may arise from both direct and indirect mech-</p><p>anisms. Indirect mechanisms include interactions between b-END</p><p>and 5-HT and NE systems. For example, in a rat model of depres-</p><p>sion, 5-HT–mediated b-END release in the nucleus accumbens</p><p>was impaired and re-established with chronic antidepressant</p><p>treatment (Zangen et al., 2002). b-END also has direct inhibitory ef-</p><p>fects on AVP (another HPA axis secretagogue) release from hypo-</p><p>thalamic and posterior pituitary neurons (Knepel et al., 1985;</p><p>Knepel and Reimann, 1982; Liu et al., 1999). Interpretation of study</p><p>results are hampered by reported variations in b-END levels across</p><p>the day (Genazzani et al., 1986; Matthews et al., 1986).</p><p>b-END is an endogenous opioid receptor agonist, with equipo-</p><p>tent affinities for l-and d-opioid receptors and low to moderate</p><p>affinity for other opioid receptors (Raynor et al., 1994; Tseng,</p><p>2001). The majority of behavioural and clinical studies on have fo-</p><p>cused on b-END in relation to l-opioid receptor interactions and</p><p>thus will be the main focus of this review. Studies in rats have</p><p>mapped out areas of intense l-opioid receptor immunoreactivity</p><p>in the CNS, including cell bodies and dendrites of the striatum,</p><p>medial habenular nuclei, interpeduncular nuclei, the NTS and brain</p><p>stem connections with the vagus nerve, the medial raphe, LC and</p><p>specific regions of the medullary and spinal dorsal horns (Ding</p><p>et al., 1996; Nomura et al., 1996). Similar binding characteristics</p><p>between central and peripheral opioid receptors have been noted</p><p>(Hassan et al., 1993).</p><p>Peripheral and central co-localizations of l-opioid receptors</p><p>with other receptors or neuropeptides highlight multiple potential</p><p>mechanisms by which b-END and other endogenous opioids influ-</p><p>ence neural processes and behaviours related to stress responses</p><p>and MDD. For example, in the CA1 region of rat hippocampus,</p><p>l-opioid receptors are expressed selectively on inhibitory GABAer-</p><p>gic interneurons and activation of these receptors decreases GABA</p><p>release, thus increasing hippocampal pyramidal cell excitability</p><p>(McQuiston and Saggau, 2003; Svoboda et al., 1999). In addition,</p><p>those hippocampal interneurons that express l-opioid receptors</p><p>commonly co-express somatostatin and neuropeptide Y (Drake</p><p>and Milner, 2002), both of which have been implicated in the neu-</p><p>robiology of MDD (Engin et al., 2008; Southwick et al., 2005). Other</p><p>examples of co-localization of l-opioid receptors include bradyki-</p><p>nin B2 receptors in the dorsal root ganglion (Rashid et al., 2004),</p><p>a2-adrenoceptors and A1 adenosine receptors on primary afferent</p><p>neurons (Aley and Levine, 1997) and CRF receptors on the somato-</p><p>dendritic processes of LC neurons (Reyes et al., 2007). While many</p><p>of these potential interactions have been examined more in rela-</p><p>tion to nocioception, it is likely that work with animal models of</p><p>depression and clinical populations would yield evidence that</p><p>these multiple interactions have implications for the affective</p><p>and cognitive elements of stress disorders. For example, co-locali-</p><p>zation of l-opioid receptors with adrenergic receptors may reflect</p><p>interactions within the sympathetic–adrenal–medullary axis, a key</p><p>stress response system.</p><p>3. b-Endorphin and behaviour</p><p>b-END is involved in the regulation of homeostatic and behav-</p><p>ioural processes, including anti-nocioception (Tseng, 2001; Cannon</p><p>et al., 1982), autonomic regulation (Hill et al., 2002.), HPA axis</p><p>activity (Makino et al., 2002), cellular effects of exercise (through</p><p>mitochondrial adaptation, promotion of cell proliferation, HPA axis</p><p>activation and decreased insulin resistance) (Boveris and Navarro,</p><p>2008; Koehl et al., 2008; Makino et al., 2002; Su et al., 2005), hypo-</p><p>thalamic–pituitary–gonadal axis activity (Przewlocki and Przewlo-</p><p>cka, 2001; Yen et al., 1985), stress-induced analgesia (Akil et al.,</p><p>1986; Bodnar, 1986) and attachment (review by Weller and Feld-</p><p>man (2003)), as well as possessing mood-enhancing and anxiolytic</p><p>effects (Przewlocki (2002)). Many of these processes are altered in</p><p>MDD, suggesting that b-END is involved in the pathophysiology of</p><p>this mood disorder (Kelley et al., 2002). More consistent preclinical</p><p>evidence exists for relationships between specific depression</p><p>symptoms and opioid systems.</p><p>Neural circuits that include the amygdala, nucleus accumbens,</p><p>hypothalamus, BNST and the LC are implicated in positive and neg-</p><p>ative affective states, autonomic arousal and fear conditioning. The</p><p>LC, subgenual anterior cingulated cortex and amygdala also regu-</p><p>late processes involved in emotionally mediated attention, the for-</p><p>mation of memories and the attachment of emotional significance</p><p>to such memories (Haas and Canli, 2008). It is well recognized that</p><p>those with MDD selectively attend to more negative stimuli have</p><p>problems with focussed attention. Multiple opioids, including b-</p><p>END, acting within specific brain regions can modulate these pro-</p><p>cesses and influence the formation of memories and the regulation</p><p>of emotional states (McGaugh, 2000).</p><p>PET methodology has been used to elucidate the contribution</p><p>of l-receptors to affect, using a sustained sad mood induction</p><p>paradigm in healthy subjects. The study demonstrated reductions</p><p>in l-opioid binding in the rostral anterior cingulate, ventral pal-</p><p>lidum, amygdala and inferior temporal cortex, which correlated</p><p>with increases in negative affect ratings (Zubieta et al.,</p><p>2001).</p><p>Higher baseline l-opioid receptor binding potential has also been</p><p>associated with lower regional cerebral blood flow in the left</p><p>inferior temporal pole during the presentation of aversive emo-</p><p>tional stimuli (Liberzon et al., 2002). However, this reduction in</p><p>l-opioid receptor binding is not limited to mood disorders. Har-</p><p>ris et al. (2007) used PET to show reduced l-opioid receptor</p><p>binding potential (in particular in the nucleus acumbens, amyg-</p><p>dala and dorsal cingulate) in those with fibromyalgia, a chronic</p><p>pain syndrome often associated with risk for mood disorder.</p><p>Compared to healthy males, men with combat-related PTSD also</p><p>displayed reduced l-opioid receptor binding potential in the</p><p>same regions as seen in other studies, but increased binding po-</p><p>tential in the orbitofrontal cortex (Liberzon et al., 2007). Thus,</p><p>the various neuroimaging paradigms do suggest a deficiency in</p><p>l-opioid neurotransmission in depressed individuals. However,</p><p>it is challenging to connect neuroimaging data with previous</p><p>neurochemical data.</p><p>Almost half of MDD patients experience symptoms of chronic</p><p>pain (Ohayon and Schatzberg, 2003; Simon et al., 1999). Not sur-</p><p>prisingly, there is substantial overlap in the cited physiological cor-</p><p>relates of chronic stress, MDD and chronic pain. Nocioception and</p><p>endogenous anti-nocioceptive processes serve to support an</p><p>organism’s survival during threat and recuperation after injury</p><p>(Fanselow, 1986). Stress-induced analgesia in animals serves to</p><p>prevent potentially disruptive effects of nocioception on coordi-</p><p>nated defensive behaviours in response to a predator (Fanselow,</p><p>1986). Stress-induced analgesia has been more associated with</p><p>PTSD (van der Kolk et al., 1989). However, inescapable chronic</p><p>footshock is associated with learned helplessness, a well-accepted</p><p>animal model of depression (Hemingway and Reigle, 1987).</p><p>Another common health problem that is often comorbid with</p><p>MDD is substance abuse disorder. Evidence supports b-END influ-</p><p>ences on processes related to reward and motivation, likely medi-</p><p>ated through mesolimbic dopamine pathways (Herz, 1988, 1997).</p><p>Positive affect induced by tasty and/or high calorie foods activate</p><p>release of ventral striatal opioids and selective l-receptor agonists</p><p>increase food intake (Kelley et al., 2002). The rewarding effects of</p><p>alcohol are at least partially accounted for by b-END-mediated</p><p>activation of l receptors in the ventral tegmental area and the nu-</p><p>cleus accumbens (Herz, 1997).</p><p>K.M. Hegadoren et al. / Neuropeptides 43 (2009) 341–353 345</p><p>One salient feature of MDD is the female bias in prevalence</p><p>rates for MDD (Kessler et al., 1994). Animal studies have shown</p><p>estrogen-induced changes in l-receptor activity and density with-</p><p>in limbic and hypothalamic nuclei (Eckersell et al., 1998; Mills</p><p>et al., 2004). Chronic exposure to estrogen in rats was neurotoxic</p><p>to b-END-containing neurons in the arcuate nucleus, while sparing</p><p>other neuronal populations (Desjardins et al., 1995). These effects</p><p>were accompanied by up-regulation of l-opioid receptors and</p><p>attenuated by treatment with antioxidants.</p><p>Human studies have examined l-opioid binding and in both</p><p>healthy and clinically depressed populations. Anti-nocioceptive re-</p><p>sponses to tonic pain have reported sex differences, attributed in</p><p>part to female sex hormones (Cicero et al., 2002; D’Souza et al.,</p><p>2002). PET imaging has shown larger magnitudes of l-opioid sys-</p><p>tem activation in healthy men than women in the anterior thala-</p><p>mus, ventral basal ganglia, and amygdala; while women</p><p>demonstrated reductions in the basal state of activation of the l-</p><p>opioid system in the nucleus accumbens during pain stimulation</p><p>(Zubieta et al., 2002). Further PET studies examined the impact</p><p>of menstrual and reproductive status on the observed differences</p><p>in l-opioid system activation. Under a sustained pain condition</p><p>with PET in healthy men and women, Smith et al. (2006) showed</p><p>that under high estrogens (around ovulation), women had in-</p><p>creased l-opioid receptor binding potential at baseline and the</p><p>pain stressor increased activation of opioid receptors (similar re-</p><p>sponse as seen in the males). However, under low estrogen status</p><p>(luteal phase), women had lower l-opioid receptor binding poten-</p><p>tial and an exaggerated response to the pain stimulus compared to</p><p>the other two groups. Another PET study in healthy individuals</p><p>showed an increasing density of l-opioid receptors with age and</p><p>influences of sex and reproductive status on l-opioid binding (pre-</p><p>menopausal females > males > postmenopausal females) (Zubieta</p><p>et al., 1999). PET studies using a sustained sadness paradigm in</p><p>women with MDD revealed a number of regions with increased</p><p>l-opioid system activation compared with controls (Kennedy</p><p>et al., 2006).</p><p>4. Methodological considerations</p><p>Prior to summarizing the neurochemical data supporting a role</p><p>for b-END in the pathophysiology of depressive symptoms and</p><p>MDD, it is important to examine methodological issues that have</p><p>challenged the interpretation of experimental data. There are a</p><p>number of endogenous analogs and precursors of b-END that differ</p><p>in biological activity and interfere with commercial biological as-</p><p>says used to examine levels of b-END in humans. Of these, b-lipo-</p><p>tropin (b-LPH; a 91-amino acid precursor to b-END), a-endorphin</p><p>(b-LPH61–76), and c-endorphin (b-LPH61–77) have proven to be</p><p>the most troublesome in isolating biologically active b-END</p><p>(b-LPH61–91). The reactions within a radioimmunoassay (RIA) are</p><p>determined by antigenic structure, not biological function; thus,</p><p>many of the commercial RIA kits have high sensitivity but low</p><p>selectivity, reacting with a number of POMC-derived fragments</p><p>and peptides. Many ELISA kits for b-END also have low specificity,</p><p>with high levels of cross-reactivity listed for a number of undesir-</p><p>able analogs and precursors, in particular b-lipotropin, which has</p><p>up to 100% cross-reactivity with b-END (Peninsula Laboratories). In</p><p>additional to low specificity, ELISA kits for b-END also suffer from</p><p>low sensitivity, thus making them impractical for repeated plasma</p><p>measurements of b-END (MD Biosciences, Phoenix Pharmaceuticals).</p><p>Desiderio and Zhu (1998) published a liquid secondary ion mass</p><p>spectrometry and tandem mass spectrometry assay for b-END, but</p><p>this method was not used by any of the reviewed papers.</p><p>Since RIA is the primary means of determining levels of b-END</p><p>in human studies, biological concentrations are often expressed as</p><p>‘‘immunoreactive” levels of b-END, a general term encompassing</p><p>all POMC derivatives that react within a specific assay protocol.</p><p>Some investigators have attempted to rectify this issue by employ-</p><p>ing isolation and purification strategies (Desiderio and Zhu, 1998).</p><p>However, many researchers do not, thus resulting in the inclusion</p><p>of a whole spectrum of compounds under the category of ‘‘immu-</p><p>noreactive” b-END levels. Various drugs and endogenous products</p><p>can also affect b-END levels, including chronic neuroleptic use</p><p>(Schmauss and Emrich, 1985), exogenous opiates (Hartwig, 1991)</p><p>and chronic estrogen exposure (Desjardins et al., 1995). PET data</p><p>suggest that smoking also affects l-opioid receptor binding poten-</p><p>tial (Scott et al., 2007).</p><p>The degree to which peripheral measures reflect central pro-</p><p>cesses is an ever-present challenge to clinical researchers. b-END</p><p>is no exception, with multiple pools contributing to circulating</p><p>concentrations. b-END, whether from central neurons, the adrenal</p><p>medulla or immune-derived tissues is released in response to di-</p><p>verse stimuli and thus changes in peripheral measures of b-END</p><p>may reflect the organism’s overall response to the stimuli.</p><p>However, plasma levels alone do not answer questions whether</p><p>b-END release is a simple by-product of HPA activation or has</p><p>specific targets with behavioural and physiological correlates.</p><p>While there are strong beliefs regarding the superiority of tech-</p><p>niques that assess central levels of neuropeptides in psychiatric</p><p>disorders, b-END and other opioids may be an exception.</p><p>Evidence</p><p>supports bidirectional movement of b-END in (Gerner et al., 1982)</p><p>and out (King et al., 2001) of the CNS. These data provide a compel-</p><p>ling argument for the routine use of plasma measures of b-END.</p><p>However, further research is required to determine whether, and</p><p>under what circumstances, peripheral measures of b-END directly</p><p>reflect central activity, especially in the absence of inflammation.</p><p>Most human studies linking MDD and b-END have limited their</p><p>scope to examining plasma levels, although other measures have</p><p>been reported. Higher levels of plasma b-END and b-lipotropin,</p><p>but not CSF levels, were found in individuals with MDD compared</p><p>with healthy controls (Facchinetti et al., 1986). Panerai and</p><p>colleagues (2002) used peripheral blood mononuclear cell b-END</p><p>concentrations to compare individuals with MDD versus chronic</p><p>fatigue syndrome. They suggested that mononuclear cells reflect</p><p>central b-END concentrations better than plasma concentrations,</p><p>although this supportive evidence is questionable (Sacerdote</p><p>et al., 1991).</p><p>Stress hormones show distinctive diurnal rhythms and thus</p><p>differences in the timing of any experimental manipulation may</p><p>also contribute to disparities between studies. Young and</p><p>colleagues (1997) showed that administration of the corticosteroid</p><p>synthesis inhibitor, metyrapone, in the morning produced no</p><p>change in levels of plasma b-END, whereas afternoon administra-</p><p>tion produced a clear increase in b-END levels. Studies focusing</p><p>on changes in the affinity or density of l-receptors may not solely</p><p>be related to b-END, as other endogenous agonists besides b-END</p><p>include dynorphin and its analogs and the more recently identified</p><p>endomorphins can interact with l-receptors (Machelska, 2007;</p><p>Fichna et al., 2008).</p><p>Many other potential confounds exist in the studies that have</p><p>examined the role of b-END in psychiatric disorders. Important is-</p><p>sues that needed to be carefully considered across studies include:</p><p>different definitions of non-suppression in challenge studies; di-</p><p>verse inclusion/exclusion criteria, especially around comorbidity;</p><p>heterogeneity of depression; differing experimental protocols</p><p>across studies and even across sites within the same study with</p><p>no acknowledgment of the implications; small sample sizes;</p><p>pooled data that do not match on key variables and key demo-</p><p>graphic variables that may affect results (e.g. weight or BMI, age,</p><p>menstrual phase, medication use, time of sampling). The synthesis</p><p>and catabolic pathways for b-END involve a number of enzymes, all</p><p>346 K.M. Hegadoren et al. / Neuropeptides 43 (2009) 341–353</p><p>of which exhibit tissue specificity and perhaps inter-individual var-</p><p>iability, which could represent another potential source of varia-</p><p>tion in plasma levels of b-END (Akil et al., 1988). Despite these</p><p>significant challenges to examining opioid system involvement in</p><p>stress responses and MDD, accumulated evidence does suggest</p><p>alterations in central b-END activity and l-opioid receptor binding.</p><p>5. Serotonin, depression and b-END</p><p>As previously mentioned, one of the major etiological theories</p><p>of depression involves monoamine systems, in particular the</p><p>5-HT system. Animal studies support links between b-END and</p><p>5-HT systems, yet few human studies exist that have investigated</p><p>this relationship. Microdialysis studies on rats have demonstrated</p><p>dose-dependent increases in b-END levels in the diasylate from the</p><p>arcuate nuclei in response to 5-HT (Zangen et al., 1999). Increases</p><p>in b-END levels were also seen in the nucleus accumbens, but only</p><p>at the highest doses of 5-HT. Chemical lesioning with 5,7-dihydr-</p><p>oxytryptomine decreased b-END levels and adding fluoxetine to</p><p>the perfusion media increased b-END levels in both regions. Ago-</p><p>nists at 5-HT1 and 5-HT2 receptors also increased plasma b-END</p><p>immunoreactivity in rats (Bagdy et al., 1990). However, plasma</p><p>b-END levels did not change in response to fenfluramine, an indi-</p><p>rect 5-HT agonist in a small sample of depressed subjects (Weiz-</p><p>man et al., 1988). Acute administration of 5-hydroxytryptamine</p><p>attenuated the suppression of b-END in response to dexametha-</p><p>sone (DEX) in subjects with MDD (Maes et al., 1996). Despite the</p><p>paucity of studies, the extensive 5-HT involvement in hypotha-</p><p>lamic function and the concentration of b-END-releasing neurons</p><p>in the hypothalamus would suggest multiple potential interactive</p><p>links between the two.</p><p>6. The HPA axis, depression and b-END</p><p>Most studies that have examined b-END in MDD have done so</p><p>in the context of investigating MDD-mediated changes in HPA axis</p><p>activity. Thus, a brief summary of salient findings of core HPA axis</p><p>abnormalities in MDD is provided (for more extensive reviews of</p><p>the HPA axis and depression see Holsboer and Barden (1996),</p><p>Nemeroff (1996) and Pariante and Lightman (2008)). Elevated ba-</p><p>sal cortisol levels are observed in up to 2/3 of depressed individuals</p><p>(Carroll et al., 1981; Gold et al., 1988; Holsboer and Barden, 1996;</p><p>Zangen et al., 2002), although rates may be lower in community</p><p>samples (Strickland et al., 2002) and depressed women (Young</p><p>et al., 2001).</p><p>Cortisol levels obtained in the context of neuroendocrine chal-</p><p>lenges are often more informative about dysregulation than basal</p><p>measures. The most widely described challenge paradigm in</p><p>MDD studies is the DEX suppression test (DST), where a single dose</p><p>of DEX (ranging from 0.25–1.5 mg) suppresses cortisol release</p><p>from the adrenal cortex for about 12–24hrs. A significant number</p><p>of depressed individuals exhibit DEX non-suppression, defined as</p><p>a cortisol level</p><p>comorbid disorders</p><p>were exclusionary. Changes in levels of b-END have been noted in</p><p>PTSD (Baker et al., 1997; Hamner and Hitri, 1992; Hoffman et al.,</p><p>1989; van der Kolk et al., 1989), and other anxiety disorders (Darko</p><p>et al., 1992; Eriksson et al., 1989; Pitkanen et al., 1989; Weizman</p><p>et al., 1988). Third, medication status and length of any washout</p><p>period at the time b-END levels were collected were not always</p><p>specified. There is some evidence to suggest that amitryptiline</p><p>(Jadric et al., 2006), specific selective serotonin reuptake inhibitors</p><p>(SSRIs) (Zalewska-Kaszubska et al., 2008; Djurovic et al., 1999;</p><p>Petraglia et al., 1984) and electroconvulsive therapy (Alexopoulos</p><p>et al., 1983; Ebert et al., 1994; Ghadirian et al., 1988; Weizman</p><p>et al., 1987, 1990) may alter plasma levels of b-END in depressed</p><p>individuals. Fourth, the reported amount of assay cross-reactivity</p><p>with b-lipotropin varies between 0% and 100%. If b-END levels dif-</p><p>fered between experimental groups, an inherent assumption is</p><p>that b-lipotropin levels are static and do not change with depres-</p><p>sive symptoms, drug administration, or comorbid psychiatric con-</p><p>ditions. Data to evaluate this assumption are not available. Finally,</p><p>most sample populations consisted of both men and women, but</p><p>data on menstrual phase was not included. b-END levels do fluctu-</p><p>ate over the course of the menstrual cycle (Laatikainen et al., 1985;</p><p>Petraglia et al., 1986) and thus these studies are open to gender-</p><p>specific interpretative difficulties.</p><p>Thus, similar to HPA axis studies, findings from studies of basal</p><p>b-END levels in MDD have been equivocal, provided no clear con-</p><p>clusions. Of the 19 studies included in the table, seven reported in-</p><p>creases in b-END levels in MDD compared to controls; seven</p><p>reported no change and five reported decreased b-END levels. Sig-</p><p>nificant variability was seen in how the depressed patients were</p><p>sub-grouped, included comorbidities and medication usage. The</p><p>degree of cross-reactivity with b-lipoprotein did not seem to affect</p><p>the direction of any observed changes in b-END levels.</p><p>Other lines of evidence that supports decreased b-END levels in</p><p>MDD include a small study of suicide victims with known MDD</p><p>Table 1</p><p>Studies reporting basal b-END plasma levels in patients with MDD vs controls.</p><p>Reference Na Depression type Comorbidity Medicated Cross-reactivity</p><p>(100% b-ENDb +)</p><p>Results</p><p>Akil et al. (1993) 21 MDD,c endogenous subtype Unspecified Unmedicated � 14 days 100% b-lipod * vs. controls</p><p>Ball et al. (1987) 8 MDD + M + Me Unspecified Unmedicated � 14 days;</p><p>some benzodiazepines</p><p>100% b-lipo , vs. controls</p><p>Cohen et al. (1984) 25 MDD, minor depression Yes Unmedicated</p><p>levels were collected at 0800 h, DEX was gi-</p><p>ven on the same day at 2300 h but the post-DEX blood sample was</p><p>collected at 1600 h the next day. Diurnal studies with b-END sug-</p><p>gest that blood sampling for comparative studies should be done at</p><p>the same time across the day (Genazzani et al., 1986; Matthews</p><p>et al., 1986). Clinically, there does not appear to be a significant</p><p>advantage in measuring both cortisol and b-END non-suppression</p><p>by DEX in depressed individuals. When measuring cortisol non-</p><p>suppression only, the DST is able to identify about half to two</p><p>thirds of depressed individuals. Measurement of both cortisol</p><p>and b-END non-suppression leads to identification of about two</p><p>thirds to three quarters of depressed individuals.</p><p>Additional factors influencing post-DEX b-END suppression in-</p><p>clude MDD with melancholia (term used to describe a severe form</p><p>of classical depression) or psychotic features (Maes et al., 1990),</p><p>neurotic depression (Genazzani et al., 1986) and symptom severity</p><p>(Maes et al., 1990; Meador-Woodruff et al., 1987). In addition to</p><p>examining the relationship between non-suppression of b-END</p><p>and cortisol, several authors have examined the relationship</p><p>Table 2</p><p>Studies reporting b-END response in patients with MDD vs. controls after dexamethasone</p><p>Reference Na F Depression type Comorbid</p><p>Akil et al. (1993) 21 17/21 MDDc, endogenous subtype Unspecifi</p><p>Ball et al. (1987) 8 7/8 MDD + M Unspecifi</p><p>Galard et al. (2002) 14 10/14 Mixed depression groups Unspecifi</p><p>Genazzani et al. (1986) 9 0/9 Unspecified Unspecifi</p><p>Karkkainen et al. (1987) 35 22/35 Moderate to severe mixed</p><p>depression groups</p><p>Unspecifi</p><p>Lin et al. (1986) 42 Not</p><p>specified</p><p>MDD, endogenous subtype Unspecifi</p><p>Maes et al. (1990) 35 Not</p><p>specified</p><p>MDD ± M Minor depression Unspecifi</p><p>Matthews et al. (1986) 47 24–33/47 Mixed depression groups;</p><p>some remitted</p><p>Other axi</p><p>I disorder</p><p>Meador-Woodruff</p><p>et al. (1987)</p><p>44 Mixed depression groups Unspecifi</p><p>Morphy et al. (1992) 30 0/30 MDD Unspecifi</p><p>Rupprecht et al. (1988) 50 35/50 Mixed depression groups Unspecifi</p><p>Young et al. (1993) 73 50–52/73 MDD, mostly endogenous</p><p>subtype</p><p>Unspecifi</p><p>aSample size.</p><p>bMajor depressive disorder.</p><p>cb-Endorphin.</p><p>db-Lipoprotein.</p><p>between b-END and ACTH under a number of conditions in</p><p>depressed individuals. Gispen-De-Wied and colleagues (1987)</p><p>examined ACTH and b-END levels in depressed cortisol suppressors</p><p>and non-suppressors in response to DEX. In depressed non-</p><p>suppressors ACTH and b-END were unchanged, while levels of both</p><p>decreased in suppressors. Levels of both ACTH and b-END did not</p><p>differ from controls at baseline. Another group found decreased</p><p>ACTH and b-END levels in both cortisol suppressors and non-</p><p>suppressors (Rupprecht et al., 1988).</p><p>Other neuroendocrine challenge tests have been used to inves-</p><p>tigate b-END in MDD and are summarized in Table 3. While CRH</p><p>induces a rise in b-END levels, no differences were found between</p><p>depressed individuals and controls (Lisansky et al., 1992; Ruppr-</p><p>echt et al., 1989; Young et al., 1990), suggesting that even in the</p><p>presence of MDD, CRH can activate b-END release. However, a</p><p>blunted b-END response is observed with those with MDD after</p><p>infusion of cortisol and hydrocortisone infusion have been re-</p><p>ported (Goodwin et al., 1992; Young et al., 1990,1991). Interest-</p><p>ingly, one study used a psychosocial stressor in MDD patients to</p><p>activate stress response systems and they too were able to demon-</p><p>strate a blunted b-END response (Young et al., 2000) Using the</p><p>more sensitive DEX/CRH challenge produced significant increases</p><p>in b-END levels in major depressives with melancholia compared</p><p>to those with dysthymia or MDD without melancholia (Maes</p><p>et al., 1994). These data again highlight the need for researchers</p><p>suppression test.</p><p>ity Medicated Cross-reactivity</p><p>(100% b-ENDb +)</p><p>Results</p><p>ed Unmedicated � 14 days 100% b-lipod * rate of b-endorphin non-</p><p>suppression vs controls</p><p>ed Unmedicated � 14 days;</p><p>some benzodiazepines</p><p>100% b-lipo Correlation between</p><p>suppression of cortisol and</p><p>b-END</p><p>ed Medicated (10/14) Not specified 33% MDD were non-</p><p>suppressors, +ACTH,</p><p>b-endorphin and salivary</p><p>cortisol</p><p>ed Unmedicated � 10 days 100% b-lipo b-END unaffected by DEX in</p><p>patients; % suppression not</p><p>provided</p><p>ed Mixed drug classes 100% b-lipo Post-DEX b-END * in non-</p><p>suppressors than</p><p>suppressors</p><p>ed Unspecified</p><p>in</p><p>n</p><p>on</p><p>-s</p><p>u</p><p>pp</p><p>re</p><p>ss</p><p>or</p><p>s</p><p>of</p><p>co</p><p>rt</p><p>is</p><p>ol</p><p>M</p><p>or</p><p>ph</p><p>y</p><p>et</p><p>al</p><p>.(</p><p>19</p><p>92</p><p>)</p><p>30</p><p>0/</p><p>30</p><p>M</p><p>D</p><p>D</p><p>U</p><p>n</p><p>sp</p><p>ec</p><p>ifi</p><p>ed</p><p>U</p><p>n</p><p>m</p><p>ed</p><p>ic</p><p>at</p><p>ed</p><p>0%</p><p>b</p><p>-l</p><p>ip</p><p>o</p><p>M</p><p>et</p><p>yr</p><p>ap</p><p>on</p><p>e/</p><p>D</p><p>EX</p><p>+</p><p>b</p><p>-E</p><p>N</p><p>D</p><p>in</p><p>M</p><p>D</p><p>D</p><p>vs</p><p>.c</p><p>on</p><p>tr</p><p>ol</p><p>s</p><p>fo</p><p>ll</p><p>ow</p><p>in</p><p>g</p><p>bo</p><p>th</p><p>ch</p><p>al</p><p>le</p><p>n</p><p>ge</p><p>s</p><p>R</p><p>u</p><p>pp</p><p>re</p><p>ch</p><p>t</p><p>et</p><p>al</p><p>.(</p><p>19</p><p>89</p><p>)</p><p>13</p><p>6/</p><p>13</p><p>M</p><p>ix</p><p>ed</p><p>de</p><p>pr</p><p>es</p><p>si</p><p>on</p><p>gr</p><p>ou</p><p>ps</p><p>U</p><p>n</p><p>sp</p><p>ec</p><p>ifi</p><p>ed</p><p>U</p><p>n</p><p>m</p><p>ed</p><p>ic</p><p>at</p><p>ed</p><p>�</p><p>3</p><p>da</p><p>ys</p><p>5%</p><p>b</p><p>-l</p><p>ip</p><p>o</p><p>h</p><p>C</p><p>R</p><p>H</p><p>h</p><p>,</p><p>vs</p><p>.c</p><p>on</p><p>tr</p><p>ol</p><p>s</p><p>Y</p><p>ou</p><p>n</p><p>g</p><p>et</p><p>al</p><p>.(</p><p>19</p><p>90</p><p>)</p><p>11</p><p>1/</p><p>11</p><p>M</p><p>D</p><p>D</p><p>,b</p><p>ip</p><p>ol</p><p>ar</p><p>de</p><p>pr</p><p>es</p><p>si</p><p>on</p><p>U</p><p>n</p><p>sp</p><p>ec</p><p>ifi</p><p>ed</p><p>U</p><p>n</p><p>m</p><p>ed</p><p>ic</p><p>at</p><p>ed</p><p>�</p><p>14</p><p>da</p><p>ys</p><p>10</p><p>0%</p><p>b</p><p>-l</p><p>ip</p><p>o</p><p>oC</p><p>R</p><p>H</p><p>b</p><p>-E</p><p>N</p><p>D</p><p>re</p><p>sp</p><p>on</p><p>se</p><p>,</p><p>in</p><p>pa</p><p>ti</p><p>en</p><p>ts</p><p>,</p><p>vs</p><p>.c</p><p>on</p><p>tr</p><p>ol</p><p>s;</p><p>ea</p><p>rl</p><p>ie</p><p>r</p><p>sh</p><p>u</p><p>t-</p><p>of</p><p>f</p><p>se</p><p>cr</p><p>et</p><p>io</p><p>n</p><p>of</p><p>b</p><p>-E</p><p>N</p><p>D</p><p>in</p><p>pa</p><p>ti</p><p>en</p><p>ts</p><p>Y</p><p>ou</p><p>n</p><p>g</p><p>et</p><p>al</p><p>.(</p><p>19</p><p>91</p><p>)</p><p>16</p><p>8/</p><p>16</p><p>M</p><p>D</p><p>D</p><p>U</p><p>n</p><p>sp</p><p>ec</p><p>ifi</p><p>ed</p><p>U</p><p>n</p><p>m</p><p>ed</p><p>ic</p><p>at</p><p>ed</p><p>�</p><p>14</p><p>da</p><p>ys</p><p>10</p><p>0%</p><p>b</p><p>-l</p><p>ip</p><p>o</p><p>H</p><p>yd</p><p>ro</p><p>co</p><p>rt</p><p>is</p><p>on</p><p>e</p><p>in</p><p>fu</p><p>si</p><p>on</p><p>+</p><p>b</p><p>-e</p><p>n</p><p>do</p><p>rp</p><p>h</p><p>in</p><p>M</p><p>D</p><p>D</p><p>vs</p><p>.c</p><p>on</p><p>tr</p><p>ol</p><p>s</p><p>Y</p><p>ou</p><p>n</p><p>g</p><p>et</p><p>al</p><p>.(</p><p>20</p><p>00</p><p>)</p><p>10</p><p>4/</p><p>10</p><p>M</p><p>D</p><p>D</p><p>A</p><p>n</p><p>xi</p><p>et</p><p>y</p><p>di</p><p>so</p><p>rd</p><p>er</p><p>s,</p><p>n</p><p>o</p><p>PT</p><p>SD</p><p>i</p><p>U</p><p>n</p><p>m</p><p>ed</p><p>ic</p><p>at</p><p>ed</p><p>U</p><p>n</p><p>sp</p><p>ec</p><p>ifi</p><p>ed</p><p>So</p><p>ci</p><p>al</p><p>st</p><p>re</p><p>ss</p><p>or</p><p>+</p><p>re</p><p>sp</p><p>on</p><p>se</p><p>in</p><p>M</p><p>D</p><p>D</p><p>vs</p><p>.c</p><p>on</p><p>tr</p><p>ol</p><p>s</p><p>a</p><p>Sa</p><p>m</p><p>pl</p><p>e</p><p>si</p><p>ze</p><p>.</p><p>b</p><p>R</p><p>at</p><p>io</p><p>fe</p><p>m</p><p>al</p><p>e</p><p>to</p><p>m</p><p>al</p><p>e.</p><p>c</p><p>b</p><p>-E</p><p>n</p><p>do</p><p>rp</p><p>h</p><p>in</p><p>.</p><p>d</p><p>M</p><p>aj</p><p>or</p><p>de</p><p>pr</p><p>es</p><p>si</p><p>ve</p><p>di</p><p>so</p><p>rd</p><p>er</p><p>.</p><p>e</p><p>b</p><p>-L</p><p>ip</p><p>op</p><p>ro</p><p>te</p><p>in</p><p>.</p><p>f</p><p>O</p><p>vi</p><p>n</p><p>e</p><p>co</p><p>rt</p><p>ic</p><p>ot</p><p>ro</p><p>ph</p><p>in</p><p>re</p><p>le</p><p>as</p><p>in</p><p>g</p><p>h</p><p>or</p><p>m</p><p>on</p><p>e.</p><p>g</p><p>D</p><p>ex</p><p>am</p><p>et</p><p>h</p><p>as</p><p>on</p><p>e.</p><p>h</p><p>H</p><p>u</p><p>m</p><p>an</p><p>co</p><p>rt</p><p>ic</p><p>ot</p><p>ro</p><p>ph</p><p>in</p><p>re</p><p>le</p><p>as</p><p>in</p><p>g</p><p>h</p><p>or</p><p>m</p><p>on</p><p>e.</p><p>i</p><p>Po</p><p>st</p><p>tr</p><p>au</p><p>m</p><p>at</p><p>ic</p><p>st</p><p>re</p><p>ss</p><p>di</p><p>so</p><p>rd</p><p>er</p><p>.</p><p>K.M. Hegadoren et al. / Neuropeptides 43 (2009) 341–353 349</p><p>to develop consensus regarding the classification of important sub-</p><p>types of depression.</p><p>9. Discussion</p><p>In recent years, interest in the role of b-END in MDD has been</p><p>rekindled, after being largely abandoned in the 1980s. The poor</p><p>sensitivity of the DST as a relevant paradigm has been replaced</p><p>by neuroimaging methods and improved test paradigms and as-</p><p>says. Examining the data presented in this review,</p><p>it is readily</p><p>apparent that despite multiple studies using various experimental</p><p>designs, the role of b-END in MDD remains unclear. Evidence sup-</p><p>porting some type of dysregulation in b-END and opioid-related</p><p>neural networks exists, but is subject to significant methodological</p><p>problems. Supportive evidence includes DEX challenge studies that</p><p>show high rates of b-END non-suppression in individuals with</p><p>MDD. Additionally, challenge with cortisol, hydrocortisone, and</p><p>CRH demonstrated altered b-END release in depressed individuals</p><p>compared to controls.</p><p>Based on the pharmacological challenge data, we can infer that</p><p>changes in of glucocorticoid/mineralocorticoid receptor density</p><p>and/or affinity may play a role in the altered release of b-END in</p><p>some depressed individuals. As discussed earlier, dysregulated glu-</p><p>cocorticoid feedback on the HPA axis remains one of the most</p><p>widely studied phenomena in individuals with MDD. However,</p><p>much remains unclear about feedforward and feedback mecha-</p><p>nisms linking glucocorticoids and b-END. For example, one study</p><p>observed glucocorticoid control over all b-END-containing arcuate</p><p>nucleus neurons (Cintra et al., 1991), while a later study suggested</p><p>strong glucocorticoid control over b-END-containing corticotrophs</p><p>in the anterior pituitary but not within b-END-containing melano-</p><p>trophs of the intermediate pituitary lobe (Cintra and Bortolotti,</p><p>1992).</p><p>The interaction between b-END and CRH both in the periphery</p><p>and in the CNS needs to be investigated further with regards to</p><p>stress disorders in which CRH hypersecretion has been observed</p><p>(both MDD and PTSD). In the periphery, CRH and opioid receptor</p><p>interactions have been well documented with regards to pain reg-</p><p>ulation (Smith, 2008). In particular, b-END and CRH receptors are</p><p>co-expressed in macrophage/monocytes, granulocytes, and lym-</p><p>phocytes within blood and inflamed subcutaneous tissues (Mousa</p><p>et al., 2003). CRH interacts with CRH receptors on immune tissues</p><p>to release b-END, resulting in the inhibition of inflammatory pain</p><p>(Smith, 2008). These findings are particularly relevant in stress dis-</p><p>orders such as MDD and PTSD where comorbid somatic symptoms</p><p>are common and high levels of pro-inflammatory cytokines have</p><p>been observed. CRH challenge in individuals with MDD was not</p><p>informative, but may provide more information if relevant sub-</p><p>groups of MDD were examined or if specific depressive symptom</p><p>clusters were analyzed individually. A number of potential dysreg-</p><p>ulatory processes that influence the synthesis, release, and interac-</p><p>tion of b-END with opioid receptors under the influence of CRH</p><p>may contribute to symptoms observed in depressed individuals</p><p>and may be particularly important in those with comorbid chronic</p><p>pain conditions or anxiety.</p><p>Plasma measures of b-END in depressed individuals lend little</p><p>insight into whether any observed changes derive from specific</p><p>pools or pathways within the CNS, endocrine systems of peripheral</p><p>immune cells. While CSF measures are generally considered more</p><p>desirable when examining neuroactive substances originating in</p><p>the CNS, CSF measurements of b-END did not discriminate be-</p><p>tween controls and MDD patients and present ethical and method-</p><p>ological issues in human subjects. However, examination of</p><p>peripheral measures in conjunction with neuroimaging might indi-</p><p>cate whether central and peripheral changes are coordinated.</p><p>350 K.M. Hegadoren et al. / Neuropeptides 43 (2009) 341–353</p><p>Finally, due to synthesis of both inactive and active forms of</p><p>b-END and the inability of some assays to differentiate between</p><p>all the products of POMC, changes in b-END levels may not neces-</p><p>sarily reflect alterations in biological activity at the level of opioid</p><p>receptors. Modification of published analytical methods that do</p><p>not use commercial kits and more detailed information about the</p><p>assay protocol might help resolve sensitivity and cross-reactivity</p><p>issues.</p><p>10. Conclusion</p><p>Human studies aimed at examining the role of b-END in the</p><p>pathophysiology and treatment response in MDD have produced</p><p>many contradictory results. However, some consistencies have</p><p>emerged, including the observation that endogenously depressed</p><p>individuals appear to have lower levels of b-END compared with</p><p>non-endogenously depressed individuals. Unfortunately, this</p><p>method of sub-typing depressed individuals is now outdated and</p><p>it is unclear what the implications of these findings are in the con-</p><p>text of the current DSM-IV categorization of MDD. The review of</p><p>data relating to basal b-END levels in depression highlights the</p><p>need to focus future studies on more clearly delineated groups of</p><p>depressed individuals, paying careful attention to diagnostic crite-</p><p>ria and the presence of specific clusters of symptoms. The inclusion</p><p>of individuals with bipolar disorder as well as certain types of per-</p><p>sonality disorders, among others in ‘‘depressed” samples con-</p><p>founds attempts to develop a theoretical framework relating</p><p>opioid systems to the pathophysiology of MDD. Also, emerging</p><p>data suggests that traumatic life events may alter b-END levels</p><p>(Liberzon et al., 2007) and thus, accurate recording of past and cur-</p><p>rent serious stressors is necessary. Current comorbid psychiatric</p><p>syndromes as well as subthreshold syndromes may further compli-</p><p>cate data interpretation (Baker et al., 1997; Hamner and Hitri,</p><p>1992; Hoffman et al., 1989). The development of international col-</p><p>laborative research networks would allow consensus building</p><p>around definitional issues, lead to standardized experimental pro-</p><p>tocols using similar psychological and biological tools across stud-</p><p>ies and ultimately allow for the integration of both psychological</p><p>and neurobiological data, which is essential for theory</p><p>development.</p><p>Finally, little research exists examining the effects of gender on</p><p>b-END activity in depressed individuals. Increasingly, the impor-</p><p>tance of gender in depression studies is recognized. Government</p><p>publications (Health Canada, 2002) and numerous studies from</p><p>both psychosocial and biological literature call for more gender</p><p>specific research (Blair-West and Mellsop, 2001; Bremner and Ver-</p><p>metten, 2001; Carpenter and Addis, 2000; Cutler and Nolen-Hoek-</p><p>sema, 1991; Davidson et al., 1993; Dawkins and Potter, 1991).</p><p>Future studies must include detailed data on menstrual phase, life</p><p>stage (premenopausal, perimenopausal or postmenopausal) and</p><p>the use of hormone therapies (oral contraceptives as well as hor-</p><p>mone replacement therapies) to allow for accurate interpretation</p><p>of b-END data in depressed women.</p><p>In conclusion, there is still much work to be done to enhance</p><p>our understanding of the role of b-END in MDD. Recent neuroimag-</p><p>ing data highlight that gender and menstrual phase are important</p><p>determinants of l-opioid receptor binding potential. PET data in</p><p>MDD populations are limited to date, are not unequivocal and re-</p><p>quire replication. Further development of a specific and highly sen-</p><p>sitive assay specific for biologically active b-END would allow</p><p>researchers to more accurately interpret data from behavioural</p><p>and neuroendocrine challenges. While studies examining systemic</p><p>circulation of b-END are often more practical to carry out, more fo-</p><p>cus on the CNS using neuroimaging and CSF measures is required</p><p>to more fully understand the functional relationship between cen-</p><p>tral and peripheral measures of b-END. 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