NEUROPHYSIOLOGY_OF_PAIN

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behaviour of these individuals implies a very marked
upregulation of nociceptive system function and
consequent upon this, enormous neuroplasticity and
PERIPHERAL SENSITIZATION
Manual Therapy (1999) 4(4), 196–202
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change in many aspects of central nervous system
(CNS) function. It has become abundantly obvious
that factors other than the injuring stimulus influence
pain perception and that many psychosocial factors
can contribute to the neuroplasticity that occurs in
response to an initial pain stimulus.
Over the last 20 years, an increasing body of re-
search has developed describing the ways in which
nociceptive system function can be upregulated, and
pointing to the e€ects of upregulation of the no-
ciceptive system on somatomotor and somatosympa-
thetic function.
The nociceptive system is normally a very quiescent
system requiring strong, intense, potentially dama-
ging stimulation before it becomes activated. Yet,
Many early studies pointed to sensitization of
peripheral nociceptors as a mechanism underlying
the increased sensitivity to subsequent stimulation
that takes place following tissue injury. It is apparent
that many peripheral nociceptors are polymodal in
the sense that they respond to chemical as well as
mechanical and thermal nociceptive stimulation
(Kymazawa 1996). It is also apparent, from a large
number of studies on both humans and animals, that
chemical mediators released into the tissues as a
result of tissue injury promote sensitization of
peripheral nociceptors. Some of the key mediators,
which have been identified, include bradykinin,
serotonin, histamine, potassium, adenosine, protons,
prostaglandins, leukotriences and cytokines (Dray
1995). The e€ects of these mediators involve binding
to specific receptors, activation of ion channels for
depolarization, activation of intra-cellular messenger
systems, release of a range of neuropeptides to
Anthony Wright BSc(Hons) Phty. Grad Cert Ed, Mphty St (Manip
Ther), PhD, School of Medical Rehabilitation, Faculty of
Medicine, University of Manitoba, T258–770 Bannatyne Avenue,
Recent concepts in the neurophysiology
A. Wright
School of Medical Rehabilitation, Faculty of Medicine,
SUMMARY. This paper describes many of the processe
response to tissue injury. The processes of peripheral and
between the nociceptive, motor and autonomic systems a
influence neuroplasticity within the nociceptive system is
INTRODUCTION
In clinical practice we are well aware of the impact
of pain on an individual. We see people rapidly
transformed from a situation in which they are
experiencing no pain or minimal levels of pain to a
situation in which their pain experience is so severe
and pervasive that it drives all of their behaviours and
becomes the central focus of their existence. Exam-
ples of patients who have sustained a whiplash injury
or other significant musculoskeletal trauma provide
an indication of the impact of pain on previously pain
free individuals. The level of change that occurs in the
Winnipeg, Manitoba, Canada R3E OW3.
196
f pain
niversity of Manitoba, Canada
that exist for upregulation of the nociceptive system in
entral sensitization are described. Potential interactions
e considered. The potential for psychosocial factors to
lso discussed. # 1999 Harcourt Publishers Ltd.
once an individual is experiencing pain, relatively
innocuous stimuli activate the system and trigger pain
perception. This altered perceptual state is encom-
passed by the phenomenon of hyperalgesia, an
exaggerated or increased response to a noxious
stimulus, and the related phenomenon of allodynia,
the production of pain by a stiumulus that would not
normally be painful (IASP 1986). These phenomena
have been the subject of numerous research studies
since the 1930s (Lewis 1936; Hardly et al. 1950;
Meyer et al. 1985; Torebjork et al. 1992; Willis 1992).
promote neurogenic inflammation and alteration of
Neurophysiology of pain 197
neuronal properties by modifying gene transcription.
(Dray 1995; Bevan 1996). A number of receptors and
second messenger systems may be activated following
the release of di€erent inflammatory mediators
(Mizamura & Kumazawa 1996). While polymodal
receptors respond to a range of stimuli, it is apparent
that di€erent receptors and second messenger systems
are involved in excitation and sensitization for
di€erent stimulation modalities (Mizamura &
Kumazawa 1996). One of the most fundamental
influences on nociceptor sensitivity is the pH of the
surrounding tissue. High local proton concentrations
are known to occur in many inflammatory states and
the consequent reduction in pH can contribute to
senstization of polymodal nociceptors (Handwerker
& Reeh 1991; 1992; Reeh & Steen 1996). Altered pH
of the local chemical environment of peripheral
nociceptors is a particularly important factor in
inducing mechanical sensitization and ischaemic pain
(Steen et al. 1992, Dray 1995). Combinations of
inflammatory mediators and combinations of chemi-
cal mediators with altered tissue pH appear to be
more e€ective in inducing sensitization than indivi-
dual chemical mediators alone (Handwerker & Reeh
1991). Thus, in the natural situation it appears to be
a combination of chemical mediators, which Hand-
werker and Reeh have referred to as ‘an inflamma-
tory soup that produces sensitization of peripheral
nociceptors’ (Handwerker & Reeh 1991).
It is also clear that endogenous chemicals act on a
variety of receptors, activate a number of di€erent
intracellular second messenger systems and influence
di€erent ion channels (Dray 1995; Mizamura &
Kumazawa 1996). It is therefore possible for noci-
ceptors to exhibit di€erent forms of sensitization and
for distinctions to be made between the processes
leading to thermal, mechanical and chemical sensiti-
zation (Mizamura & Kumazawa 1996). For example,
prostaglandins may induce sensitization to chemical
mediators at much lower concentrations than those
required to induce sensitization to heat stimuli
(Mizamura & Kumazawa 1996).
Sensitization can also be produced through a
number of di€erent mechanisms. It can occur as a
result of a direct influence of mediators such as
protons and serotonin on membrane ion channels,
particularly sodium channels, to increase membrane
permeability and cellular excitability (Dray 1995).
Many mediators act indirectly via G proteins and a
variety of second messengers to induce changes in
membrane ion channels. Adenosine, bradykinin,
serotonin and prostaglandins may act on receptors
that produce changes in potassium ion permeability
(Dray 1995).
It is also apparent that kinins such as bradykinin
act on the B2 receptor that is coupled to a G protein
causing phospholipase C activation amongst other
e€ects. This leads to the release of intracellular
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calcium and activation of ion channels to increase
membrane permeability, particularly for sodium and
calcium ions (Dray 1995). Increased intracellular
calcium ion concentration also leads to the release of
neuropeptides such as substance P and the stimula-
tion of arachidonic acid production (Dray 1995).
Another mechanism by which peripheral sensitiza-
tion can occur is the inhibition of the hyperpolariza-
tion that occurs after impulse generation. This slow
after-hyperpolarization limits the number of action
potentials that can be generated following stimula-
tion. Prostaglandins and bradykinin act to inhibit this
phenomenon allowing the neuron to fire repetitively
(Dray 1995). This may also be one of the mechanisms
activiated by serotonin (Dray 1996).
Sensitization following the release of cytokines and
leukotrienes appears to occur via indirect mechan-
isms whereby these agents stimulate other cells to
release sensitizing agents. For example,leukotriene
B4 stimulates the release of 8R, 15SdiHETE from
leucocytes and this then acts to sensitize polymodal
nociceptors (Levine et al. 1993). Some of these agents
may also act to induce receptors for other inflamma-
tory mediators (Rang & Urban 1995).
There is increasing evidence for the role of nerve
growth factor (NGF) as a mediator of hyperalgesia
(Anand 1995). Its actions include stimulating the
release of neuropeptides and regulating other pro-
teins such as proton activated ion channels (Anand
1995; Dray 1995; 1996). The induced hyperalgesia
may be reduced by the administration of anti-NGF
antibodies (Woolf et al. 1994).
It is now well established that in many tissues there
is a significant population of nociceptors that remain
essentially inactive under normal conditions. These
sleeping or silent nociceptors are activated as a result
of tissue injury with consequent release of chemical
mediators and increased tissue hypoxia (Schmidt
1996). Schmidt estimates that they may represent
approximately one-third of the total nociceptor
population in joints (Schmidt 1996). They appear
to be present in skin, joints and visceral tissue, how-
ever their presence in muscle tissue has yet to be
demonstrated (Mense 1996). Once activated, these
neurons exhibit marked sensitization with increased
spontaneous discharge rates, reduced thresholds for
evoked discharge and increased discharge rates in
response to stimulation.
The processes of peripheral sensitization are clearly
one way in which nociceptive system activity can be
upregulated in response to tissue injury. It is apparent
that the sensitization process is relatively complex
and that di€erent forms of sensitization may develop
depending on the nature of the injury or disease.
Recruitment of previously inactive nociceptors,
spontaneous discharge, reduced activation thresholds
and increased discharge rates in response to supra-
threshold stimulation contribute to both spatial and
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198 Manual Therapy
temporal summation of nociceptive input within the
CNS. Ultimately, increased impulse activity in noci-
ceptive neurons may be interpreted as pain at higher
levels within the CNS. It is apparent, however, that
there is not an invariable link between the degree of
tissue damage and the level of pain experienced.
Consequently, there must be other processes which
contribute to upregulation of the nociceptive system
and which can substantially modify the influence of
changes occurring in the peripheral component of the
nociceptive system.
CENTRAL SENSITIZATION
The process of central sensitization (Woolf 1994) is
another important aspect of neuroplasticity that
contributes to upregulation of the nociceptive system
in response to injury. This process may provide a link
between the presence of pain and sensorimotor and
autonomic dysfunction in patients with musculo-
skeletal disorders. Central sensitization describes the
changes occurring at a cellular level to support the
process of neuronal plasticity that occurs in nocicep-
tive system neurons in spinal cord and in supraspinal
centres, as a result of activation of the nociceptive
system (Woolf 1994).
This process is initiated by activity in peripheral
nociceptors, particularly those associated with un-
myelinated a€erent neurons but it appears that the
process can also be sustained in the absence of
peripheral nociceptor input (Woolf 1983; Coderre &
Melzack 1987). Excitatory amino acid (EAA) recep-
tors, particularly those of the N-methyl-d-aspartate
(NMDA) subtype, have been strongly implicated in
the generation of central sensitization (Woolf 1994;
Dickenson 1995; Mao et al. 1995). Release of EAAs
such as glutamate and concomitant release of
excitatory neuropeptides such as substance P and
neurokinin A from the presynaptic terminals of
nociceptive a€erents initiates a cascade of changes
in postsynaptic spinal cord neurons (Duggan et al.
1988; 1990; Wilcox 1991). These include G protein
mediated activation of phospholipse C leading to the
release of Ca++ from intracellular compartments as
well as the production of diacyl glycerol, activating
protein kinase C, which in turn modulates ion
channel activity (Woolf 1994; Mao et al. 1995). These
changes upregulate NMDA receptors and enhance
the neuron’s responsiveness to subsequent EAA
release (Woolf 1994). One outcome of this upregula-
tion of NMDA receptors is an increased Ca++ influx
into the cell. Increased intracellular Ca++ concen-
tration reduces transmembrane potential, activities
NMDA receptor ion channels and renders the cell
more excitable. One other e€ect of increased intra-
cellular Ca++ concentration is to trigger the
production of nitric oxide which is thought to be
Manual Therapy (1999) 4(4), 196–202
capable of di€using out of the cell to bring about
increased activation of the primary a€erent neuron
(Meller & Gebhart 1993).
While in recent years there has been a very strong
emphasis on the role of the NMDA receptor in the
central sensitization process, it has now become
apparent that activation of the NMDA receptor
may not be critical to the development of all forms of
central sensitization. It has been suggested that the
NMDA receptor is particularly important in relation
to thermal sensitization and that it may not play a
major role in mechanical sensitization (Meller et al.
1996). Coactivation of spinal a-amino-3-hydroxyl-5-
methyl-isoxazoleproprionic acid (AMPA) and meta-
botrophic glutamate receptors induces an acute
mechanical sensitization (Meller et al. 1996). This is
mediated through activation of phospholipase A2
leading to the production of arachidonic acid. It
appears to be the products of the cyclooxygenase
pathway for metabolism of arachidonic acid that are
of most importance in generating mechanical sensi-
tization (Meller et al. 1996). Activation of NMDA
receptors, phospholipase C, protein kinase C, or the
production of nitric oxide do not appear to be
important factors in the production of mechanical
sensitization (Meller et al. 1996).
It is apparent, therefore, that the process of central
sensitization is a relatively complex one and that in
common with peripheral processes, the nature of
molecular changes underlying central sensitization
may vary depending on the nature of the inducing
stimulus. In both cases it is becoming increasingly
apparent that distinctions can be made between the
processing of mechanical and thermal nociceptive
information. Central sensitization contributes to a
number of aspects of neuroplasticity including
increased excitability of wide-dynamic range cells
(Woolf 1989), increased receptive field size (Cook
et al. 1987) and changes in somatic withdrawal
reflexes (Woolf 1984). The development of tenderness
(Tunks et al. 1988), the spread of pain from a primary
location (Simons & Travell 1983), increased guarding
of an a€ected area and alterations in skin tempera-
ture (Diakow 1988) are amongst some of the clinical
characteistics which may be manifestations of neuro-
plasticity due to central sensitization.
The major consequences of these molecular
changes in spinal cord neurons are increased synaptic
ecacy and increased neuronal excitability. Neuronal
plasticity leading to increased synaptic ecacy
and increased neuronal excitability in spinal cord
neurons conveying nociceptive information is also
likely to influence activity in other neuronal pools
with which the central nociceptive neurons make
synaptic connections. This could account for changes
in motor and autonomic nervous system function,
which are clinical features of most musculoskeletal
pain states.
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Neurophysiology of pain 199
MOTOR DYSFUNCTION
It is clear that this hyperactive state of spinal cord
neurons is associated with important changes in
terms of sensorimotor function. Woolfhas shown
that the establishment of central sensitization is
associated with facilitation of flexor withdrawl reflex
responses (Woolf 1984). A prolonged increase in the
response duration is maintained for several days and
in some cases may still be present weeks later, when
tissue healing is presumed to have occurred (Woolf
1984).
In addition to increased muscle activation attribu-
table to the influence of pain and tissue damage on
alpha motor neuron function, it has been suggested
that pain may influence the excitability of gamma
motor neurons contributing to the development of
increased muscle tension or spasm. The vicious cycle
model is often alluded to in the literature. As outlined
by Johansson and Sojka (1991), the basic concept is
that stimulation of nociceptive a€erents from muscles
excites dynamic and static fusimotor neurons enhan-
cing the sensitivity of primary and secondary muscle
spindle a€erents. Increased activity of the primary
muscle spindle a€erents increases muscle sti€ness.
This increased muscle sti€ness then leads to increased
metabolite production and following the vicious cycle
formula, a further increase in muscle sti€ness. In
addition, increased activity in the secondary spindle
a€erents projects back onto the gamma system
perpetuating the enhanced muscle sti€ness. These
e€ects are thought to be important in generating
muscle spasm and pain (Johansson & Sojka 1991).
There are several studies by Johansson’s group
demonstrating enhanced activity in primary and
secondary spindle a€erents following the application
of chemical mediators such as potassium chloride,
lactic acid, bradykinin and serotonin (Johansson
et al. 1993; Djupsjobacka et al. 1995). In addition
to altered responses following local muscle injection,
these researchers have also demonstrated modulation
of secondary muscle spindle a€erents following
injection of bradykinin into the contralateral muscle
(Djupsjobacka et al. 1995). This model may provide
some explanation of muscle spasm when it is a
significant component of the clinical presentation.
However, it provides very little explanation of
situations in which we see muscle inhibition and
wastage as a result of pain and a number of studies
have failed to show an increase in resting EMG
activity as might be postulated by this model. Lund
et al. (1991) refute the vicious cycle model and
suggest that pain reduces the ability to contract
muscles rather than making them hyperactive. Their
model is strongly linked to the phenomenon of
central sensitization. They propose that the e€ect of
noxious stimulation is to alter the activity of type II
spinal cord interneurons, such that there is increased
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inhibition of agonist motor units and increased
facilitation of antagonist motor units. This leads to
an overall limitation of movement in any desired
direction. The proposed alterations in neural function
would be manifest as a reduction in the ability to
activate the agonist muscle, a time delay in activating
the agonist muscle and a reduction in the maximum
force output from the agonist muscle. Increased
activity in antagonist muscles and a delay in
producing reciprocal inhibition of these muscles
might also be anticipated. Movement becomes
slower, muscles appear to be weaker and the overall
range of movement accomplished may be reduced
(Lund et al. 1991).
Deficits of this type have been demonstrated in
patients with low back pain and in normal subjects
following the injection of hypertonic saline into the
lumbar paraspinal muscles (Arendt-Nielsen et al.
1996) and the muscles of mastication (Svensson et al.
1996). It appears that this model may represent a good
explanation of the limitation of movement that occurs
in the acute pain situation. It is apparent, however,
that motor dysfunction in chronic pain states may be a
somewhat more complex phenomenon.
SYMPATHETIC DYSFUNCTION
Peripheral and central sensitization have also been
implicated in changes in the autonomic function that
are a feature of many pain states. Several authors
have recognized that a link may exist between the
experience of pain and alterations of sympathetic
function and suggest that sympathetic outflow may
influence or maintain a€erent activity in nociceptive
neurons (Roberts 1986; Campbell et al. 1992; Janig
& Koltzenburg 1992; Devor 1995). The potential role
of the SNS and postganglionic noradrenergic neurons
in complex regional pain syndromes remains contro-
versial, and little consideration has been given to the
role of such mechanisms in less severe musculo-
skeletal disorders. Nevertheless, alterations in SNS
function have been noted and abnormalities of
somatosympathetic reflex responses have been de-
monstrated in patients with musculoskeletal disorders
(Mani et al. 1989; Thomas et al. 1992; Smith et al.
1994).
Under normal physiological conditions, there
appears to be no communication between sympa-
thetic postganglionic neurons and a€erent neurons
(Janig & Koltzenburg 1992). A€erent neurons are not
sensitized or excited by activity in sympathetic
e€erents or the release of nor adrenaline (Shea & Perl
1985). Under pathophysiological conditions, however,
increased alpha-adrenergic sensitivity in injured
nociceptors has been demonstrated experimentally
(Sato & Perl 1991; Devor 1995; Janig et al. 1996).
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200 Manual Therapy
In sympathetically maintained pain states, Roberts
(1986) proposed that central sensitization is main-
tained by ongoing activity of mechanoreceptors that
are excited by sympathetic e€erents. He hypothesized
that a vicious cycle is established in which central
sensitization maintains increased e€erent sympathetic
activity that in turn maintains peripheral mechano-
receptor sensitization. Alternatively, it has been
proposed that low-grade activity of nociceptors may
be necessary to maintain chronic central sensitization
(Treede et al. 1992). Several mechanisms may account
for an interaction between sympathetic e€erents and
mechanoreceptor a€erents in the case of peripheral
nerve injury (Devor 1995; Janig et al. 1996; Sato &
Kumazawa 1996). These include coupling between
sympathetic fibres and a€erent terminals in a
neuroma, coupling between unlesioned postganglio-
nic and a€erent terminals following partial nerve
lesion and coupling following collateral spreading in
dorsal root ganglia following peripheral nerve lesion
(Janig et al. 1996).
It is clear, however, that the process of peripheral
sensitization is essential for the expression of nor
adrenergic sensitivity in the case of tissue injury or
inflammation (Janig et al. 1996; Sato & Kumazawa
1996). A form of indirect hyperalgesia, mediated by
sympathetic postganglionic noradrenergic neurons
has been proposed and is referred to as sympa-
thetic–dependent or maintained hyperalgesia (Levine
et al. 1992). It appears that nor adrenaline acts to
stimulate prostaglandin release, which in turn induces
nociceptor sensitization (Janig et al. 1996; Sato &
Kumazawa 1996). An important aspect of this model
is that it does not require any increase in SNS e€erent
activity but rather implies increased sensitivity to the
normal release of nor adrenaline.
It is apparent that activation and upregulation of
the nociceptive system induces changes in somato-
motor and somatosympathetic function. The nature
of these changes may be somewhat more complex
than originally envisaged. There is still a good deal of
research required to bring about a comprehensive
understanding of the linkages between these systems.
CENTRAL INTEGRATION OF NOCICEPTIVE
INPUT
Pain and nociceptive inputs can exert a strong in-
fluence on motor function, autonomic function and
emotional state. As well as interactions at spinal cord
level integration of nociception and other CNS
functions must occur at higher centres. Itis also
clear that pain perception can be strongly modulated
by descending systems originating in various parts of
the brain and that the nociceptive system is normally
in a state of tonic inhibition (Stamford 1995; Cervero
& Laird 1996). This modulation can take the form of
Manual Therapy (1999) 4(4), 196–202
upregulation of pain perception as well as down
regulation of pain perception associated with analge-
sic e€ects (Cervero & Laird 1996). It is now becoming
apparent that, as well as being inflenced by pain
motor activity, autonomic functions and emotional
state can in turn influence pain perception. As a
consequence, the CNS is better viewed as an
integrated cyclical system rather than the simple
cause and e€ect system enshrined in the distinction
between a€erent and e€erent aspects of function.
In recent years, functional imaging studies have
provided abundant evidence of the distributed nature
of the nociceptive system and the potential for close
association between areas of the nervous system
responding to pain and areas controlling autonomic
and motor function and emotional state (Porro &
Cavazzuti 1996). For example, it is clear that both the
basal ganglia and the periaqueductal gray (PAG)
region receive nociceptive inputs as well as coordinat-
ing important aspects of movement and motor
control (Lovick 1991; Chudler & Dong 1995). Those
regions of the brain encompassing the limbic system
and areas such as the PAG also provide a neuro-
anatomical substrate for interactions between noci-
ception, emotional state and autonomic activity
(Lovick 1991; Chapman 1996). There is a consider-
able overlap between the neuroanatomical and
neurotransmitter systems modulating pain perception
and those controlling emotional state (Chapman
1996). Other papers in this issue deal with the
importance of psychosocial factors in relation to
pain perception and pain behaviour. Functional
brain imaging studies are increasingly providing a
means of bridging the gap between psychological
studies and basic neurophysiological studies and
allowing us to gain some basic understanding of the
way in which nociception is intimately integrated
with many other aspects of CNS function.
CONCLUSION
Recent advances in our knowledge of pain have
provided a much greater insight into the many ways
in which nociceptive system activity can be upregu-
lated in response to tissue injury. It is clear that both
peripheral and central mechanisms are important and
the subtle variations in the mechanims activated can
result in di€erent forms of altered sensitivity being
induced. Rapidly developing areas of research are
also improving our knowledge of the interrelation-
ship between pain, motor and autonomic function
and emotional state. We are beginning to move away
from a largely peripheralist view of tissue injury to a
much more integrated understanding of the influence
of pain and injury on the central nervous system and
the patient as a whole. Ultimately this should lead to
the development of a more comprehensive approach
# 1999 Harcourt Publishers Ltd
Neurophysiology of pain 201
to the management of patients with musculoskeletal
disorders.
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Manual Therapy (1999) 4(4), 196–202
 # 1999 Harcourt Publishers Ltd
	INTRODUCTION
	PERIPHERAL SENSITIZATION
	CENTRAL SENSITIZATION
	MOTOR DYSFUNCTION
	SYMPATHETIC DYSFUNCTION
	CENTRAL INTEGRATION OF NOCICEPTIVE INPUT
	CONCLUSION
	References