2001 current pain and headache reports
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Pathophysiologic Mechanismsof Neuropathic Pain
Bradley K. Taylor, PhD
Address
Division of Pharmacology, School of Pharmacy, University of
Missouri-Kansas City, 2411 Holmes Street, M3-C15,
Kansas City, MO 64108, USA.
E-mail: taylorb@umkc.ed
Current Pain and Headache Reports 2001, 5:151 –161
Current Science Inc. ISSN 1531–3433
Copyright © 2001 by Current Science Inc.
Distinctive Features of Neuropathic PainNeuropath ic pain is defined as "pain initiated or caused
by a primary lesion or dysfun ction in the n ervous system"
[1]. Certain cha racteristics of repo rted abn orm al sensa-
tions m ay suggest a diagnosis of neuropath ic pain [2].
Of these sensations, tactile allod ynia is the m ost striking.
Allodynia refers to the p ain evoked b y a gentle tactile
stimulus; even very mild som atosensory stimu li, such as
slight ben ding of h airs, contact with b edcovers, or the
wearing of clothes, can become excruciating. Allodynia is
usually foun d n ear the cutaneou s territory inn ervated bythe d amaged nerves, the skin itself being otherwise healthy.
The term allodynia is increasingly being used in appro-
priately to imp ly a distinct patho physiologic mechan ism,
and should b e avoided in th at context [3]. In addition,
neuropathic pain com mon ly has a burning and/o r shoo t-
ing quality with unusual tingling, crawling, or electrical
dysesthesias. Such sensations are o ften experienced spon-
taneo usly, in the absence of an external stimulus. A third
suggestive feature is th e pro gressive worsen ing of p ain
during slow repetitive stimu lation with a m ildly no xious
stimulus, such as a pin prick. Occasionally, this manifests
itself as hyperpath ia—a delayed p ainful aftersensation to
a stimu lus, particularly when p resented repeti t ively.
Th is rare, paradoxical pain often occurs in an area tha t is
no rmally hypoesthetic, but can b ecome explosive after
exposure to a n oxious stimulus or a stimulus that n ormally
produces another sensation. Fourth, if small-diameter
fibers of a cutaneou s nerve are damaged, then the area
of skin repor ted as painful m ay be coextensive wi th
or within a zon e of hypoesthesia to no xious stimu lation.
In considering the diagnosis of neuropathic pain, it must
be kept in mind that patients with p eripheral nerve lesion
or dysfun ct ion can experience more than on e type of
abno rmal sensation, and each sensation may reflect a
distinct pathophysiologic mechanism.
With recent advances in o ur understanding of the patho-
ph ysiology and ph armacotherapy of pain, we can n ow
distinguish neuropathic pain from other types of pain—
transient and inflammatory pain (Fig. 1) [4]. A transient
noxious stimulus, such as noninjurious brief exposure to
ho t metal o r a sharp o bject, acts as an early warning device
that helps to prevent tissue damage. Transient pain (also
den oted by mo re ambiguous terms such as “physiologicpain” or “normal pain”) elicits a coordinated, reflexive
response constellation. Behavioral responses include with-
drawal from the stimulus, whereas autono mic responses
include increases in blood pressure and heart rate, and other
emotion al or stress responses, which include activation of
the hypoth alamic-pituitary-adrenal axis [5,6]. If non-neural
tissue dam age does occur, as in the setting of inflamm atory
pain , a set of excitatory chan ges in the periphery and in the
central nervous system ( CNS) establish a m ore persistent,
bu t reversible, hypersensitivity in th e inflamed and sur-
roun ding tissue. Reversible in flamm atory pain is associated
with hyperalgesia and an expansion of receptive fields,
typically of a quantitative nature. The resulting imm ob il-ization and protective beh aviors prevent further dam age,
and thus assist in wound repair. As illustrated in Figure 1,
transient pain and reversible inflamm atory pain serve physi-
ologic, adap tive functions. In contrast, certain d iseases
such as arthritis are associated with chronic inflammation ,
leading to a pathologic pain state.
In con trast to no n-neural tissue d amage, nerve injury
can produce sensory/m otor deficits and oth er paradoxical
sensations of a qualitative nature. As might be expected,
impaired cond uction of afferent n erve activity leads to an
New animal models of peripheral nerve injur y have
facilitated our understanding of neuropathic painmechanisms. Nerve injury increases expression and
redistribution of newly discovered sodium channels from
sensory neuron somata to the injury site; accumulation
at both loci contr ibutes to spontaneous ectopic discharge.
Large myelinated neurons begin to express nociceptive
substances, and their central terminals sprout into
nociceptive regions of the dorsal horn. Descending
facilitation from the brain stem to the dorsal horn
also increases in the sett ing of nerve injury. These
and other mechanisms drive various pathologic states
of central sensitization associated with distinct
clinical symptoms, such as touch-evoked pain.
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152 Neuropath ic Pain
area of sensory deficit , felt by patients as n um bn ess,
whereas impaired conduction of efferent nerve activity
leads to m uscle deficits, experienced by patien ts as weak-
ness. These are termed “negative symptoms,” or “negative
ph eno men a.” Many pa t i en t s , ho wever, a l so r epor t
enh anced sensations; these are termed “positive phen om -
ena,” or “po sitive symp tom s.” They range from p ares-
thesias such as t ingling and prickling sensations, to
hyperesthesias (heightened but n onp ainful appreciation of
sensation ), to d ysesthesias (unp leasant or painful sensa-
tions) [7]. Thu s, the qu ality and pattern o f altered sensi-
tivity in neuropa thic pain clearly differs from transient o r
inflammatory pain. For example, a cold stimulus such as
ice may reduce inflammatory pain in the n ormal person,
but p rodu ce excruciating pain in th e neurop athic pain
patient. These q ualitative d ifferences in sensation suggest
tha t nerve injury leads to a reorganization of sensory trans-
mission pathways that persist long after the normal heal-
ing period. Such a reorganization in the n ervou s system
would suggest that simple knowledge of pain pathwaysand n eurotransmission is not enough to un derstand
chronic neuropathic pain. Thus, because neurop athic pain
involves qualitative alteration s of sensory transm ission
path ways, neurop athic pain mu st be studied and treated
separately from transient or inflamm atory pain. Indeed,
certain drugs that b lock nociceptive pain , such as no n-
steroidal an ti-inflammato ry drugs, prod uce on ly small
analgesic effects at best in neuropathic pain. In contrast,
the n ew generation of anti-epileptic drugs reduce n euro-
pathic pain bu t not transient pain [8,9].
New Models of Neuropathic PainOver the past decade, we have experienced an explosion o f
research d irected toward an un derstanding of the path o-
ph ysiologic neu ral chan ges associated with n europ athic
pain. Most of this research stems from th e developm ent
of new anim al mod els of peripheral nerve injury [10],
and fr om exper im en t a l hum an s t ud i e s o f pa in and
sensory changes after dermal injection of capsaicin. In the
capsaicin mo del, controlled clinical information usually
comes in th e form of neurop hysiologic recordings and the
results of pharmacologic treatment trials [11••].
As illustrated in Figure 2, po pular an imal m od els of
neuropathic pain include partial injury of the sciatic nerve
[12,13] o r ligation of spinal n erves [14]. In con trast with
previous mo dels involving com plete section of the sciatic
nerve, these newer mo dels leave a large prop ortion of
mo tor fibers intact, allowing beh avioral m easurement.
Nerve injury–induced p ain-like behavior in an imals share
some key distinguishing characteristics with sympto ms of
neuropathic pain in humans. In a promising new model
[15,16••], for example, ligation of certain peripheral
branches of the sciatic nerve perm its behavioral testing of
the noninjured skin territories adjacent to the denervated
areas. This surgery leads to robust and long-lasting behav-
ioral mo dification s, includin g increased tactile an d cold
sensitivity (characteristic of neuropathic pain) without any
change in heat thermal thresholds (not characteristic of
neuro pathic pain ). This suggests that similar mechan isms
drive sensory hypersensit ivity in an imal m od els and
human patients. Although key differences do exist, such
as variability and tem po ral progression , stud ies of thesimilarities have greatly contributed to our understanding
of the specific mechanisms th at un derlie the posit ive
symp toms o f neuropath ic pain and the therapeutic effects
of new drugs. Already, detailed studies of neurop athic pain
in patients and anim al mod els have converged to ind icate
that changes in both the peripheral and central nervous
system cause and maintain signs of abnormal sensory
funct ion fol lowing n erve d amage. These al terat ions
include biochemical, anatomic, and physiologic changes
in th e soma tosensory system at th e level of the primary
afferent n euron, spinal cord dorsal horn, and brain.
Primary Afferent Neuronal MechanismsAs alluded to earlier, the p eripheral m echanism s gener-
ating neuropathic pain consist of important differences
from tho se generating oth er types of pain. With transient
pain, events at the p eripheral terminals of no ciceptors
initiate axonal impulses. Periph eral nociceptive terminals
selectively express transdu cer proteins, which respo nd to
therm al, tactile, or chem ical stimu li. If the current is suffi-
cient, action potentials are initiated and conducted to the
central termin als in the spin al cord, leading to the release
Figure 1. Categorization of pain bymechanism and adaptive nature. Noxious
stimuli that either do not damage tissue(transient) or that damage non-neural tissue
(acute inflammatory) typically produce an
adaptive physiologic pain state that prevents
further damage or promotes healing. When
the non-neural tissue damage persists (chronicinflammation), or when neural tissue is injured
(neuropathic), a maladaptive pathophysiologic
pain state may ensue. The overlap betweeninflammatory and neuropathic pain
represents neuroimmune interactions.
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Pathoph ysiologic Mechan isms of Neuropath ic Pain • Taylor 153
of nociceptive transmitters such as glutamate. Glutamate
activates AMPA and kainate ligand-gated ion channels on
second -order neurons in th e spinal cord, which th en relay
the n ociceptive signals to a n um ber of brain stem areas as
well as the thalamus. It is these pathways that also m ediate
inflamm atory pain; if the n oxious insult is severe and
dam ages tissue, num erous changes may take place within
the n ervous system. Some o f these are also characteristic of
neurop athic pain, such as central sensitization, chan ges in
neurochemical phen otype, and certain supraspinal m echa-
nism s, as discussed later. However, inju ry to the n ervou s
system prod uces addi t ional lon g-term chan ges that
contribute to neuropathic pain. We begin with a d iscussion
of how p rimary afferent neuron s acquire spontan eous andstimulus-evoked activity at loci other than peripheral
terminals, nam ely the nociceptor axons and cell bodies.
Ectopic activity of damaged nerves
Wall and Gutnick [17] foun d that spon taneous (stimu lus-
independent) activity and robust mechanical (stimulus-
depen den t) sensitivity develops in the afferent axona l
sprouts inn ervating the neuro ma ( Fig. 3). The ab no rmal
impulses arising from these sites are called ectopic because
they do not originate from the normal transduction elements
of peripheral terminals of the primary afferent nociceptor.
Ectopic activity has been observed in animal models of
neuropathic pain, including the chronic constriction injurymodel [18,19] and the spinal nerve lesion m odel [20• ,21• ],
and is a key determinant in the generation and maintenance
of positive neuropathic symptom s such as spontaneous pain
[22]. The specific sensory disturbances and types of pain that
may be associated with neurom as vary greatly amo ng
individuals, however, and are not yet well understood.
Stimulus-dependent activity
Health y senso ry n erve axons are no rmally insen sitive
to no n-noxious mechan ical stimulation. In the setting of
nerve injury, however, they develop extreme mechanical
sensit ivity, such th at arterial pulsation s may becom e
painful. The m echanosensitivity of neuromas h as been
shown by manip ulating them o r probin g their surface,
which prod uces bursts of impulses, sometimes in lon g
trains [22]. In hu man s, electrical discharges from neuro-
ma s have been recorded usin g microelectrodes placed
within the n erves. Such m icron eurographic recordings
from patients with traumatic or ampu tation n euromas
have shown that tapping the n euroma evokes nerve dis-
charges accomp anied either by sensation s of electric
shocks (Tinel's sign) or pain [23]. These responses can
often be blocked with local anesthetic injections directly
at the n euroma, suggesting that stimulus-dependen t painarises from the n eurom a itself.
Stimulus-independent activity
Normally, the spontaneous activity of primary afferent
neuron s is quite low. In p atients with chron ic periph eral
neu ropath y, however, direct m icron eurograph ic record-
ings demonst r a t ed enhan ced spon taneous f i ring of
no ciceptors innervating the p ainful region, in dicating
that abnormally active nociceptors contribute to neuro-
pathic pain [23]. Also, animal models demonstrate that
axotomized primary afferent neurons generate ongoing
ectopic discharges. Damaged an d regenerating distal
axon terminals do no t appear to be the sou rce of theseectopic impu lses, because local an esthetic application,
such as lidocaine infiltration of a periph eral neurom a,
does no t change spon t aneous d i scha r ge and pa i n .
This indicates that the neurom a is no t the only source of
spontan eous pain impu lses [23]; rather, afferent neuron s
supp lying skeletal mu scle, but n ot skin afferents, gener-
ate ectopic activity [24]. In addition , as illustrated in
Figure 3, a region n ear the dorsal root ganglion (DRG)
becomes capable of generating spontaneo us imp ulses
after nerve injury [22,25].
Figure 2. Animal models of neuropathicpain. Increases in tactile and thermal
sensitivity arise following 1) spinal nerveligation [14]; 2) placement of four loose
ligatures about the sciatic nerve [13]; 3)
partial li gation of the sciatic nerve [12];
and 4) ligation and section of the ti bial andcommon peroneal nerves [16• • ]. In the
latter model, a robust and long-lasting
increase in tactile sensitivity, in the
absence of decreased thermal threshold,
best mimics neuropathic pain in humans.
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154 Neuropath ic Pain
Abno rmal expression o f peripheral sodium channels
Sodium channels contribute to st imu lus-independ ent
pathologic pain states. As discussed in further detail next,
nerve injury triggers either an increase in the expression
of some sodium chan nels, or a redistr ibution of other
sodium chann els from th e soma to th e site of injury [26–
28]. The resulting accumulation o f sodium chan nels low-
ers action potential threshold and causes spontaneous
ectopic discharge. Anticon vulsants, such as carbam azepine,and an tiarrhythmics, such as m exiletine, no nselectively
block sodium chann els and th us stabilize membranes at
aberrantly active loci. Both are used in the treatm ent o f
neurop athic pain. Although th e dose required for such
actions is small relative to effects on uninjured axons, it is
still high enough to significantly inhibit sodium chann els
on cardiac myocytes, leading to dan gerous adverse effects.
The search for sodium channel blockers without these side
effects has led to an explosion o f research investigating the
biology of sodium chann els.
Dorsal root ganglion neurons specifically express at least
six distinct sodium chann el subunits [29]. Two of these, SNS
(for “sensory-nerve-specific,” also known as PN3) [30 ,31• • ]
and SNS2 (also known as NaN) [32 ,33], exist specifically on
no ciceptive neurons of dorsal root an d trigeminal ganglia,
and are tetrodotoxin-resistant. As illustrated in Figure 3, nerve
injury decreases gene expression of SNS and NaN in the soma
[34•,35• • ], but prom otes the translocation of SNS to the site
of injury [28]. Although enhanced NaN activity does not
appear to contribute to hyperalgesia and allodynia in mice
[31• • ], removal of SNS function alleviates allodynia and
hyperalgesia. Thus, selective "knock-down" of the SNS pro-
tein with specific antisense oligodeoxynucleotides prevents
hyperalgesia and allodynia caused by chron ic nerve injury
[31• • ]. Conversely, “knock-ou t” of the SNS gene does not
alleviate such beh aviors in m ice [31• • ]. Knock-down tech-
niqu es may decrease the expression of proteins other than
SNS, whereas knock-out techniques may produce compensa-
tory increases in proteins other than SNS, and so the con tri-
bution of SNS to neuropath ic pain remains controversial.
In contrast to the down-regulation o f the SNS and NaN
sodium chann els, nerve injury upregulates the expression
of the tetrodo toxin-sensitive alpha-III emb ryon ic sodium
channel in sensory neurons (Fig. 3) [36]. Type III is no rmally
expressed only during development—nerve injury appar-
ently mimics the environmental conditions ( ie, production
of growth factors) necessary for its re-expression . Interest-
ingly, both alpha-III induction an d reduction in expression
of SNS/NaN are reversed by the continuous intrathecal deliv-
ery of growth factors such as glial cell-derived n eurotrophic
factor, suggesting that neurotroph ins p rotect n eurons from
injury-induced changes in sodium channel expression
[34• ,35•• ]. Just what will happ en to nerve injury–inducedallodynia and hyperalgesia when the function of the alpha-
III channel is removed ( ie, with type III antagonists or knock-
down o r conditional knock-out techniques) remains an
open question that will likely be answered soon.
Sensory-sympathetic coupling
Physiologic evidence for sensory-sympathetic coupling
Under physiologic conditions, primary afferent nerve endings
are not sensitive to catecholamines and are functionally dis-
tinct from the efferent sympathetic nervous system. Normally,
symp athetic activity does no t prod uce pain . Nerve injury,
however, can induce norad renergic supersensitivity; this sen-
sory-sympathetic coupling may contribute to stimu lus-inde-pendent neuropathic pain in some patients. In hum ans, the
application of norepinephrine at or near a neuroma increases
electrical discharges and produces severe burning pain [37].
Furtherm ore, anim al stud ies suggest that intra-arterial
injections of noradrenaline can activate or sensitize intact C
nociceptors in the partially injured nerve [38]. Finally, electri-
cal stimulation of the sympathetic chain, causing endogenous
release of no repineph rine, increases the discharge of unm yeli-
nated sprouts that have regenerated in to a neurom a [39].
Alpha-2 adrenergic receptors contribute to th e increased sen-
Figure 3. Sodium channel-mediated ectopic activity. Under
normal conditions (top ), the tetrodotoxin-resistant sodium channels
sensory-nerve-specific (SNS) (hourglass shapes ) and SNS2 (NaN)
(circles ) are expressed on the cell membrane of dorsal root gangli a
(DRG) neurons. In the setting of nerve transection (middle ), thealpha-III embryonic sodium channel (squares ) is now expressed,
and SNS is translocated from the DRG soma to the site of injury
and neuroma formation (marked by an X). As a result (bottom ),alpha-III accumulates at the DRG, and SNS accumulates at the
neuroma (dashed circle ), leading to ectopic activi ty at both sites
(flare, denoted by short lines about the neuroma and cell body).
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Pathoph ysiologic Mechan isms of Neuropath ic Pain • Taylor 155
sitivity to norepineph rine [38], but the relative importance of
the alph a-1 receptor (or an un discovered type of adreno-
ceptor specific to nerve damage) remains controversial [20• ].
Anatomic evidence for sensory-sympathetic coupling
After nerve dam age in the rat, no repineph rine-con taining
sym pathetic po stganglionic fibers that no rmally innervate
small blood vessels sprout, a process that is likely triggered by
a neurotrophin such as nerve growth factor [40]. In add ition
to m aking nonsynaptic contacts with sensory endings, sym-
pathetic sprouts can actually encircle large-diameter DRG
som ata, formin g “baskets” [41]. The n et result of thisincreased sympathetic innervation could be the creation of a
new source of releasable norepinephrine. Whether or not
this additional neu rotransmitter is com plemen ted by an
increased expression o f adrenergic receptor in DRG neurons,
however, has not been demonstrated.
Clinical significance of the sympathetic nervous system and
the use of sympathetic blockade for neuropathic pain
Several lines of clinical evidence imp licate a sym path etic
contribution to n europathic pain [40]. First, and most com-
pelling, surgical destruction or pharmacologic blockade of
sympathetic outflow to th e affected region o ften produces
pain relief. Secon d, neuropathic pain is worsened by stim-
uli that evoke a sympath etic discharge, including the startle
respon se and em otiona l arousal. Third, patients with n eu-
ropath ic pain often h ave accom pan ying signs possibly
attributable to abn orm al symp athetic activity, including
skin vasomotor and sweating abnorm alities and dystrophic
changes in skin, hair, nails, and b on e. Despite this an d
other evidence, however, adrenosensitivity may no t contrib-
ute to a s man y cases as was on ce thou ght. For example,
rando mized, placebo-con trolled trials of patients with
complex regional pain syndrome have failed to demon-
strate a large benefit of sympatho lytic procedures [42]. Like-
wise, neurop athic pain in anim al models is often resistant
to symp athectomy [43• ]. And alth ough symp athectomy
reduces pain, paresthesias, and au ton om ic instability in
some patients, these symptoms often return after 6 month s.
Thus, despite intensive study over the past two decades, the
contribution o f the autono mic nervous system to neu ro-
path ic pain remains frustratingly uncertain.
Phenotypic changes in damaged and
undamaged nerves
Nerve injury elicits a complex pattern of phenotypic changes
in DRG neurons, including alterations in the expression of
neurotransmitters, neuromodulators, receptors, ion chan-
nels, and structural proteins. Whereas som e of these changes
are related to repair or regeneration, others may contribute
to n europathic pain . As illustrated in Figure 4, nerve injury
induces the expression of pronociceptive substances, such
as substance P in spared A- fibers [44], which normally
transmit only non-noxious tactile messages. This switchin neurochemical phenotype to a nociceptive mod e may
contribute to the touch-evoked pain that is so characteristic
of many neuropathies [45•• ].
Possibly in response to the increased expression of noci-
ceptive substan ces and ensuin g increase in pain tran s-
mission, a compensatory increase in inhibitory substances at
the DRG may also occur. For example, nerve injury induces a
dramatic up regulation of an tinociceptive substances such as
neu ropeptid e Y in sp ared A- fibers [46], an d in creases
the release of neuropeptide Y in the dorsal horn [47]. The
final b alance between pro- an d antino ciceptive changes in
neurochemical “signatu re” in the p rimary afferent neuron
may determine the degree of positive neurop athic painsymptoms following nerve injury [48,49].
Neuroimmune interactions
As with dam age to non-neu ral tissue, injury to nerves leads
to an inflammatory response. At the site of nerve damage,
m a c r o p h a g es a n d o t h e r im m u n o c o m p e t e n t c el l s
have been foun d in injured nerves and in the DRG [50].
Activated macroph ages at the site of n erve inflammation
produ ce nu merou s proinflamm atory substances, such as
tumor necrosis factor (TNF) and interleukin 1. When
Figure 4. Nerve injury-induced structural and neurochemicalreorganizations. U nder normal conditions (top ), myelinated A-
fibers transmit innocuous information to lamina III/IV and along thedorsal column somatosensory pathway, whereas unmyelinated
C fibers transmit noxious information to lamina I/II, where the
signal is relayed via the spinothalamic tract to the brain. Substance
P (SP) is expressed only in unmyelinated or thinly myelinated afferent
fibers, and postganglionic sympathetic fibers do not interact with thesensory pathways. After nerve injury (bottom ), A- fibers sprout
into the lamina II region vacated by central terminals of C fibers,
large dorsal root ganglion neurons express SP, and pain transmissionneurons in lamina II express a greater number of NK1 (SP) receptors.
Consequently, innocuous stimuli can activate pain transmissionpathways, possibly leading to touch-evoked allodynia in the
patient with neuropathic pain.
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156 Neuropath ic Pain
injected sub cutaneou sly or ap plied to the n erve, TNF
induces ectop ic activity in p rimary afferent nocicepto rs and
prod uces pain beh avior [51,52• ]. Also, produ ction of a
focal neuritis in the sciatic nerve produces pain behavior
[53• ]. The target of inflamm atory substances could be
nociceptors along the trunk of the nerve itself, specifically
in the nervi nervorum, which innervates the connective
tissues of the n erves. As such, the n erve becomes a p ain-
sensitive structure similar to o ther som atic and visceral
tissue [54]. The possible interaction between the imm une
system and th e nervous system suggests that d rugs modu-
lating the immune system may become useful therapies in
some n europathic pain states.
Pathologic interactions between C and A- fibers
In the intact peripheral nervous system, each primary
sensory neuron functions as an independent comm un i-
cation channel until it reaches the first central synapse. In
the setting of nerve injury, however, the ensuing d isruption
of glial ensheathment allows adjacent d enuded axons
to make contact, permitt ing bo th electrical (ephap tic)
and chemical (via a diffusible substance) cross-excitation
[22,55]. Furtherm ore, the activity of a group of neu rons
can alter th e end ogenous repetitive firing activity of their
neighbors. Indeed, a key pathogenic mechan ism of neuro-
pathic pain involves the appearance of abno rmal responses
in primary afferent axons that travel in the damaged nerve.
This “crossed afterdischarge” can even occur b etween
un dam aged neuro ns of different types [56• ]. By these
mechanisms, A fibers may directly activate C fibers, such
that a n on -noxious stimulus can produce pain. In this way,
the peripheral nervous system itself can account for tactile
allodynia. Mechan osensitive, low thresho ld, A- fiberactivity also drives tactile allodynia by several other mecha-
nism s involving the spinal cord, as described next.
Spinal MechanismsIn add i t ion to p r imary af ferent m echan i sms in the
periph ery, studies over the past 1 5 years strongly suggest
that lon g-term changes in th e spinal cord and b rain
contribute to the dysesthesias associated with neuro -
pathic pain. Indeed, it is no longer surprising that neuro-
path ic pain is often no t suppressed by isolation of the
dam aged nerve from the CNS, whether by nerve block
or surgical nerve/ ro ot t ransect ion. Even after theseperipheral treatments, abno rmal activit ies in the CNS
may continu e to drive neuropathic pain.
Phenotypic changes in the spinal cord
In the intact nervous system, unmyelinated small-diameter
primary afferent neurons (C fibers) terminate in the super-
ficial dorsal horn ( lamina I and II) and b est transmit no x-
ious information, whereas large-diameter primary afferent
neurons (A- fibers) either terminate in th e deeper lamina
III and IV or in the brain do rsal colum n n uclei, and transmit
innocuous tactile information . The transection o f peripheral
nerves leads to a substantial degeneration and loss of the
central terminals of C fibers in lamina II [57]. This deaffer-
entation d eprives pain transmission n eurons in the super-
ficial dorsal ho rn o f their norm al no ciceptive inpu t, and
causes patients to experience negative sympto m s [58]. In
add ition, as illustrated in Figure 4, a switch to regenerative
mechan isms can occur. Althou gh an intuitively correct
respon se to in jury, aberrant regeneration can lead to positive
symptoms. In particular, the central projections of surviving
A- fibers in lamina III and IV may be stimulated by growth
factors to sprou t into the “foreign” territory vacated by C-
fiber terminals from lamina II [59]. These sprouts may even
establish contacts with deafferentated p ain tran smission
neurons [60]. The effects of this organizational change are
compoun ded by the p henotypic transformation o f A-
fibers to a sub stance P–synth esizing m od e, as described
previously [44], and by the upregulation o f substan ce P
(NK1) receptors in the superficial dorsal horn [61]. Thus, the
reorganization and phenotypic changes associated with
nerve injury allows inn ocuous input to reach lam ina II, a
pain transmission region of the spin al cord. As a result,
stimulation of low threshold mechanoreceptors abnormally
activates pain transmission n eurons in lamina II of the
spinal cord [62•• ]. As mention ed earlier, such a m echan ism
could contribute to the touch-evoked pain that is so charac-
teristic of many neuropath ies.
It is difficult to p rove that this functional reorganization
is a m echan ism of allodynia in the clinical situation; h ow-
ever, it is intriguing that some patients with postherpetic
neuralgia report intense allodynia along with th e mo re
expected loss of normal transient pain [58]. Presumably,
the n ormal function of C fibers was destroyed by the virus,and had been replaced with allodynia m ediated by A fibers.
These patien ts have experienced a shift in th e qu ality of
pain, from physiologic to pathologic (Fig. 1), as predicted
by a shift in pain processing from C fibers to A- fibers.
Pathologic sensitization of spinal cord neurons
Any prolon ged or massive inpu t from C-no ciceptors
enhan ces the respon se of dorsal horn n eurons to all sub-
sequent afferent inpu ts [63]. In the setting of inflamm ation,
for example, dorsal horn n euron threshold and p ain thresh-
old are reduced. In add ition , the receptive field of the dorsal
ho rn n euron grows [64]. This process, called central sensi-
tization, involves the spinal release of neu ropep tides andglutamate from nociceptors. These excitatory neurochemicals
act at n eurokin in, AMPA, an d N -methyl-D -aspartate
receptors on postsynaptic spinal neurons, leading to a
depo larization-induced influx of calcium and th e subse-
quent triggering of secondary events such as nitric oxide syn-
thesis and p rotein phosphorylation. Central sensitization is a
no rmal physiologic response of the und amaged nervous
system, and function s as a protective mechanism in the
setting of inflammation. Central sensitization is not neces-
sarily pathologic, and is normally kept in check by a balance
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Pathoph ysiologic Mechan isms of Neuropath ic Pain • Taylor 157
of inhibitory controls, such as an enhan cemen t of gamma-
aminobutyric acid (GABA)-mediated inhibition [48,65• ].
Once established, central sensitization critically depends
on persistent p rimary afferent input, and is norm ally revers-
ible in the setting of acute inflammation [6]. In th e absence
of ectopic activity, central sensitization will subside as input
declines du ring tissue h ealing. However, in th e setting of
abnormal ectopic activity and its associated A-associated
inpu t to the spinal cord, established central sensitization,
and possibly the increased sensitivity associated with it, may
becom e path ologic and p ersist ind efinitely. For example,
partial peripheral nerve injury leads no t on ly to persistent
ectopic activity [21•], but also to a long-term increase in the
activity [66] an d respon siveness of spinal cord neuro ns.
Pathologic central sensitization may contribute to neuro-
pathic pain. For example, in postherpetic neuralgia, con-
trolled app lication of capsaicin to the skin in creased pain
and allodynia in patients who h ad h igher daily pain, higher
allodynia ratings, and relatively preserved sensory function
[11• • ]. It is the continued induction of hypersensitivity that
is important here: blockade of early events alone with local
anesthetics or opioids do not reduce long-term hyperalgesia
and al lod ynia fol lowing nerve injury or amp utat ion
[67,68• ,69]. This lack of a preem ptive effect using conven-
tional analgesics has also been concluded in studies of post-
operative pain [70•]. Thus, the increased m echanical
sensitivity induced an d main tained b y persistent ectopic
activity, rather than that in duced o nly du ring the early
afferent discharge, predominan tly contributes to the patho-
logic positive symptoms associated with nerve injury.
Loss of inhibitory neurotransmission
Nerve injury may disrupt one o r more end ogenous p aininhibitory systems, including the A- fiber mediated inh ibi-
tion originally proposed by the gate control theory [71] and
the GABA-mediated inhibition of pain transmission neu-
rons in the dorsal horn . In the setting of nerve injury, a loss
of this inh ibitory activity (likely within interneuron s) could
release the brake on central sensitization o f dorsal horn neu-
rons, leading to stimulus-independ ent pain . Experimen tal
nerve injury produces a decrease in spinal cord GABA con-
centrations and GABA recepto r binding sites [72], and spi-
nal adm inistration o f GABA or a benzodiazepine decreases
hypersensitivity in an imal m od els [65• ,73]. The loss of
spinal GABA concentrations following sciatic nerve injury
could be restored with spinal cord stimulation in rats [74].Thus, direct damage to A- fibers, or a secondary loss of spi-
nal cord inhib itory systems following nerve injury, may con-
tribute to spontaneous pain, hyperalgesia, and allodynia.
Supraspinal Mechan ismsIncrease in descending facilitation
from the brain stem
The brain stem rostral ventral medulla (RVM) exerts both
inh ibi tory and exci tatory inf luences on d orsal horn
neurons [75]. Inh ibitory bulbospinal path ways have lon g
been kn own to contribu te to th e analgesic effects of
opio ids with regard to transient pain [76], and a nerve
injury–induced antagonism of this pathway could theoreti-
cally contribute to n europath ic pain. H owever, recent evi-
dence suggests that it is an enhancement of the facilitatory
pathways that contributes to neuropathic pain [77,78]. For
example, inactivation of the RVM with lidocaine attenu ates
the tactile allodynia an d th ermal hyperalgesia tha t accom -
pan ies spinal nerve injury [79,80]. The persistent n oxious
input associated with inflammatory pain causes long-term
changes in the activity of RVM neurons and the release of
neu rotransm itters in the RVM region [81,82], bu t little is
known regarding the primary afferent systems (A- or C
fiber–mediated pathways) that drive central facilitation in
the setting of nerve injury. Microinjection studies, however,
do ind icate that bo th glutamate and the neuropeptide
cholecystokinin may drive this tonic descending facilitation
to maintain neuropathic pain [80,83]. In summary, nerve
i n j u r y sh i f t s t he ove r a l l i n f l uence o f de scend i ng
pain modulation toward persistent facilitation of nocicep-
tive transmission in th e spinal cord, thus contributin g
to neuropathic pain.
Reorganization in the thalamus and cortex
Nociceptive signals are sent to the thalamus and cortex for
higher levels of processing. Although d ata is limited, n erve
injury may increase the excitability of and reo rganize the
connections of neurons in these supraspinal centers [84].
For example, patients with neuropathic pain demonstrate
a dram atic reorganization o f sensory mo dalities in the
thalamu s [85]. Also, the phan tom limb p ain following
arm amputation is associated with a spatial reorganizationof som atosenso ry cortical mapp ing [86]. In rats, sciatic
ligation increased the responsiveness of thalamic and S1
neuron s to tactile and cold thermal stimulation o f the paw,
and S1 d isplayed a reorganization o f somatic inp ut [87].
Thus, like the spinal cord dorsal horn and RVM, plasticity
in h igher b rain centers may con tribute to th e severity and
quality of neuropathic pain.
Treatment of Neuropathic PainNumerous etiologies, anatomic sites of nerve lesion, and
pathoph ysiologic mechan isms can prod uce a wide variety
of pa in syndrom es. Indeed , the m ost complex pa incases involve multiple nerves and /o r mu ltiple som atic
and visceral structures. This diversity in cause and site
is reflected by the nu merou s categories of patients with
neuro pathic pain with peripheral nerve disease, including
trigeminal neuralgia, nerve entrapment, neurom a, diabetic
neuropathy, malignancy, nerve inflammation, postherpetic
neu ralgia, and the p olyneurop athies [3,88]. Such classifi-
cation is useful for the diagno sis and treatment o f the
disease itself, and indeed th e etiologic cause of neuro-
path ic pain sho uld first be targeted. But th is strategy is not
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158 Neuropath ic Pain
effective in many neuropath ic pain d isorders. For example,
the pain of postherpetic neuralgia persists even after heal-
ing has taken place. In such situations, pain con trol is the
on ly therapy left, yet the treatment of neuropath ic pain in
such situations is largely emp iric [89• • ]. Apart from the
strong response of trigeminal neuralgia to carbamazepine,
and the recently demo nstrated responsiveness of diabetic
neuro pathy [8,90] and po stherpetic neuralgia [9,90]
to gabapen tin and tricyclic antidep ressants, we cann ot
provide adequate treatment to a vast numb er of patients
wi th establ ished neurop athic pain. Fur ther progress
in neuropathic pain m anagement is contingent on further
clinical and basic science research leading to a m ore
detailed description o f the sympto ms an d pathop hysio-
logic mechan isms associated with n europath ic pain. Such
progress will lead to specific pha rmacologic, surgical, or
ph ysical therapy intervention s for each iden tified m echa-
nism involved in a particular syndrome [45• • ,91].
ConclusionsThe q uality and p attern of altered sensitivity in n euro-
path ic pain clearly differs from transient o r inflamm atory
pain . These qualitative differences in sensation suggest that
nerve injury leads to a reorganization of sensory transmis-
sion pa thways that persist lon g after the no rmal healing
period . Over the past decade, we have experienced an
explosion of research directed toward an understand ing of
these pathophysiologic neural changes. Most of this
research stems from the developm ent of new anim al mod -
els of periph eral nerve injury. At th e level of the periphery,
nerve injury tr iggers an increase in th e expression o f
sodium chann els in the DRG (such as alpha-III) and aredistribution o f the sod ium chan nels to the site of injury
(such a s SNS). The resultin g accumu lation o f sod ium
channels at both loci lowers action p otential threshold and
causes spon taneo us ectopic d ischarge. Nerve in jury also
induces the expression of pronociceptive substances, such
as substance P in spared A- fibers, thus switching the
no rmally innocuous phenotype of this fiber type to a noci-
ceptive phenotype. Other peripheral mechanisms that may
contribute to som e cases of neuropathic pain include inter-
actions between unmyelinated primary afferents neurons
with the immune system, myelinated afferents via a
crossed afterdischarge, or th e sympath etic nervous system.
At the level of the CNS, nerve injury induces the sprout-ing of central terminals of A- fibers from a no n-nocicep-
tive to a nociceptive region of the spinal cord. As a result,
low threshold stimulation aberrantly activates pain trans-
mission neurons, possibly explaining the touch-evoked
pain that is so characteristic of many neuropathies. Persis-
tent ectopic activity and A-associated inpu t could also
lead to the chronic release of excitatory neurotransm itters
in spin al cord lam ina II and brain stem RVM, creating
a situation of increased descend ing facilitation and patho -
logic central sensitization in the spin al cord. Further
progress in neuropathic pain management is contingent
on further clinical and basic science research, leading to a
mo re detailed description of the symptom s and path o-
physiologic mechanisms associated with neurop athic
pain. Such p rogress will lead to specific pharmacolo gic,
surgical , or p hysical th erapy intervent ions for each
identified mechanism involved in a particular syndrom e.
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