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: [email protected]

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.



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.



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.




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).




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.




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




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




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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