mechanisms of neuropathic pain: the role of cytokines

MECHANISMS

DRUG DISCOVERY

TODAY

DISEASE

Drug Discovery Today: Disease Mechanisms Vol. 1, No. 4 2004

Editors-in-Chief

Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA

Tamas Bartfai – Harold L. Dorris Neurological Research Center and The Scripps Research Institute, USA

Pain

Mechanisms of neuropathic pain:the role of cytokinesClaudia Sommer*, Maria SchafersDepartment of Neurology, University of Wurzburg, Josef-Schneider-Strasse 11, 97080 Wurzburg, Germany

Many experimental studies have provided evidence

that pro-inflammatory cytokines induce or increase

neuropathic pain. Direct receptor-mediated actions

of cytokines have been demonstrated in addition to

those involving further mediators. In spite of the redun-

dancy and pleiotropy of the cytokine network, specific

actions of individual cytokines have been identified.

Preliminary clinical data point to a possible beneficial

role of cytokine inhibition in patients with painful neu-

ropathy or radiculopathy.

*Corresponding author: (C. Sommer) [email protected]

1740-6765/$ � 2004 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddmec.2004.11.018

Section Editor:Eija Kalso – Helsinki University Central Hospital, Finland

Claudia Sommer and her coworkers at the University of Wurzburg are

pioneers in the research of cytokines and neuropathic pain.Proinflammatory cytokines increase the sensitivity of damaged

neurones to nociceptive and non-nociceptive stimuli. Cytokines may bean important link between infections, inflammation and the

development and maintenance of certain types of neuropathic pain.Blocking or inhibiting the effects of cytokines offers an exciting new

approach to the prevention and treatment of some neuropathic painstates.

Introduction

CYTOKINES are extracellular signaling proteins phylogenetically

related to opioid peptides [1] (see Glossary). They establish

communication between the immune system and the ner-

vous system, acting at hormonal concentrations through

high-affinity receptors and producing endocrine, paracrine

and autocrine effects. In contrast to circulating hormones,

they exert their effects over short distances onto nearby cells.

Cytokines are called ‘pleiotropic’, because of a broad range of

redundant, frequently overlapping functions. Their activa-

tion or dysregulation is implied in a variety of disease states,

for example, sepsis, rheumatoid arthritis, ankylosing spon-

dylitis, Crohn’s disease, multiple sclerosis and skin diseases.

Some cytokines are labeled ‘pro-inflammatory’ or ‘Th1’,

others ‘anti-inflammatory’ or ‘Th2’, depending on their

effects on immune cells, in particular on lymphocytes.

Recently, evidence has emerged that cytokines are involved

in the generation of pain and hyperalgesia in inflammatory

and neuropathic conditions.

Cytokines in neuropathic pain

Most of the evidence for a role of cytokines in neuropathic

pain comes from animal studies using nerve injury models. In

these models, cytokine levels are altered (mostly increased) in

the peripheral and central nervous system (CNS). Modulation

of the cytokine system either by application of agonists or

antagonists or by transgenic approaches modulates pain

behavior. Hypotheses on potential mechanisms involved

in cytokine actions derived from in vitro studies. In addition,

clinical studies measuring cytokine levels in humans with

neuropathic pain or using drugs modulating cytokine func-

tion further support the idea of key role of cytokines in the

development and maintenance of neuropathic pain states.

Evidence from animal models

Cytokine regulation after nerve injury

In response to axonal lesions a series of inflammatory media-

tors, including cytokines are upregulated (for review see [2,3]).

In a frequently used model of neuropathic pain, the chronic

constriction injury (CCI) of the rat or mouse sciatic nerve,

increased levels of tumor necrosis factor-alpha (TNF-A), inter-

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Drug Discovery Today: Disease Mechanisms | Pain Vol. 1, No. 4 2004

Glossary

Cytokines: extracellular signaling proteins within the immune system

and between the immune system and nervous system.

Etanercept: a TNF-receptor fusion protein that serves as a TNF-a

inhibitor in human autoimmune disorders, mainly used in rheumatoid

arthritis. Is beginning to be used for Crohn’s disease and sciatica.

IL-1b: interleukin-1b, pro-inflammatory cytokine with algesic actions

and with many properties similar to TNF-a. At higher endocrine

concentrations it is associated with fever and formation of acute-phase

plasma proteins in the liver.

IL-4: interleukin-4, anti-inflammatory cytokine that has also been shown

to have analgesic properties.

IL-6: cytokine with mostly pro-inflammatory and algesic actions, mem-

ber of the IL-6 cytokine family that includes leukemia inhibitory factor

(LIF) and ciliary neurotrophic factor (CNTF).

IL-10: interleukin-10, anti-inflammatory cytokine that has also been

shown to have analgesic properties.

Infliximab: monoclonal antibodies to TNF-a that serve as a TNF-a

inhibitor in human autoimmune disorders.

Nucleus pulposus: inner content of the spinal discs, surrounded by

anulus fibrosus and released in the case of spinal disc herniation.

TNF-a: tumor necrosis factor-alpha, pro-inflammatory cytokine, mem-

ber of the ‘TNF-superfamily’, together with the structurally related

peptide lymphotoxin (LT-a, formerly TNF-b) and several other struc-

turally related proteins.

leukin-1b (IL-1B) and interleukin-6 (IL-6) (seeGlossary)havebeen

shown at the mRNA, and partly also at the protein level [4–7]

(Fig. 1). By contrast, protein levels of a prototypical anti-

inflammatory cytokine, interleukin-10 (IL-10) are decreased

in the injured nerve [7]. Cytokines in peripheral nerves have

been mostly localized to Schwann cells or macrophages, occa-

sionally to fibroblasts (Fig. 2). In dorsal root ganglion (DRG)

neurons, cytokine levels are not only increased after nerve

injury [8], but there is also a phenotypic switch leading to TNF-

a expression in a population of medium size DRG neurons [9],

indicating a possible alteration in the function of these neu-

rons. Increases in cytokine expression have also been found in

the lumbar spinal cord after CCI and in other partial nerve

injury models [10–12] as well as inparticular regions of the CNS

[13,14]. In particular, spinal glia was found to be important in

cytokine expression after nerve injury [15].

Studies using cytokine application or inhibition

Intra- or epineurial injection of IL-1b or TNF-a produces a

concentration-dependent pain behavior in rats ([16,17], M.

Zelenka et al., unpublished). Several investigators have shown

an antihyperalgesic and antiallodynic effect of cytokine inhi-

bition in models of neuropathic pain (for review and further

references see [2]). Antagonism to IL-1 by using neutralizing

antibodies to IL-1RI reduces thermalhyperalgesiaandmechan-

ical allodynia in mice with CCI and attenuates the endoneurial

increase of TNF immunoreactivity. Intrathecal application of

anti-IL-6 antibodies decreases tactile allodynia in the model of

spinal nerve ligation (SNL). Epineurial injection of antibodies

to the IL-6 receptor attenuates thermal hyperalgesia and

442 www.drugdiscoverytoday.com

mechanical allodynia in CCI. Pain-related behavior in CCI

and other models is reduced by substances blocking TNF

production, its release from the cell membrane or its function.

ThehyperalgesicactionofTNFseemstobemediatedbyTNFR1,

becauseneutralizingantibodies toTNFR1butnot toTNFR2can

reduce hyperalgesia. Anti-inflammatory cytokines like IL-4

and IL-10 seem to have antihyperalgesic actions in animal

models of neuropathic pain [18]. IL-10 pre-treatment also

reduces the hyperalgesic responses to intraplantar injections

of carrageenin, IL-1b, IL-6 and TNF-a [19]. IL-4 delivered by a

viralvector reducesbehavioral signsofpain inananimalmodel

of bone cancer [20], and intrathecally applied human IL-2 hasa

short-lived antinociceptive effect in the CCI-model [21].

Spinal administration of TNF-a antagonists prevents or

reduces allodynia and hyperalgesia in animals with nerve

injury and pain behavior. Whereas intrathecal IL-1b antago-

nists alone are seemingly without effect in nerve injury

models, they synergize with TNF-a antagonists causing a

further reduction of allodynia [22]. Spinal administration

of IL-6, by contrast, appears to reduce electrically evoked

C-fiber activity [23]. Furthermore, intrathecal application

of inhibitors of glial metabolism also reduce neuropathic

pain, indicating that indeed glial cells increase pain through

the action of cytokines [24].

Nucleus pulposus, the material within the vertebral discs, is

highly enriched with a variety of pro-inflammatory cyto-

kines. Subsequent to disc herniation, this material probably

comes into contact with the dorsal roots. Application of

autologous nucleus pulposus to dorsal roots or experimental

disc herniation in animals results in pain behavior as well as

both ongoing and enhanced evoked activity in spinal noci-

ceptive neurons [25]. Animals treated with either neutralizing

antibodies to TNF-a directly on the nerve root or with sys-

temic TNF-a antagonists show a marked reduction of both

the neuronal activity and the pain behavior, implicating a

role for TNF-a in the process [25].

Mechanisms of action

IL-1b, among other actions involving secondary production

of nitric oxide, bradykinin or prostaglandins, has a direct

excitatory action on nociceptive fibers, which are activated

within 1 min by IL-1b application [26]. In a skin-nerve in vitro

preparation, brief exposure of the skin to IL-1b facilitates

heat-evoked calcitonin gene-related peptide release [27],

which is a direct effect independent of changes in gene

expression or receptor up-regulation. Brief applications of

IL-1b to nociceptive neurons yielded a potentiation of

heat-activated inward currents and a shift of activation

thresholds towards lower temperatures without altering

intracellular calcium levels. This IL-1b-induced heat sensiti-

zation is mediated by activation of protein kinases. IL-1

receptor is expressed in DRG neurons, such that IL-1b can

act directly on sensory neurons to increase their susceptibility

Vol. 1, No. 4 2004 Drug Discovery Today: Disease Mechanisms | Pain

Figure 1. Relative gene expression of the pro-inflammatory cytokines IL-1b, TNF-a, the chemokine MCP-1 and the anti-inflammatory cytokine IL-10 in

degenerating mouse nerve segments after chronic constriction injury (CCI; left panel) compared to sciatic nerve (SN) crush (right panel) as revealed by real-

time RT-PCR and normalization against the housekeeping gene 18s RNA. Note the rapid increase in transcripts at day one after injury and the higher and more

sustained expression levels after CCI. Abbreviations: Ctrl., Control nerves. Data from [6].

to noxious heat [28]. Similar effects have been shown for IL-6

in conjunction with the soluble IL-6 receptor.

TNF-a lowers mechanical activation thresholds in C noci-

ceptors of the rat sural nerve when injected subcutaneously

[29], a result that might be due to an acute TNF-induced

decrease in K+ conductance [30] or to a protein kinase A-

dependent mechanism [31]. In vitro perfusion of TNF-a to

dorsal root ganglia (DRG) elicits neuronal discharges in both

A and C-fibers (Fig. 3). The firing frequency is markedly higher

and the discharge longer-lasting after nerve injury, indicating

an increased sensitivity of injured afferent neurons to TNF-a

[32]. Injection or perfusion of TNF-a into or onto rat DRGs in

vivo induces allodynia. Subthreshold quantities of TNF-a

injected into a DRG when its spinal nerve is ligated results

in faster onset of allodynia and increased spontaneous pain

behavior. Thus, there is strong in vivo and in vitro evidence that

nerve injury results in increased endogenous TNF-a and that

injured nerve fibers are sensitized to the excitatory effects of

TNF-a. Receptor-mediated activation of protein kinases or

calcium mobilization in sensory neurons may confer the sen-

sitizing effects that TNF-a has on nociceptors in vitro [33].

Downstream of TNF-a receptor activation, hyperalgesia

induced by nerve injury is mediated via p38 MAPK [34]. The

TNF-a inhibitor etanercept reduces both allodynia and p38

MAPK phosphorylation in the SNL-model ofneuropathic pain,

indicating that the TNF-a-p38 signal transduction cascade in

the DRG is a significant participant in the generation of

mechanical allodynia following nerve injury (Fig. 4).



Figure 3. In vitro extracellular dorsal root single fiber recording. (a)

Schematic of the preparation. The ganglion is suspended in the middle

chamber; the dorsal root and spinal nerve are in the adjacent mineral oil-

filled chambers for recording (R) and stimulation (S), respectively. (b)

Activity was recorded from one A-delta fiber while the DRG was

perfused with TNF-a. The fiber responds with firing in response to

perfusion of the DRG with TNF-a (here 100 pg/ml).

Figure 2. TNF immunolocalization in rat lumbar dorsal root ganglion

(DRG) neurons and sciatic nerve four days after CCI: single labeling on

serial sections demonstrating a heavy co-localization (yellow) of TNF

(red) and the neuronal marker PGP 9.5 (green). Double staining

demonstrating almost no co-localization of TNF-a (red) and ED1

(green). In the sciatic nerve, TNF-a (red) co-localizes (yellow) with

the Schwann cell marker S-100 (green). There is almost no co-localiza-

tion of TNF-a and ED1-positive macrophages (green).

In addition to the direct actions on nerve fibers, indirect

actions of the cytokines mediated by other algogenic com-

pounds, are likely in many paradigms (Fig. 5). Nerve growth

factor (NGF) is one candidate mediator of cytokine-induced

hyperalgesia. For example, IL-1b induces transcription of

NGF in Schwann cells [35], and IL-1b-induced hyperalgesia

can be prevented by anti-NGF antibodies [36], indicating that

IL-1b hyperalgesia is mediated via the increase in NGF in

inflamed nerves. Furthermore, prostaglandins, bradykinin

and neuropeptides might mediate cytokine–hyperalgesia.

TNF-a enhances the sensitivity to capsaicin of rat sensory

neurons [37], probably via the neuronal production of pros-

taglandins. Long-time exposure of primary afferent neurons

to IL-1b induces substance P release via the cyclooxygenase

(COX)-2 system [38]. IL-6 induces the production of galanin

in sensory neurons [39]. These changes in neurotransmitter

expression might contribute to alter pain processing after

nerve injury.

An interesting finding is the possible relevance of spinal

cytokines to opioid tolerance. In rats, chronic administration

of morphine activates spinal glia to upregulated pro-inflam-

matory cytokines, a process which is further enhanced in

nerve injured rats. Inhibition of pro-inflammatory cytokines

at the spinal level restores acute morphine antinociception in

these rats and reverses the development of morphine toler-

ance [40]. Thus, the long-term response to opioids in neuro-

pathic pain might be improved by concomitant modulation

of the cytokine system.

Evidence from human diseases

Information about the role of cytokines in neuropathic pain

in humans is derived from studies correlating cytokine levels


in body fluids or biopsied tissues and from a few, mostly

uncontrolled, treatment trials.

A striking correlation between cytokine levels and neuro-

pathic pain was observed in patients with leprosy, where a

subgroup of patients with elevated serum levels of TNF-a and

IL-1b suffer from excruciating pain [41]. Treatment with

thalidomide reduces TNF-a secretion in peripheral blood

mononuclear cells by >90% and greatly reduces pain in these

patients [42]. In other human neuropathies, preliminary data

also point to a correlation between cytokine expression and

pain [43,44]. In a series of sural nerve biopsies, cytokine levels

were increased more often in patients with painful neuropa-


Figure 4. Pain-behavior induced by spinal nerve ligation (SNL) is

attenuated by systemic inhibition of TNF and intrathecal inhibition of

the MAPK p38. (a) Treatment with the TNF antagonist etanercept

attenuates mechanical allodynia induced by SNL. (b) Treatment with

the p38 inhibitor SB203580 attenuates mechanical allodynia if started

two days before SNL, but not if starting seven days after SNL. Data from

[34].

Table 1. Key therapies – pre-clinical to market

Target Therapy against target Stage of developm

TNF-a � Etanercept (dimeric TNFR2

fusion protein)

� Infliximab (chimeric

monocloncal TNF antibody)

� Adalimumab (human IgG1

anti-tumor necrosis factor

alpha monoclonal antibody)

On market for rheum

arthritis, Crohn’s dise

Case reports for low

back pain, sciatica

IL-1 Anakinra (IL-1 inhibitor) On market for rheum

IL-2, IL-4, IL-10 Gene therapy Experimental use

for cancer pain,

neuropathic pain,

inflammatory pain

thies. Recently, an increase in serum IL-8 was identified as a

predictor for the development of postherpetic neuralgia

(PHN) after acute herpes zoster [45]. If this finding holds true

in further case series, IL-8 might represent not only a pre-

dictor but also a possible target for the prevention of PHN.

Several studies have reported increased levels of cytokines in

the vicinity of herniated discs and a correlation of their

presence to sciatica [46–48]. Inhibitors of TNF-a have been

used successfully for patients with chronic nerve root pain,

but up to now only data from case reports and uncontrolled

studies are available [49].

Occasionally, TNF-a inhibitors have been used to treat

inflammatory neuropathies, but data on pain are lacking in

these reports [50]. One remarkable case report describes

remission of long standing complex regional pain syndrome

(CRPS) after treatment with thalidomide for Behcet’s disease

[51]. Anti-TNF-a strategies have been used in various non-

neuropathic painful conditions like AIDS-associated procti-

tis, rheumatoid arthritis and HIV-associated aphthous ulcers

(for review on earlier studies see [52]). Many other reports

have followed since the advent of etanercept and infliximab,

for example, a controlled trial showing a beneficial effect of

etanercept in ankylosing spondylitis [53], and a prospective

study with historical controls using infliximab in low back

pain [54] (Table 1). Controlled trials are warranted to estab-

lish the role of cytokine inhibition in these painful condi-

tions. Obviously, caution is necessary because of the

pleiotropy of the cytokines. Treatment with antagonists

might not only reduce the target symptom (pain) but also

have undesired side effects in other systems. Furthermore,

given the redundancy of the cytokine system, blockade of one

cytokine may be compensated by upregulation of others with

similar effects. Therefore, combined antagonistic strategies

might be necessary.

Summary and conclusions

Numerous experimental studies provide evidence that pro-

inflammatory cytokines induce or facilitate neuropathic

ent Advantages/Disadvantages References

atoid

ase

Mostly well-tolerated

Rare side effects are: injections site

reactions, rash, respiratory tract

infections, for example, tuberculosis,

demyelinating disorders, aplastic

anemia, worsening of congestive heart

failure, back pain

[54–59]

atoid arthritis Unknown [60]

Unknown [21,61]



Figure 5. Possible currently discussed mechanisms by which TNF as the prototypical proinflammatory cytokine induces neuropathic pain: TNF exerts

pleitropic effects on Schwann cells, endothelial cells, axons, dorsal root ganglia neurons and the CNS. Abbreviations: EC, endothelial cells; NGF, nerve growth

factor; CGRP: calcitonin gene-related peptide; DRG, dorsal root ganglion; CNS: central nervous system; MAPK: mitogen-activated protein kinases; PKA,

proteinkinase A; SPA, spontaneous activity.

� How can we identify those patients in whom cytokines play a major

role in the generation of pain?

� Is blockade of one cytokine (as exemplified in the TNF inhibitors) a

valid strategy for pain control in selected diseases, or would a more

successful approach involve shifting the balance between pro- and

anti-inflammatory cytokines?

pain. Direct receptor-mediated actions of cytokines on affer-

ent nerve fibers as well as cytokine effects involving further

mediators have been reported. Furthermore, endogenous

cytokine levels may modulate the response to opioids. Cyto-

kine levels are rapidly and markedly upregulated in periph-

eral nerves, DRGs and in the spinal cord after peripheral nerve

injuries. Whereas direct application of exogenous pro-inflam-

matory cytokines induces pain, blockade of these cytokines

or application of anti-inflammatory cytokines reduces pain

behavior in most experimental paradigms. A finding of par-

ticular clinical importance may be the involvement of TNF-a

released from spinal discs in the generation and maintenance

of sciatica. Cytokine measurements might identify patients at

risk to develop chronic pain associated to their neuropathic

conditions, as in the examples of peripheral neuropathies and

PHN. Case reports and uncontrolled trials point to a positive

effect of TNF-a inhibition in sciatica and possibly other

neuropathic conditions. Because of the pleiotropy and redun-

Outstanding questions

� What are the molecular mechanisms through which cytokines induce

or maintain pain?

� Could p38 mitogen-activated protein kinase be an alternative target

for pain control?


dancy of the cytokine system, the successful approach might

not be the inhibition of one particular cytokine but the

strategies shifting the balance between pro- and anti-inflam-

matory cytokines in properly selected patients.

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