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  • Print publication year: 2013
  • Online publication date: December 2013

Chapter 7 - Pathophysiology of neuropathic pain: inflammatory mediators

from Section 2 - The Condition of Neuropathic Pain


This chapter summarizes a standard approach to identifying neuropathic pain for the clinician. For neuropathic pain, and for the condition of complex regional pain syndrome (CRPS) especially, the six Ss should be queried when obtaining details regarding the affected region. A useful tool to rapidly and accurately localize sources of chronic pain and assist in the diagnosis of causes of neuropathic pain is a pain diagram. The examination of a chronic pain patient should start with an appropriate and directed general examination including a neurological examination. Quantitative sensory testing (QST) provides indirect information used to evaluate underlying sensory function abnormalities using only small, portable tools and with less time requirement than protocols developed by the German Neuropathic Research Network. In the future, bedside QST is expected to continue to play a role in determining potential pain mechanisms to help direct further evaluation and treatment.


1. MoalemG, TraceyDJ.Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 2006;51:240–64.
2. AustinPJ, Moalem-TaylorG.The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 2010;229:26–50.
3. TalbotS, Theberge-TurmelP, LiazoghliD, et al. Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [Nalpha-Bodipy]-des-Arg9-bradykinin. J Neuroinflammation 2009;6:11.
4. RashidMH, InoueM, MatsumotoM, UedaH.Switching of bradykinin-mediated nociception following partial sciatic nerve injury in mice. J Pharmacol Exp Ther 2004;308:1158–64.
5. WangH, KohnoT, AmayaF, et al. Bradykinin produces pain hypersensitivity by potentiating spinal cord glutamatergic synaptic transmission. J Neurosci 2005;25:7986–92.
6. WernerMF, KassuyaCA, FerreiraJ, et al. Peripheral kinin B(1) and B(2) receptor-operated mechanisms are implicated in neuropathic nociception induced by spinal nerve ligation in rats. Neuropharmacology 2007;53:48–57.
7. LuizAP, SchroederSD, ChichorroJG, et al. Kinin B(1) and B(2) receptors contribute to orofacial heat hyperalgesia induced by infraorbital nerve constriction injury in mice and rats. Neuropeptides 2010;44:87–92.
8. FerreiraJ, BeirithA, MoriMA, et al. Reduced nerve injury-induced neuropathic pain in kinin B1 receptor knock-out mice. J Neurosci 2005;25:2405–12.
9. MoalemG, GrafeP, TraceyDJ.Chemical mediators enhance the excitability of unmyelinated sensory axons in normal and injured peripheral nerve of the rat. Neuroscience 2005;134:1399–411.
10. GuJG, MacDermottAB.Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature 1997;389:749–53.
11. HideI, TanakaM, InoueA, et al. Extracellular ATP triggers tumor necrosis factor-α release from rat microglia. J Neurochem 2000;75:965–72.
12. TsudaM, Shigemoto-MogamiY, KoizumiS, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003;424:778–83.
13. TrangT, BeggsS, SalterMW.ATP receptors gate microglia signaling in neuropathic pain. Exp Neurol 2012;234:354–61.
14. HonoreP, Donnelly-RobertsD, NamovicM, et al. The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1αβ knockout mice. Behav Brain Res 2009;204:77–81.
15. ChessellIP, HatcherJP, BountraC, et al. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 2005;114:386–96.
16. McGaraughtyS, ChuKL, NamovicMT, et al. P2X7-related modulation of pathological nociception in rats. Neuroscience 2007;146:1817–28.
17. SorgeRE, TrangT, DorfmanR, et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med 2012;18:595–9.
18. MaedaM, TsudaM, Tozaki-SaitohH, InoueK, KiyamaH.Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn. Glia 2010;58:1838–46.
19. Tozaki-SaitohH, TsudaM, MiyataH, et al. P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci 2008;28:4949–56.
20. MaW, ChabotJG, VercauterenF, QuirionR.Injured nerve-derived COX2/PGE2 contributes to the maintenance of neuropathic pain in aged rats. Neurobiol Aging 2010;31:1227–37.
21. Cruz DuarteP, St-JacquesB, MaW.Prostaglandin E2 contributes to the synthesis of brain-derived neurotrophic factor in primary sensory neuron in ganglion explant cultures and in a neuropathic pain model. Exp Neurol 2012;234:466–81.
22. St-JacquesB, MaW.Role of prostaglandin E2 in the synthesis of the pro-inflammatory cytokine interleukin-6 in primary sensory neurons: an in vivo and in vitro study. J Neurochem 2011;118:841–54.
23. NamakaM, GramlichCR, RuhlenD, et al. A treatment algorithm for neuropathic pain. Clin Ther 2004;26:951–79.
24. NoguchiK, OkuboM.Leukotrienes in nociceptive pathway and neuropathic/ inflammatory pain. Biol Pharm Bull 2011;34:1163–9.
25. JainNK, KulkarniSK, SinghA.Role of cysteinyl leukotrienes in nociceptive and inflammatory conditions in experimental animals. Eur J Pharmacol 2001;423:85–92.
26. OkuboM, YamanakaH, KobayashiK, NoguchiK.Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain. Glia 2010;58:599–610.
27. ZuoY, PerkinsNM, TraceyDJ, GeczyCL.Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells. Pain 2003;105:467–79.
28. CannonKE, LeursR, HoughLB.Activation of peripheral and spinal histamine H3 receptors inhibits formalin-induced inflammation and nociception, respectively. Pharmacol Biochem Behav 2007;88:122–9.
29. MedhurstSJ, CollinsSD, BillintonA, et al. Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain. Pain 2008;138:61–9.
30. OssipovMH.Growth factors and neuropathic pain. Curr Pain Headache Rep 2011;15:185–92.
31. PettyBG, CornblathDR, AdornatoBT, et al. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 1994;36:244–6.
32. WildKD, BianD, ZhuD, et al. Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance. J Pharmacol Exp Therapeut 2007;322:282–7.
33. KatzN, BorensteinDG, BirbaraC, et al. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain 2011;152:2248–58.
34. AckermannPW. Katz, et al., Efficacy and safety of tanezumab in the treatment of chronic low back pain [Pain 2011;152:2248–2258] and Hill, Blocking the effects of NGF as a route to safe and effective pain relief – fact or fancy? [Pain 2011;152:2200–2201]. Pain 2012;153:1128–9; author reply 1129–31.
35. CoullJA, BeggsS, BoudreauD, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005;438:1017–21.
36. YuanH, ZhuX, ZhouS, et al. Role of mast cell activation in inducing microglial cells to release neurotrophin. J Neurosci Res 2010;88:1348–54.
37. Balkowiec-IskraE, Vermehren-SchmaedickA, BalkowiecA.Tumor necrosis factor-α increases brain-derived neurotrophic factor expression in trigeminal ganglion neurons in an activity-dependent manner. Neuroscience 2011;180:322–33.
38. AdlerJE, NicoL, VandeVordP, SkoffAM.Modulation of neuropathic pain by a glial-derived factor. Pain Med 2009;10:1229–36.
39. GuoJ, JiaD, JinB, et al. Effects of glial cell line-derived neurotrophic factor intrathecal injection on spinal dorsal horn glial fibrillary acidic protein expression in a rat model of neuropathic pain. Int J Neurosci 2012; doi:10.3109/00207454.2012.672500.
40. EcheverryS, ShiXQ, RivestS, ZhangJ.Peripheral nerve injury alters blood–spinal cord barrier functional and molecular integrity through a selective inflammatory pathway. J Neurosci 2011;31:10819–28.
41. WeiXH, ZangY, WuCY, et al. Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodynia via upregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway. Exp Neurol 2007;205:471–84.
42. JungerH, SorkinLS.Nociceptive and inflammatory effects of subcutaneous TNFalpha. Pain 2000;85:145–51.
43. HeX-H, ZangY, ChenX, et al. TNF-alpha contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. Pain 2010;151:266–79.
44. KawasakiY, ZhangL, ChengJK, JiRR.Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 2008;28:5189–94.
45. SchaibleHG, von BanchetGS, BoettgerMK, et al. The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann N Y Acad Sci 2010;1193:60–9.
46. SommerC, SchafersM, MarziniakM, ToykaKV.Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 2001;6:67–72.
47. KorhonenT, KarppinenJ, PaimelaL, et al. The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial. Spine (Phila Pa 1976) 2006;31:2759–66.
48. WhiteheadKJ, SmithCG, DelaneySA, et al. Dynamic regulation of spinal pro-inflammatory cytokine release in the rat in vivo following peripheral nerve injury. Brain Behav Immun 2010;24:569–76.
49. NadeauS, FilaliM, ZhangJ, et al. Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF: implications for neuropathic pain. J Neurosci 2011;31:12533–42.
50. MurphyPG, RamerMS, BorthwickL, et al. Endogenous interleukin-6 contributes to hypersensitivity to cutaneous stimuli and changes in neuropeptides associated with chronic nerve constriction in mice. Eur J Neurosci 1999;11:2243–53.
51. KiguchiN, MaedaT, KobayashiY, et al. The critical role of invading peripheral macrophage-derived interleukin-6 in vincristine-induced mechanical allodynia in mice. Eur J Pharmacol 2008;592:87–92.
52. DominguezE, MauborgneA, MalletJ, DesclauxM, PohlM.SOCS3-mediated blockade of JAK/STAT3 signaling pathway reveals its major contribution to spinal cord neuroinflammation and mechanical allodynia after peripheral nerve injury. J Neurosci 2010;30:5754–66.
53. OhtoriS, MiyagiM, EguchiY, et al. Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica. Eur Spine J 2012;21:2079.
54. TsudaM, MasudaT, KitanoJ, et al. IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci USA 2009;106:8032–7.
55. RaczI, NadalX, AlferinkJ, et al. Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J Neurosci 2008;28:12136–45.
56. Gomez-NicolaD, Valle-ArgosB, SuardiazM, TaylorJS, Nieto-SampedroM.Role of IL-15 in spinal cord and sciatic nerve after chronic constriction injury: regulation of macrophage and T-cell infiltration. J Neurochem 2008;107:1741–52.
57. KleinschnitzC, HofstetterHH, MeuthSG, et al. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol 2006;200:480–5.
58. KimCF, Moalem-TaylorG.Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain 2011;12:370–83.
59. NomaN, KhanJ, ChenIF, et al. Interleukin-17 levels in rat models of nerve damage and neuropathic pain. Neurosci Lett 2011;493:86–91.
60. MiyoshiK, ObataK, KondoT, OkamuraH, NoguchiK.Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci 2008;28:12775–87.
61. ShibataK, SugawaraT, FujishitaK, et al. The astrocyte-targeted therapy by Bushi for the neuropathic pain in mice. PLoS One 2011;6:e23510.
62. LoramLC, HarrisonJA, SloaneEM, et al. Enduring reversal of neuropathic pain by a single intrathecal injection of adenosine 2A receptor agonists: a novel therapy for neuropathic pain. J Neurosci 2009;29:14015–25.
63. WilkersonJL, GentryKR, DenglerEC, et al. Intrathecal cannabilactone CB2R agonist, AM1710, controls pathological pain and restores basal cytokine levels. Pain 2012;153:1091–106.
64. ÜçeylerN, TopuzoğluT, SchießerP, HahnenkampS, SommerC. IL-4 deficiency is associated with mechanical hypersensitivity in mice. PLoS One 2011;6:e28205.
65. HaoS, MataM, GloriosoJC, FinkDJ.HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain. Mol Pain 2006;2:6.
66. EcheverryS, ShiXQ, HawA, et al. Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects. Mol Pain 2009;5:16.
67. TramullasM, LanteroA, DiazA, et al. BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) reveals the involvement of the transforming growth factor-beta family in pain modulation. J Neurosci 2010;30:1502–11.
68. GaoYJ, JiRR.Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther 2010;126:56–68.
69. WhiteFA, SunJ, WatersSM, et al. Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci USA 2005;102:14092–7.
70. TanakaT, MinamiM, NakagawaT, SatohM.Enhanced production of monocyte chemoattractant protein-1 in the dorsal root ganglia in a rat model of neuropathic pain: possible involvement in the development of neuropathic pain. Neurosci Res 2004;48:463–9.
71. GaoYJ, ZhangL, SamadOA, et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 2009;29:4096–108.
72. ThackerMA, ClarkAK, BishopT, et al. CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 2009;13:263–72.
73. AbbadieC, LindiaJA, CumiskeyAM, et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci USA 2003;100:7947–52.
74. VergeGM, MilliganED, MaierSF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004;20:1150–60.
75. LindiaJA, McGowanE, JochnowitzN, AbbadieC.Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain. J Pain 2005;6:434–8.
76. MilliganED, ZapataV, ChacurM, et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur J Neurosci 2004;20:2294–302.
77. StanilandAA, ClarkAK, WodarskiR, et al. Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. J Neurochem 2010;114:1143–57.
78. LandryRP, JacobsVL, Romero-SandovalEA, DeLeoJA.Propentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages. Exp Neurol 2012;234:340–50.