Role of the Immune system in chronic pain

Key Points

  • Chronic pain is a major health problem worldwide. Despite prolonged and extensive study in this field, it is only recently that the immune system has been implicated in peripheral neuropathic pain. The immune system might also have a role in the pain that is associated with CNS damage.

  • The immune system does not seem to have an active role in acute responses to painful stimuli (nociception). However, it is an active player in persistent pain states.

  • Several types of immune cell and, more importantly, many factors that these cells can release, are involved in inflammatory pain conditions. The sequential response of immune cells and the factors that contribute to inflammatory pain are well known and have led to new therapeutics. For example, tumour necrosis factor-α antibodies and neutralizing reagents have been used successfully to treat the pain of rheumatoid arthritis.

  • After peripheral nerve injury, the immune system seems to have a crucial role in the establishment of pain. Indeed, sequential infiltration of various immune cells into peripheral nervous structures occurs after this type of lesion. These cells release cytokines and chemokines that contribute directly and/or indirectly to pain. A common peripheral mechanism of action of these factors might be the induction of cyclooxygenase enzymes. However, the lack of effect of cyclooxygenase inhibitors in patients with neuropathic pain indicates that this mechanism is of limited importance. Another mechanism could be the retrograde transport of these mediators to the CNS.

  • Peripheral nerve injury leads to central changes that include, remarkably, changes in immune cell function. Microglia (the resident CNS macrophages) are activated in different neuropathic pain models, and several studies have shown that this response is particularly important in the initiation, as opposed to the maintenance, of neuropathic pain. However, the factors that activate microglia are still poorly understood. Whatever the mechanism of this activation, microglia can release several factors that directly and/or indirectly modulate pain-processing neurons.

  • Despite some inconsistencies and uncertainties in the literature, microglia seem to have a crucial role in peripheral neuropathic pain. The role of the immune system in pain after central damage is still relatively unexplored. However, there is circumstantial evidence that it is involved in the pain of spinal cord injury and multiple sclerosis.

  • From the perspective of pain, the challenge is to exploit this new knowledge of immune system involvement in nociceptive processing to develop novel analgesic strategies without interfering with the potential beneficial effects of the immune response.

Abstract

During the past two decades, an important focus of pain research has been the study of chronic pain mechanisms, particularly the processes that lead to the abnormal sensitivity — spontaneous pain and hyperalgesia — that is associated with these states. For some time it has been recognized that inflammatory mediators released from immune cells can contribute to these persistent pain states. However, it has only recently become clear that immune cell products might have a crucial role not just in inflammatory pain, but also in neuropathic pain caused by damage to peripheral nerves or to the CNS.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Physiological pain.
Figure 2: Inflammatory pain.
Figure 3: Neuropathic pain.

References

  1. 1

    Numazaki, M. & Tominaga, M. Nociception and TRP Channels. Curr. Drug Targets CNS Neurol. Disord. 3, 479–485 (2004).

    Article  CAS  Google Scholar 

  2. 2

    Lewin, G. R. & Moshourab, R. Mechanosensation and pain. J. Neurobiol. 61, 30–44 (2004).

    Article  Google Scholar 

  3. 3

    Cook, S. P., Vulchanova, L., Hargreaves, K. M., Elde, R. & McCleskey, E. W. Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387, 505–508 (1997).

    Article  CAS  Google Scholar 

  4. 4

    Stassen, M., Hultner, L. & Schmitt, E. Classical and alternative pathways of mast cell activation. Crit. Rev. Immunol. 22, 115–140 (2002).

    Article  CAS  Google Scholar 

  5. 5

    Drummond, P. D. The effect of cutaneous mast cell degranulation on sensitivity to heat. Inflamm. Res. 53, 309–315 (2004).

    Article  CAS  Google Scholar 

  6. 6

    Parada, C. A., Tambeli, C. H., Cunha, F. Q. & Ferreira, S. H. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception. Neuroscience 102, 937–944 (2001).

    Article  CAS  Google Scholar 

  7. 7

    Ribeiro, R. A. et al. Involvement of resident macrophages and mast cells in the writhing nociceptive response induced by zymosan and acetic acid in mice. Eur. J. Pharmacol. 387, 111–118 (2000).

    Article  CAS  Google Scholar 

  8. 8

    Hoogerwerf, W. A. et al. The role of mast cells in the pathogenesis of pain in chronic pancreatitis. BMC Gastroenterol. 5, 8 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Piovezan, A. P. et al. Endothelins contribute towards nociception induced by antigen in ovalbumin-sensitised mice. Br. J. Pharmacol. 141, 755–763 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Oberpenning, F., van Ophoven, A. & Hertle, L. Interstitial cystitis: an update. Curr. Opin. Urol. 12, 321–332 (2002).

    Article  Google Scholar 

  11. 11

    Thomazzi, S. M., Ribeiro, R. A., Campos D. I., Cunha, F. Q. & Ferreira, S. H. Tumor necrosis factor, interleukin-1 and interleukin-8 mediate the nociceptive activity of supernatant of LPS-stimulated macrophages. Mediators Inflamm. 6, 195–200 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Souza, G. E., Cunha, F. Q., Mello, R. & Ferreira, S. H. Neutrophil migration induced by inflammatory stimuli is reduced by macrophage depletion. Agents Actions 24, 377–380 (1988).

    Article  CAS  Google Scholar 

  13. 13

    Brack, A. & Stein, C. Potential links between leukocytes and antinociception. Pain 111, 1–2 (2004).

    Article  Google Scholar 

  14. 14

    Heuft, H. G., Goudeva, L. & Blasczyk, R. A comparative study of adverse reactions occurring after administration of glycosylated granulocyte colony stimulating factor and/or dexamethasone for mobilization of neutrophils in healthy donors. Ann. Hematol. 83, 279–285 (2004).

    Article  CAS  Google Scholar 

  15. 15

    Chou, T. C., Chang, L. P., Li, C. Y., Wong, C. S. & Yang, S. P. The antiinflammatory and analgesic effects of baicalin in carrageenan-evoked thermal hyperalgesia. Anesth. Analg. 97, 1724–1729 (2003).

    Article  CAS  Google Scholar 

  16. 16

    McMahon, S. B., Cafferty, W. B. & Marchand, F. Immune and glial cell factors as pain mediators and modulators. Exp. Neurol. 192, 444–462 (2005). This article reviews immune and glial components of experimental pain, highlighting the actions of some of the key immune-derived mediators and modulators of pain transmission.

    Article  CAS  Google Scholar 

  17. 17

    Bennett, G., al Rashed, S., Hoult, J. R. & Brain, S. D. Nerve growth factor induced hyperalgesia in the rat hind paw is dependent on circulating neutrophils. Pain 77, 315–322 (1998).

    Article  CAS  Google Scholar 

  18. 18

    Farquhar-Smith, W. P. & Rice, A. S. A novel neuroimmune mechanism in cannabinoid-mediated attenuation of nerve growth factor-induced hyperalgesia. Anesthesiology 99, 1391–1401 (2003).

    Article  Google Scholar 

  19. 19

    Sibilia, J. Novel concepts and treatments for autoimmune disease: ten focal points. Joint Bone Spine 71, 511–517 (2004).

    Article  Google Scholar 

  20. 20

    McMahon, S. B., Bennett, D. L. H. & Bevan S. in Textbook of Pain (eds McMahon, S. B. & Koltzenburg, M.) Chapter 3 (Elsevier, London, in the press).

  21. 21

    Omote, K. et al. Peripheral nitric oxide in carrageenan-induced inflammation. Brain Res. 912, 171–175 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Thomsen, L. L. & Olesen, J. Nitric oxide in primary headaches. Curr. Opin. Neurol. 14, 315–321 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Aley, K. O., McCarter, G. & Levine, J. D. Nitric oxide signaling in pain and nociceptor sensitization in the rat. J. Neurosci. 18, 7008–7014 (1998).

    Article  CAS  Google Scholar 

  24. 24

    Hanauer, S. B. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: overview of randomized clinical studies. Rev. Gastroenterol. Disord. 4 (Suppl. 3), S18–S24 (2004).

    PubMed  PubMed Central  Google Scholar 

  25. 25

    Roberts, L. & McColl, G. J. Tumour necrosis factor inhibitors: risks and benefits in patients with rheumatoid arthritis. Intern. Med. J. 34, 687–693 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Bonnington, J. K. & McNaughton, P. A. Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. J. Physiol. (Lond.) 551, 433–446 (2003).

    Article  CAS  Google Scholar 

  27. 27

    Hwang, S. W. et al. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc. Natl Acad. Sci. USA 97, 6155–6160 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Noorbakhsh, F., Vergnolle, N., Hollenberg, M. D. & Power, C. Proteinase-activated receptors in the nervous system. Nature Rev. Neurosci. 4, 981–990 (2003).

    Article  CAS  Google Scholar 

  29. 29

    Oh, S. B. et al. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J. Neurosci. 21, 5027–5035 (2001). The first evidence that chemokines have a direct effect on primary nociceptive neurons, and, therefore, a potential role in pain transmission.

    Article  CAS  Google Scholar 

  30. 30

    Sindrup, S. H. & Jensen, T. S. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83, 389–400 (1999).

    Article  CAS  Google Scholar 

  31. 31

    Le Bars, D., Gozariu, M. & Cadden, S. W. Animal models of nociception. Pharmacol. Rev. 53, 597–652 (2001).

    CAS  PubMed  Google Scholar 

  32. 32

    Ossipov, M. H., Lai, J., Malan, T. P. Jr & Porreca, F. Spinal and supraspinal mechanisms of neuropathic pain. Ann. NY Acad. Sci. 909, 12–24 (2000).

    Article  CAS  Google Scholar 

  33. 33

    Zuo, Y., Perkins, N. M., Tracey, D. J. & Geczy, C. L. Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells. Pain 105, 467–479 (2003).

    Article  Google Scholar 

  34. 34

    Perkins, N. M. & Tracey, D. J. Hyperalgesia due to nerve injury: role of neutrophils. Neuroscience 101, 745–757 (2000).

    Article  CAS  Google Scholar 

  35. 35

    Daemen, M. A. et al. Neurogenic inflammation in an animal model of neuropathic pain. Neurol. Res. 20, 41–45 (1998).

    Article  CAS  Google Scholar 

  36. 36

    Levine, J. D., Coderre, T. J., White, D. M., Finkbeiner, W. E. & Basbaum, A. I. Denervation-induced inflammation in the rat. Neurosci. Lett. 119, 37–40 (1990).

    Article  CAS  Google Scholar 

  37. 37

    Cui, J. G., Holmin, S., Mathiesen, T., Meyerson, B. A. & Linderoth, B. Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy. Pain 88, 239–248 (2000).

    Article  CAS  Google Scholar 

  38. 38

    Sommer, C. & Schafers, M. Painful mononeuropathy in C57BL/Wld mice with delayed Wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity. Brain Res. 784, 154–162 (1998).

    Article  CAS  Google Scholar 

  39. 39

    Myers, R. R., Heckman, H. M. & Rodriguez, M. Reduced hyperalgesia in nerve-injured WLD mice: relationship to nerve fiber phagocytosis, axonal degeneration, and regeneration in normal mice. Exp. Neurol. 141, 94–101 (1996).

    Article  CAS  Google Scholar 

  40. 40

    Liu, T., van Rooijen, N. & Tracey, D. J. Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury. Pain 86, 25–32 (2000).

    Article  CAS  Google Scholar 

  41. 41

    Heumann, R. et al. Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc. Natl Acad. Sci. USA 84, 8735–8739 (1987).

    Article  CAS  Google Scholar 

  42. 42

    Rutkowski, M. D., Pahl, J. L., Sweitzer, S., van Rooijen, N. & DeLeo, J. A. Limited role of macrophages in generation of nerve injury-induced mechanical allodynia. Physiol. Behav. 71, 225–235 (2002).

    Article  Google Scholar 

  43. 43

    Moalem, G., Xu, K. & Yu, L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience 129, 767–777 (2004).

    Article  CAS  Google Scholar 

  44. 44

    Tsai, Y. C., Won, S. J. & Lin, M. T. Effects of morphine on immune response in rats with sciatic constriction injury. Pain 88, 155–160 (2000).

    Article  CAS  Google Scholar 

  45. 45

    Tsai, Y. C. & Won, S. J. Effects of tramadol on T lymphocyte proliferation and natural killer cell activity in rats with sciatic constriction injury. Pain 92, 63–69 (2001).

    Article  CAS  Google Scholar 

  46. 46

    Lu, X. & Richardson, P. M. Responses of macrophages in rat dorsal root ganglia following peripheral nerve injury. J. Neurocytol. 22, 334–341 (1993).

    Article  CAS  Google Scholar 

  47. 47

    Sommer, C. & Schroder, J. M. HLA-DR expression in peripheral neuropathies: the role of Schwann cells, resident and hematogenous macrophages, and endoneurial fibroblasts. Acta Neuropathol. (Berl.) 89, 63–71 (1995). One of the first papers to identify a role for macrophages in pain after peripheral nerve injury.

    Article  CAS  Google Scholar 

  48. 48

    Hu, P. & McLachlan, E. M. Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat. Neuroscience 112, 23–38 (2002).

    Article  CAS  Google Scholar 

  49. 49

    Dina, O. A. et al. Integrin signaling in inflammatory and neuropathic pain in the rat. Eur. J. Neurosci. 19, 634–642 (2004).

    Article  Google Scholar 

  50. 50

    Fu, W. M. et al. Inhibition of neuropathic pain by a potent disintegrin — triflavin. Neurosci. Lett. 368, 263–268 (2004).

    Article  CAS  Google Scholar 

  51. 51

    Sweitzer, S. M., White, K. A., Dutta, C. & DeLeo, J. A. The differential role of spinal MHC class II and cellular adhesion molecules in peripheral inflammatory versus neuropathic pain in rodents. J. Neuroimmunol. 125, 82–93 (2002).

    Article  CAS  Google Scholar 

  52. 52

    Boddeke, E. W. Involvement of chemokines in pain. Eur. J. Pharmacol. 429, 115–119 (2001). An informative review about the role of chemokines in pain.

    Article  CAS  Google Scholar 

  53. 53

    George, A., Schmidt, C., Weishaupt, A., Toyka, K. V. & Sommer, C. Serial determination of tumor necrosis factor-α content in rat sciatic nerve after chronic constriction injury. Exp. Neurol. 160, 124–132 (1999).

    Article  CAS  Google Scholar 

  54. 54

    Schafers, M., Svensson, C. I., Sommer, C. & Sorkin, L. S. Tumor necrosis factor-α induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23, 2517–2521 (2003).

    Article  CAS  Google Scholar 

  55. 55

    Schafers, M., Geis, C., Svensson, C. I., Luo, Z. D. & Sommer, C. Selective increase of tumour necrosis factor-α in injured and spared myelinated primary afferents after chronic constrictive injury of rat sciatic nerve. Eur. J. Neurosci. 17, 791–804 (2003).

    Article  Google Scholar 

  56. 56

    Wagner, R. & Myers, R. R. Schwann cells produce tumor necrosis factor α: expression in injured and non-injured nerves. Neuroscience 73, 625–629 (1996).

    Article  CAS  Google Scholar 

  57. 57

    Wagner, R. & Myers, R. R. Endoneurial injection of TNF-α produces neuropathic pain behaviors. Neuroreport 7, 2897–2901 (1996). A historically important article that provided some of the first evidence that TNFα might be involved in pain modulation after peripheral nerve injury.

    Article  CAS  Google Scholar 

  58. 58

    Sommer, C. et al. Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res. 913, 86–89 (2001).

    Article  CAS  Google Scholar 

  59. 59

    Sommer, C., Schafers, M., Marziniak, M. & Toyka, K. V. Etanercept reduces hyperalgesia in experimental painful neuropathy. J. Peripher. Nerv. Syst. 6, 67–72 (2001).

    Article  CAS  Google Scholar 

  60. 60

    Lindenlaub, T., Teuteberg, P., Hartung, T. & Sommer, C. Effects of neutralizing antibodies to TNF-α on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Brain Res. 866, 15–22 (2000).

    Article  CAS  Google Scholar 

  61. 61

    Schafers, M., Brinkhoff, J., Neukirchen, S., Marziniak, M. & Sommer, C. Combined epineurial therapy with neutralizing antibodies to tumor necrosis factor-α and interleukin-1 receptor has an additive effect in reducing neuropathic pain in mice. Neurosci. Lett. 310, 113–116 (2001).

    Article  CAS  Google Scholar 

  62. 62

    Sommer, C., Schmidt, C. & George, A. Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. Exp. Neurol. 151, 138–142 (1998).

    Article  CAS  Google Scholar 

  63. 63

    George, A., Buehl, A. & Sommer, C. Tumor necrosis factor receptor 1 and 2 proteins are differentially regulated during Wallerian degeneration of mouse sciatic nerve. Exp. Neurol. 192, 163–166 (2005).

    Article  CAS  Google Scholar 

  64. 64

    Sommer, C., Petrausch, S., Lindenlaub, T. & Toyka, K. V. Neutralizing antibodies to interleukin 1-receptor reduce pain associated behavior in mice with experimental neuropathy. Neurosci. Lett. 270, 25–28 (1999).

    Article  CAS  Google Scholar 

  65. 65

    Fukuoka, H., Kawatani, M., Hisamitsu, T. & Takeshige, C. Cutaneous hyperalgesia induced by peripheral injection of interleukin-1 β in the rat. Brain Res. 657, 133–140 (1994).

    Article  CAS  Google Scholar 

  66. 66

    Obreja, O., Rathee, P. K., Lips, K. S., Distler, C. & Kress, M. IL-1 β potentiates heat-activated currents in rat sensory neurons: involvement of IL-1RI, tyrosine kinase, and protein kinase C. FASEB J. 16, 1497–1503 (2002).

    Article  CAS  Google Scholar 

  67. 67

    De Jongh, R. F. et al. The role of interleukin-6 in nociception and pain. Anesth. Analg. 96, 1096–1103 (2003). This article reviews the involvement of IL-6 in pain.

    Article  CAS  Google Scholar 

  68. 68

    Murphy, P. G. 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. 11, 2243–2253 (1999).

    Article  CAS  Google Scholar 

  69. 69

    Ramer, M. S., Murphy, P. G., Richardson, P. M. & Bisby, M. A. Spinal nerve lesion-induced mechanoallodynia and adrenergic sprouting in sensory ganglia are attenuated in interleukin-6 knockout mice. Pain 78, 115–121 (1998).

    Article  CAS  Google Scholar 

  70. 70

    Tanaka, T., Minami, M., Nakagawa, T. & Satoh, M. 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. 48, 463–469 (2004).

    Article  CAS  Google Scholar 

  71. 71

    Abbadie, C. et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl Acad. Sci. USA 100, 7947–7952 (2003).

    Article  CAS  Google Scholar 

  72. 72

    Milligan, E. D. et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur. J. Neurosci. 20, 2294–2302 (2004).

    Article  CAS  Google Scholar 

  73. 73

    Verge, G. M. 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. 20, 1150–1160 (2004). The first paper to show that fractalkine release by neurons could be an activator of microglia.

    Article  Google Scholar 

  74. 74

    Cunha, J. M., Cunha, F. Q., Poole, S. & Ferreira, S. H. Cytokine-mediated inflammatory hyperalgesia limited by interleukin-1 receptor antagonist. Br. J. Pharmacol. 130, 1418–1424 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Sommer, C. & Kress, M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci. Lett. 361, 184–187 (2004). A short review on the involvement of different cytokines in inflammatory and neuropathic pain.

    Article  CAS  Google Scholar 

  76. 76

    Ma, W. & Eisenach, J. C. Four PGE2 EP receptors are up-regulated in injured nerve following partial sciatic nerve ligation. Exp. Neurol. 183, 581–592 (2003).

    Article  CAS  Google Scholar 

  77. 77

    Ma, W. & Eisenach, J. C. Morphological and pharmacological evidence for the role of peripheral prostaglandins in the pathogenesis of neuropathic pain. Eur. J. Neurosci. 15, 1037–1047 (2002).

    Article  Google Scholar 

  78. 78

    Ma, W. & Eisenach, J. C. Intraplantar injection of a cyclooxygenase inhibitor ketorolac reduces immunoreactivities of substance P, calcitonin gene-related peptide, and dynorphin in the dorsal horn of rats with nerve injury or inflammation. Neuroscience 121, 681–690 (2003).

    Article  CAS  Google Scholar 

  79. 79

    Sweitzer, S. M., Hickey, W. F., Rutkowski, M. D., Pahl, J. L. & DeLeo, J. A. Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system: potential relationship to neuropathic pain. Pain 100, 163–170 (2002).

    Article  Google Scholar 

  80. 80

    Rutkowski, M. D., Lambert, F., Raghavendra, V. & DeLeo, J. A. Presence of spinal B7.2 (CD86) but not B7.1 (CD80) co-stimulatory molecules following peripheral nerve injury: role of nondestructive immunity in neuropathic pain. J. Neuroimmunol. 146, 94–98 (2004).

    Article  CAS  Google Scholar 

  81. 81

    De Nicola, A. F. et al. Steroid effects on glial cells: detrimental or protective for spinal cord function? Ann. NY Acad. Sci. 1007, 317–328 (2003).

    Article  CAS  Google Scholar 

  82. 82

    Meller, S. T., Dykstra, C., Grzybycki, D., Murphy, S. & Gebhart, G. F. The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 33, 1471–1478 (1994).

    Article  CAS  Google Scholar 

  83. 83

    Milligan, E. D. et al. Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein, gp120. Brain Res. 861, 105–116 (2000).

    Article  CAS  Google Scholar 

  84. 84

    Milligan, E. D. et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J. Neurosci. 23, 1026–1040 (2003).

    Article  CAS  Google Scholar 

  85. 85

    Aumeerally, N., Allen, G. & Sawynok, J. Glutamate-evoked release of adenosine and regulation of peripheral nociception. Neuroscience 127, 1–11 (2004).

    Article  CAS  Google Scholar 

  86. 86

    Raghavendra, V., Tanga, F. & DeLeo, J. A. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 306, 624–630 (2003). This paper provides the first evidence that microglia are involved in the initiation, rather than the maintenance, of neuropathic pain.

    Article  CAS  Google Scholar 

  87. 87

    Ledeboer, A. et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115, 71–83 (2005).

    Article  CAS  Google Scholar 

  88. 88

    Hassel, B., Paulsen, R. E., Johnsen, A. & Fonnum, F. Selective inhibition of glial cell metabolism in vivo by fluorocitrate. Brain Res. 576, 120–124 (1992).

    Article  CAS  Google Scholar 

  89. 89

    Zhang, S. C., Goetz, B. D. & Duncan, I. D. Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors. Glia 41, 191–198 (2003).

    Article  Google Scholar 

  90. 90

    Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003). An important study showing that P2X4 is a key mediator of microglial activation and is involved in neuropathic, but not inflammatory, pain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Guillemin, G. J. & Brew, B. J. Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J. Leukoc. Biol. 75, 388–397 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Colburn, R. W., Rickman, A. J. & DeLeo, J. A. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp. Neurol. 157, 289–304 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Colburn, R. W. et al. Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J. Neuroimmunol. 79, 163–175 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Hashizume, H., DeLeo, J. A., Colburn, R. W. & Weinstein, J. N. Spinal glial activation and cytokine expression after lumbar root injury in the rat. Spine 25, 1206–1217 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Winkelstein, B. A. & DeLeo, J. A. Nerve root injury severity differentially modulates spinal glial activation in a rat lumbar radiculopathy model: considerations for persistent pain. Brain Res. 956, 294–301 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Raghavendra, V., Tanga, F., Rutkowski, M. D. & DeLeo, J. A. Anti-hyperalgesic and morphine-sparing actions of propentofylline following peripheral nerve injury in rats: mechanistic implications of spinal glia and proinflammatory cytokines. Pain 104, 655–664 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Tanga, F. Y., Raghavendra, V. & DeLeo, J. A. Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem. Int. 45, 397–407 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Coyle, D. E. Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior. Glia 23, 75–83 (1998).

    Article  CAS  Google Scholar 

  99. 99

    Zhuang, Z. Y., Gerner, P., Woolf, C. J. & Ji, R. R. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114, 149–159 (2005).

    Article  Google Scholar 

  100. 100

    Le Feuvre, R., Brough, D. & Rothwell, N. Extracellular ATP and P2X7 receptors in neurodegeneration. Eur. J. Pharmacol. 447, 261–269 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Chessell, I. P. et al. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114, 386–396 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Klein, M. A. et al. Impaired neuroglial activation in interleukin-6 deficient mice. Glia 19, 227–233 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Winkelstein, B. A., Rutkowski, M. D., Sweitzer, S. M., Pahl, J. L. & DeLeo, J. A. Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. J. Comp. Neurol. 439, 127–139 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Tanga, F. Y., Nutile-McMenemy, N. & DeLeo, J. A. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc. Natl Acad. Sci. USA 102, 5856–5861 (2005). Showed, for the first time, the involvement of TLR4 in microglial activation in neuropathic pain models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Kim, S. Y. et al. Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport 13, 2483–2486 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Jin, S. X., Zhuang, Z. Y., Woolf, C. J. & Ji, R. R. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J. Neurosci. 23, 4017–4022 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., Koizumi, S. & Inoue, K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 45, 89–95 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Tsuda, M., Inoue, K. & Salter, M. W. Neuropathic pain and spinal microglia: a big problem from molecules in 'small' glia. Trends Neurosci. 28, 101–107 (2005). A critical review about the influence of microglia in neuropathic pain.

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Watkins, L. R. & Maier, S. F. Glia: a novel drug discovery target for clinical pain. Nature Rev. Drug Discov. 2, 973–985 (2003).

    Article  CAS  Google Scholar 

  110. 110

    Sung, C. S. et al. Intrathecal interleukin-1β administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord. Brain Res. 1015, 145–153 (2004).

    Article  CAS  Google Scholar 

  111. 111

    Reeve, A. J., Patel, S., Fox, A., Walker, K. & Urban, L. Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur. J. Pain 4, 247–257 (2000).

    Article  CAS  Google Scholar 

  112. 112

    DeLeo, J. A., Colburn, R. W., Nichols, M. & Malhotra, A. Interleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model. J. Interferon Cytokine Res. 16, 695–700 (1996).

    Article  CAS  Google Scholar 

  113. 113

    DeLeo, J. A., Colburn, R. W. & Rickman, A. J. Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy. Brain Res. 759, 50–57 (1997).

    Article  CAS  Google Scholar 

  114. 114

    Holguin, A. et al. HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS). Pain 110, 517–530 (2004).

    Article  CAS  Google Scholar 

  115. 115

    Wu, J., Fang, L., Lin, Q. & Willis, W. D. Nitric oxide synthase in spinal cord central sensitization following intradermal injection of capsaicin. Pain 94, 47–58 (2001).

    Article  CAS  Google Scholar 

  116. 116

    Durrenberger, P. F. et al. Cyclooxygenase-2 (Cox-2) in injured human nerve and a rat model of nerve injury. J. Peripher. Nerv. Syst. 9, 15–25 (2004).

    Article  CAS  Google Scholar 

  117. 117

    Broom, D. C. et al. Cyclooxygenase 2 expression in the spared nerve injury model of neuropathic pain. Neuroscience 124, 891–900 (2004).

    Article  CAS  Google Scholar 

  118. 118

    Schafers, M., Marziniak, M., Sorkin, L. S., Yaksh, T. L. & Sommer, C. Cyclooxygenase inhibition in nerve-injury- and TNF-induced hyperalgesia in the rat. Exp. Neurol. 185, 160–168 (2004).

    Article  CAS  Google Scholar 

  119. 119

    Zhu, X. & Eisenach, J. C. Cyclooxygenase-1 in the spinal cord is altered after peripheral nerve injury. Anesthesiology 99, 1175–1179 (2003).

    Article  CAS  Google Scholar 

  120. 120

    Ma, W., Du, W. & Eisenach, J. C. Role for both spinal cord COX-1 and COX-2 in maintenance of mechanical hypersensitivity following peripheral nerve injury. Brain Res. 937, 94–99 (2002).

    Article  CAS  Google Scholar 

  121. 121

    Finnerup, N. B. & Jensen, T. S. Spinal cord injury pain — mechanisms and treatment. Eur. J. Neurol. 11, 73–82 (2004). A good review about spinal cord injury and pain, with a useful section on different underlying mechanisms.

    Article  CAS  Google Scholar 

  122. 122

    Popovich, P. G. Immunological regulation of neuronal degeneration and regeneration in the injured spinal cord. Prog. Brain Res. 128, 43–58 (2000).

    Article  CAS  Google Scholar 

  123. 123

    Watanabe, T. et al. Differential activation of microglia after experimental spinal cord injury. J. Neurotrauma 16, 255–265 (1999).

    Article  CAS  Google Scholar 

  124. 124

    Marchand, F., Grist, J., Bradbury, E. J. & McMahon, S. B. Role of microglia in spinal cord injury pain in rats. Intl Assoc. Study Pain Abstr. 136265 (2005).

  125. 125

    Gris, D. et al. Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J. Neurosci. 24, 4043–4051 (2004).

    Article  CAS  Google Scholar 

  126. 126

    Oatway, M. A., Chen, Y., Bruce, J. C., Dekaban, G. A. & Weaver, L. C. Anti-CD11d integrin antibody treatment restores normal serotonergic projections to the dorsal, intermediate, and ventral horns of the injured spinal cord. J. Neurosci. 25, 637–647 (2005).

    Article  CAS  Google Scholar 

  127. 127

    Demjen, D. et al. Neutralization of CD95 ligand promotes regeneration and functional recovery after spinal cord injury. Nature Med. 10, 389–395 (2004).

    Article  CAS  Google Scholar 

  128. 128

    Pearse, D. D., Pereira, F. C., Stolyarova, A., Barakat, D. J. & Bunge, M. B. Inhibition of tumour necrosis factor-α by antisense targeting produces immunophenotypical and morphological changes in injury-activated microglia and macrophages. Eur. J. Neurosci. 20, 3387–3396 (2004).

    Article  Google Scholar 

  129. 129

    Perrin, F. E., Lacroix, S., Aviles-Trigueros, M. & David, S. Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1α and interleukin-1β in Wallerian degeneration. Brain 128, 854–866 (2005).

    Article  Google Scholar 

  130. 130

    Wang, X. et al. P2X7 receptor inhibition improves recovery after spinal cord injury. Nature Med. 10, 821–827 (2004).

    Article  CAS  Google Scholar 

  131. 131

    Hu, X. et al. Activation of nuclear factor-κB signaling pathway by interleukin-1 after hypoxia/ischemia in neonatal rat hippocampus and cortex. J. Neurochem. 93, 26–37 (2005).

    Article  CAS  Google Scholar 

  132. 132

    Qiu, J. et al. Bcl-xL expression after contusion to the rat spinal cord. J. Neurotrauma 18, 1267–1278 (2001).

    Article  CAS  Google Scholar 

  133. 133

    Plunkett, J. A., Yu, C. G., Easton, J. M., Bethea, J. R. & Yezierski, R. P. Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp. Neurol. 168, 144–154 (2001).

    Article  CAS  Google Scholar 

  134. 134

    Abraham, K. E., McMillen, D. & Brewer, K. L. The effects of endogenous interleukin-10 on gray matter damage and the development of pain behaviors following excitotoxic spinal cord injury in the mouse. Neuroscience 124, 945–952 (2004).

    Article  CAS  Google Scholar 

  135. 135

    Bethea, J. R. et al. Systemically administered interleukin-10 reduces tumor necrosis factor-α production and significantly improves functional recovery following traumatic spinal cord injury in rats. J. Neurotrauma 16, 851–863 (1999).

    Article  CAS  Google Scholar 

  136. 136

    Aicher, S. A., Silverman, M. B., Winkler, C. W. & Bebo, B. F. Jr. Hyperalgesia in an animal model of multiple sclerosis. Pain 110, 560–570 (2004).

    Article  CAS  Google Scholar 

  137. 137

    Gilden, D. H. Infectious causes of multiple sclerosis. Lancet Neurol. 4, 195–202 (2005).

    Article  CAS  Google Scholar 

  138. 138

    Vartanian, T. K., Zamvil, S. S., Fox, E. & Sorensen, P. S. Neutralizing antibodies to disease-modifying agents in the treatment of multiple sclerosis. Neurology 63, S42–S49 (2004).

    Article  CAS  Google Scholar 

  139. 139

    Mahad, D. J., Howell, S. J. & Woodroofe, M. N. Expression of chemokines in the CSF and correlation with clinical disease activity in patients with multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 72, 498–502 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Toms, R., Weiner, H. L. & Johnson, D. Identification of IgE-positive cells and mast cells in frozen sections of multiple sclerosis brains. J. Neuroimmunol. 30, 169–177 (1990).

    Article  CAS  Google Scholar 

  141. 141

    Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  Google Scholar 

  142. 142

    Panes, J., Perry, M. & Granger, D. N. Leukocyte–endothelial cell adhesion: avenues for therapeutic intervention. Br. J. Pharmacol. 126, 537–550 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Murphy, P. M. et al. International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev. 52, 145–176 (2000).

    CAS  Google Scholar 

  144. 144

    Gilroy, D. W., Lawrence, T., Perretti, M. & Rossi, A. G. Inflammatory resolution: new opportunities for drug discovery. Nature Rev. Drug Discov. 3, 401–416 (2004). A review that illustrates the concept of anti-inflammation and the endogenous control of the inflammatory response.

    Article  CAS  Google Scholar 

  145. 145

    Hannon, R. et al. Aberrant inflammatory responses and resistance to glucocorticoids in the annexin 1−/− mouse. FASEB J. 17, 253–255 (2003). This study reports the initial description of the annexin 1 null mouse, and the impact on the host inflammatory response of removing this endogenous inhibitory mediator.

    Article  CAS  Google Scholar 

  146. 146

    Malcangio, M. et al. A novel control mechanism based on GDNF modulation of somatostatin release from sensory neurones. FASEB J. 16, 730–732 (2002).

    Article  CAS  Google Scholar 

  147. 147

    Arita, M. et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201, 713–722 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Ferreira, S. H. et al. Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone. Br. J. Pharmacol. 121, 883–888 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Pieretti, S., Di Giannuario, A., De Felice, M., Perretti, M. & Cirino, G. Stimulus-dependent specificity for annexin 1 inhibition of the inflammatory nociceptive response: the involvement of the receptor for formylated peptides. Pain 109, 52–63 (2004). An important study that describes the effects of annexin 1 bioactive peptidomimetics in models of peripheral inflammatory pain.

    Article  CAS  Google Scholar 

  150. 150

    Melzer, P., Savchenko, V. & McKanna, J. A. Microglia, astrocytes, and macrophages react differentially to central and peripheral lesions in the developing and mature rat whisker-to-barrel pathway: a study using immunohistochemistry for lipocortin1, phosphotyrosine, s100β, and mannose receptors. Exp. Neurol. 168, 63–77 (2001).

    Article  CAS  Google Scholar 

  151. 151

    Le, Y. et al. Amyloid β42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J. Neurosci. 21, RC123 (2001). A comprehensive analysis of FPRL1 expression and function on microglia, with strong implications for Alzheimer's disease.

    Article  CAS  Google Scholar 

  152. 152

    Harada, M. et al. N-Formylated humanin activates both formyl peptide receptor-like 1 and 2. Biochem. Biophys. Res. Commun. 324, 255–261 (2004).

    Article  CAS  Google Scholar 

  153. 153

    Minghetti, L. et al. Down-regulation of microglial cyclo-oxygenase-2 and inducible nitric oxide synthase expression by lipocortin 1. Br. J. Pharmacol. 126, 1307–1314 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to the Wellcome Trust, the International Spinal Research Trust and the Arthritis Research Campaign UK for the financial support that has made this work possible.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Stephen B. McMahon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

BDNF

CCL2

CCR2

CGRP

COX1

COX2

CREB

CXCL8

CXCR1

CX3CL1

CX3CR1

GCSF

IL-1β

IL-6

iNOS

ITGAM

LIF

nNOS

P2X3

TLR4

TNFα

TrkA

TRPV1

FURTHER INFORMATION

The London Pain Consortium

International Association for the Study of Pain (IASP)

The William Harvey Research Institute

McMahon's laboratory

Glossary

PAIN

Pain has been defined by the International Association for the Study of Pain as an unpleasant sensory and emotional experience that is associated with actual or potential tissue damage, or described in terms of such damage.

MAST CELL

A multigranular cell that functions as a store for several key inflammatory/pain mediators (including NGF, TNFα, chemokines and histamine).

CYTOKINES

Small, secreted proteins that mediate and regulate immunity, inflammation and haematopoiesis. They act as intercellular mediators by binding to specific membrane receptors, which then signal through second messengers — often tyrosine kinases — to alter the target cell's behaviour.

CHEMOKINES

Small polypeptide cytokines that can attract leukocyte subsets.

NEUROPATHIC PAIN

This has been defined by the International Association for the Study of Pain as pain that is initiated or caused by a primary lesion or dysfunction in the nervous system.

INTEGRINS

Dimeric membrane proteins that are involved in several aspects of cell–cell interaction.

MICROGLIA

A non-neuronal cell type present in the spinal cord and brain (the resident CNS macrophage) that is characterized by its ramified morphology.

ANNEXIN 1

A member of a superfamily of proteins named after their ability to annex membranes by binding to acidic phospholipids in the presence of cations; an important endogenous counter-regulator of inflammation.

FPRL1

A member of the formyl peptide receptor family of G-protein-coupled receptors that mediates the anti-inflammatory/protective activities of lipoxins and annexin 1, as well as the activating effects of amyloid-β fragments.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Marchand, F., Perretti, M. & McMahon, S. Role of the Immune system in chronic pain. Nat Rev Neurosci 6, 521–532 (2005). https://doi.org/10.1038/nrn1700

Download citation

Further reading