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The neuropathic pain triad: neurons, immune cells and glia

Abstract

Nociceptive pain results from the detection of intense or noxious stimuli by specialized high-threshold sensory neurons (nociceptors), a transfer of action potentials to the spinal cord, and onward transmission of the warning signal to the brain. In contrast, clinical pain such as pain after nerve injury (neuropathic pain) is characterized by pain in the absence of a stimulus and reduced nociceptive thresholds so that normally innocuous stimuli produce pain. The development of neuropathic pain involves not only neuronal pathways, but also Schwann cells, satellite cells in the dorsal root ganglia, components of the peripheral immune system, spinal microglia and astrocytes. As we increasingly appreciate that neuropathic pain has many features of a neuroimmune disorder, immunosuppression and blockade of the reciprocal signaling pathways between neuronal and non-neuronal cells offer new opportunities for disease modification and more successful management of pain.

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Figure 1: Immune and glial cell responses to peripheral nerve injury.

Kim Caesar

Figure 2: Inflammatory changes associated with wallerian degeneration.

Kim Caesar

Figure 3: Immune response in the DRG.

Kim Caesar

Figure 4: Recruitment and activation of spinal microglia and astrocytes.

Kim Caesar

References

  1. 1

    Dworkin, R.H. et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch. Neurol. 60, 1524–1534 (2003).

    PubMed  Google Scholar 

  2. 2

    Streit, W.J. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40, 133–139 (2002).

    PubMed  Google Scholar 

  3. 3

    Chan, W.Y., Kohsaka, S. & Rezaie, P. The origin and cell lineage of microglia: new concepts. Brain Res. Rev. 53, 344–354 (2007).

    CAS  PubMed  Google Scholar 

  4. 4

    Hanani, M. Satellite glial cells in sensory ganglia: from form to function. Brain Res. Brain Res. Rev. 48, 457–476 (2005).

    CAS  PubMed  Google Scholar 

  5. 5

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

    CAS  PubMed  Google Scholar 

  6. 6

    Mueller, M. et al. Rapid response of identified resident endoneurial macrophages to nerve injury. Am. J. Pathol. 159, 2187–2197 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    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).

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Shubayev, V.I. et al. TNFα-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve. Mol. Cell. Neurosci. 31, 407–415 (2006).

    CAS  PubMed  Google Scholar 

  9. 9

    Zochodne, D.W. et al. Evidence for nitric oxide and nitric oxide synthase activity in proximal stumps of transected peripheral nerves. Neuroscience 91, 1515–1527 (1999).

    CAS  PubMed  Google Scholar 

  10. 10

    Stoll, G., Jander, S. & Myers, R.R. Degeneration and regeneration of the peripheral nervous system: from Augustus Waller's observations to neuroinflammation. J. Peripher. Nerv. Syst. 7, 13–27 (2002).

    PubMed  Google Scholar 

  11. 11

    Guertin, A.D., Zhang, D.P., Mak, K.S., Alberta, J.A. & Kim, H.A. Microanatomy of axon/glial signaling during Wallerian degeneration. J. Neurosci. 25, 3478–3487 (2005).

    CAS  PubMed  Google Scholar 

  12. 12

    Carroll, S.L., Miller, M.L., Frohnert, P.W., Kim, S.S. & Corbett, J.A. Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J. Neurosci. 17, 1642–1659 (1997).

    CAS  PubMed  Google Scholar 

  13. 13

    Esper, R.M. & Loeb, J.A. Rapid axoglial signaling mediated by neuregulin and neurotrophic factors. J. Neurosci. 24, 6218–6227 (2004).

    CAS  PubMed  Google Scholar 

  14. 14

    Malin, S.A. et al. Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J. Neurosci. 26, 8588–8599 (2006).

    CAS  PubMed  Google Scholar 

  15. 15

    Ma, W. & Eisenach, J.C. Cyclooxygenase 2 in infiltrating inflammatory cells in injured nerve is universally up-regulated following various types of peripheral nerve injury. Neuroscience 121, 691–704 (2003).

    CAS  PubMed  Google Scholar 

  16. 16

    Tofaris, G.K., Patterson, P.H., Jessen, K.R. & Mirsky, R. Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J. Neurosci. 22, 6696–6703 (2002).

    CAS  PubMed  Google Scholar 

  17. 17

    Zhang, N. et al. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. Proc. Natl. Acad. Sci. USA 102, 4536–4541 (2005).

    CAS  PubMed  Google Scholar 

  18. 18

    Oh, S.B. et al. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J. Neurosci. 21, 5027–5035 (2001).

    CAS  PubMed  Google Scholar 

  19. 19

    Melli, G., Keswani, S.C., Fischer, A., Chen, W. & Hoke, A. Spatially distinct and functionally independent mechanisms of axonal degeneration in a model of HIV-associated sensory neuropathy. Brain 129, 1330–1338 (2006).

    PubMed  Google Scholar 

  20. 20

    Keswani, S.C. et al. Schwann cell chemokine receptors mediate HIV-1 gp120 toxicity to sensory neurons. Ann. Neurol. 54, 287–296 (2003).

    CAS  PubMed  Google Scholar 

  21. 21

    Cunha, T.M. et al. A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc. Natl. Acad. Sci. USA 102, 1755–1760 (2005).

    CAS  PubMed  Google Scholar 

  22. 22

    Schafers, M., Lee, D.H., Brors, D., Yaksh, T.L. & Sorkin, L.S. Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J. Neurosci. 23, 3028–3038 (2003).

    CAS  PubMed  Google Scholar 

  23. 23

    Wolf, G., Gabay, E., Tal, M., Yirmiya, R. & Shavit, Y. Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in mice. Pain 120, 315–324 (2006).

    CAS  PubMed  Google Scholar 

  24. 24

    Schäfers, 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).

    PubMed  Google Scholar 

  25. 25

    Aggarwal, B.B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 3, 745–756 (2003).

    CAS  PubMed  Google Scholar 

  26. 26

    Myers, R.R., Campana, W.M. & Shubayev, V.I. The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets. Drug Discov. Today 11, 8–20 (2006).

    CAS  PubMed  Google Scholar 

  27. 27

    Lindholm, D., Heumann, R., Meyer, M. & Thoenen, H. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature 330, 658–659 (1987).

    CAS  PubMed  Google Scholar 

  28. 28

    Mack, T.G. et al. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat. Neurosci. 4, 1199–1206 (2001).

    CAS  PubMed  Google Scholar 

  29. 29

    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).

    CAS  PubMed  Google Scholar 

  30. 30

    Zhuang, Z.Y. et al. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav. Immun. 21, 642–651 (2007).

    CAS  PubMed  Google Scholar 

  31. 31

    Morin, N. et al. Neutrophils invade lumbar dorsal root ganglia after chronic constriction injury of the sciatic nerve. J. Neuroimmunol. 184, 164–171 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    White, F.A. 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 102, 14092–14097 (2005).

    CAS  PubMed  Google Scholar 

  33. 33

    Zhang, J. & De Koninck, Y. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J. Neurochem. 97, 772–783 (2006).

    CAS  PubMed  Google Scholar 

  34. 34

    Hu, P. & McLachlan, E.M. Distinct functional types of macrophage in dorsal root ganglia and spinal nerves proximal to sciatic and spinal nerve transections in the rat. Exp. Neurol. 184, 590–605 (2003).

    PubMed  Google Scholar 

  35. 35

    Tandrup, T., Woolf, C.J. & Coggeshall, R.E. Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve. J. Comp. Neurol. 422, 172–180 (2000).

    CAS  PubMed  Google Scholar 

  36. 36

    Shi, T.J. et al. Effect of peripheral nerve injury on dorsal root ganglion neurons in the C57 BL/6J mouse: marked changes both in cell numbers and neuropeptide expression. Neuroscience 105, 249–263 (2001).

    CAS  PubMed  Google Scholar 

  37. 37

    Costigan, M. et al. Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neurosci. [online] 3, 16 (2002).

    PubMed Central  Google Scholar 

  38. 38

    Arruda, J.L., Sweitzer, S., Rutkowski, M.D. & DeLeo, J.A. Intrathecal anti-IL-6 antibody and IgG attenuates peripheral nerve injury-induced mechanical allodynia in the rat: possible immune modulation in neuropathic pain. Brain Res. 879, 216–225 (2000).

    CAS  PubMed  Google Scholar 

  39. 39

    Jin, X. & Gereau, R.W. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-α. J. Neurosci. 26, 246–255 (2006).

    CAS  PubMed  Google Scholar 

  40. 40

    Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev. 87, 659–797 (2007).

    CAS  PubMed  Google Scholar 

  41. 41

    Khakh, B.S. Molecular physiology of P2X receptors and ATP signalling at synapses. Nat. Rev. Neurosci. 2, 165–174 (2001).

    CAS  PubMed  Google Scholar 

  42. 42

    Kobayashi, K. et al. Differential expression patterns of mRNAs for P2X receptor subunits in neurochemically characterized dorsal root ganglion neurons in the rat. J. Comp. Neurol. 481, 377–390 (2005).

    CAS  PubMed  Google Scholar 

  43. 43

    Kobayashi, K. et al. Neurons and glial cells differentially express P2Y receptor mRNAs in the rat dorsal root ganglion and spinal cord. J. Comp. Neurol. 498, 443–454 (2006).

    CAS  PubMed  Google Scholar 

  44. 44

    Di Virgilio, F. et al. Nucleotide receptors: an emerging family of regulatory molecules in blood cells. Blood 97, 587–600 (2001).

    CAS  PubMed  Google Scholar 

  45. 45

    Zhang, X., Chen, Y., Wang, C. & Huang, L.Y. Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc. Natl. Acad. Sci. USA 104, 9864–9869 (2007).

    CAS  PubMed  Google Scholar 

  46. 46

    Chen, Y., Li, G.W., Wang, C., Gu, Y. & Huang, L.Y. Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state. Pain 119, 38–48 (2005).

    CAS  PubMed  Google Scholar 

  47. 47

    Jarvis, M.F. et al. A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc. Natl. Acad. Sci. USA 99, 17179–17184 (2002).

    CAS  PubMed  Google Scholar 

  48. 48

    Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003).

    CAS  PubMed  Google Scholar 

  49. 49

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

    CAS  PubMed  Google Scholar 

  50. 50

    McGaraughty, S. et al. P2X7-related modulation of pathological nociception in rats. Neuroscience 146, 1817–1828 (2007).

    CAS  PubMed  Google Scholar 

  51. 51

    Amaya, F. et al. The voltage-gated sodium channel Nav1.9 is an effector of peripheral inflammatory pain hypersensitivity. J. Neurosci. 26, 12852–12860 (2006).

    CAS  PubMed  Google Scholar 

  52. 52

    Sharp, C.J. et al. Investigation into the role of P2X3/P2X2/3 receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiological study. Br. J. Pharmacol. 148, 845–852 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    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).

    CAS  PubMed  Google Scholar 

  54. 54

    Li, H.Y., Say, E.H. & Zhou, X.F. Isolation and characterization of neural crest progenitors from adult dorsal root ganglia. Stem Cells 25, 2053–2065 (2007).

    CAS  PubMed  Google Scholar 

  55. 55

    Hu, P., Bembrick, A.L., Keay, K.A. & McLachlan, E.M. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav. Immun. 21, 599–616 (2007).

    CAS  PubMed  Google Scholar 

  56. 56

    Beggs, S. & Salter, M.W. Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav. Immun. 21, 624–633 (2007).

    CAS  PubMed  Google Scholar 

  57. 57

    Marchand, F., Perretti, M. & McMahon, S.B. Role of the immune system in chronic pain. Nat. Rev. Neurosci. 6, 521–532 (2005).

    CAS  PubMed  Google Scholar 

  58. 58

    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).

    CAS  PubMed  Google Scholar 

  59. 59

    Watkins, L.R. & Maier, S.F. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol. Rev. 82, 981–1011 (2002).

    CAS  PubMed  Google Scholar 

  60. 60

    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).

    CAS  PubMed  Google Scholar 

  61. 61

    Katsura, H. et al. Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. J. Neurosci. 26, 8680–8690 (2006).

    CAS  PubMed  Google Scholar 

  62. 62

    Svensson, C.I. et al. Spinal p38β isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J. Neurochem. 92, 1508–1520 (2005).

    CAS  PubMed  Google Scholar 

  63. 63

    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).

    PubMed  Google Scholar 

  64. 64

    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).

    PubMed  Google Scholar 

  65. 65

    White, F.A., Bhangoo, S.K. & Miller, R.J. Chemokines: integrators of pain and inflammation. Nat. Rev. Drug Discov. 4, 834–844 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Kim, D. et al. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J. Biol. Chem. 282, 14975–14983 (2007).

    CAS  PubMed  Google Scholar 

  67. 67

    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).

    CAS  PubMed  Google Scholar 

  68. 68

    Dorf, M.E., Berman, M.A., Tanabe, S., Heesen, M. & Luo, Y. Astrocytes express functional chemokine receptors. J. Neuroimmunol. 111, 109–121 (2000).

    CAS  PubMed  Google Scholar 

  69. 69

    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).

    CAS  PubMed  Google Scholar 

  70. 70

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

    CAS  PubMed  Google Scholar 

  71. 71

    Trinchieri, G. & Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7, 179–190 (2007).

    CAS  PubMed  Google Scholar 

  72. 72

    Marshak-Rothstein, A. Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6, 823–835 (2006).

    CAS  PubMed  Google Scholar 

  73. 73

    Scholz, J. et al. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J. Neurosci. 25, 7317–7323 (2005).

    CAS  PubMed  Google Scholar 

  74. 74

    Echeverry, S., Shi, X.Q. & Zhang, J. Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain. Pain, published online 8, June 2007 (doi:10.1016/j.pain.2007.05.002).

    CAS  PubMed  Google Scholar 

  75. 75

    Coull, J.A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Coull, J.A. et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424, 938–942 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Nakatsuka, T. & Gu, J.G. ATP P2X receptor-mediated enhancement of glutamate release and evoked EPSCs in dorsal horn neurons of the rat spinal cord. J. Neurosci. 21, 6522–6531 (2001).

    CAS  PubMed  Google Scholar 

  78. 78

    Clark, A.K. et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. USA 104, 10655–10660 (2007).

    CAS  PubMed  Google Scholar 

  79. 79

    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).

    CAS  PubMed  Google Scholar 

  80. 80

    Griffin, R.S. et al. Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity. J. Neurosci. 27, 8699–8708 (2007).

    CAS  PubMed  Google Scholar 

  81. 81

    Kotani, N. et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N. Engl. J. Med. 343, 1514–1519 (2000).

    CAS  PubMed  Google Scholar 

  82. 82

    van Wijck, A.J. et al. The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: a randomised controlled trial. Lancet 367, 219–224 (2006).

    CAS  PubMed  Google Scholar 

  83. 83

    Arden, N.K. et al. A multicentre randomized controlled trial of epidural corticosteroid injections for sciatica: the WEST study. Rheumatology (Oxford) 44, 1399–1406 (2005).

    CAS  Google Scholar 

  84. 84

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

    CAS  PubMed  Google Scholar 

  85. 85

    Clark, A.K., Gentry, C., Bradbury, E.J., McMahon, S.B. & Malcangio, M. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur. J. Pain 11, 223–230 (2007).

    PubMed  Google Scholar 

  86. 86

    Tawfik, V.L., Nutile-McMenemy, N., LaCroix-Fralish, M.L. & DeLeo, J.A. Efficacy of propentofylline, a glial modulating agent, on existing mechanical allodynia following peripheral nerve injury. Brain Behav. Immun. 21, 238–246 (2007).

    CAS  PubMed  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).

    CAS  PubMed  Google Scholar 

  88. 88

    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).

    CAS  PubMed  Google Scholar 

  89. 89

    Sweitzer, S.M. & DeLeo, J.A. The active metabolite of leflunomide, an immunosuppressive agent, reduces mechanical sensitivity in a rat mononeuropathy model. J. Pain 3, 360–368 (2002).

    PubMed  Google Scholar 

  90. 90

    Goncharov, N.V., Jenkins, R.O. & Radilov, A.S. Toxicology of fluoroacetate: a review, with possible directions for therapy research. J. Appl. Toxicol. 26, 148–161 (2006).

    CAS  PubMed  Google Scholar 

  91. 91

    Si, Q., Nakamura, Y., Ogata, T., Kataoka, K. & Schubert, P. Differential regulation of microglial activation by propentofylline via cAMP signaling. Brain Res. 812, 97–104 (1998).

    CAS  PubMed  Google Scholar 

  92. 92

    Zemke, D. & Majid, A. The potential of minocycline for neuroprotection in human neurologic disease. Clin. Neuropharmacol. 27, 293–298 (2004).

    CAS  PubMed  Google Scholar 

  93. 93

    Umapathi, T. & Chaudhry, V. Toxic neuropathy. Curr. Opin. Neurol. 18, 574–580 (2005).

    CAS  PubMed  Google Scholar 

  94. 94

    McGaraughty, S. & Jarvis, M.F. Antinociceptive properties of a non-nucleotide P2X3/P2X2/3 receptor antagonist. Drug News Perspect. 18, 501–507 (2005).

    CAS  PubMed  Google Scholar 

  95. 95

    Donnelly-Roberts, D.L. & Jarvis, M.F. Discovery of P2X7 receptor-selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states. Br. J. Pharmacol. 151, 571–579 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Stella, N. Cannabinoid signaling in glial cells. Glia 48, 267–277 (2004).

    PubMed  Google Scholar 

  97. 97

    Valenzano, K.J. et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658–672 (2005).

    CAS  PubMed  Google Scholar 

  98. 98

    Milligan, E.D. et al. Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain. Pain 126, 294–308 (2006).

    CAS  PubMed  Google Scholar 

  99. 99

    George, A., Marziniak, M., Schafers, M., Toyka, K.V. & Sommer, C. Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-α, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. Pain 88, 267–275 (2000).

    CAS  Google Scholar 

  100. 100

    Sommer, C., Marziniak, M. & Myers, R.R. The effect of thalidomide treatment on vascular pathology and hyperalgesia caused by chronic constriction injury of rat nerve. Pain 74, 83–91 (1998).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Supported by grants from the US National Institute of Neurological Disorders and Stroke (J.S., C.J.W.) and the US National Institute of Dental and Craniofacial Research (C.J.W.).

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Scholz, J., Woolf, C. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 10, 1361–1368 (2007). https://doi.org/10.1038/nn1992

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