MAP Kinase and Cell Signaling in DRG Neurons and Spinal Microglia in Neuropathic Pain

  • Ru-Rong Ji


Nerve injury is known to produce neuropathic pain by inducing changes not only in neurons such as primary sensory neurons in the dorsal root ganglion (DRG), but also in non-neuronal cells such as microglia in the spinal cord. Increasing evidence suggests that mitogen-activated protein kinases (MAPKs) play important roles in neuropathic pain sensitization by regulating intracellular signaling in both DRG neurons and spinal cord microglia. Intrathecal injection of MAPK inhibitors for the extracellular signal-regulated kinase (ERK), p38, or c-Jun N-terminal kinase (JNK) pathway targets the MAPK pathways at both DRG and spinal cord levels and has been shown to attenuate neuropathic pain in different animal models. In particular, activation of p38 in DRG neurons by nerve growth factor and cytokines contributes to thermal hypersensitivity by increasing the expression and activity of sodium channels (e.g., Nav1.7/Nav1.8) and TRP channels (e.g., TRPV1 and TRPA1). Activation of p38 in spinal microglia by chemokines, cytokines, ATP, and proteases also contributes to neuropathic pain symptoms such as mechanical allodynia. Thus, activation of MAPK pathways in both neurons and glia and in both the peripheral and central nervous system is important for neuropathic pain sensitization, and blocking these pathways at multiple sites may lead to effective therapies for neuropathic pain.


Dorsal Root Ganglion Neuropathic Pain Nerve Injury Dorsal Root Ganglion Neuron Mechanical Allodynia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



α-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanic acid


brain-derived neurotrophic factor


cysteine protease cathepsin S


dorsal root ganglion


gamma aminobutyric acid


extracelllular signal-regulated kinase


basic fibroblast growth factor






c-Jun-N-terminal kinase


mitogen-activated protein kinases


monocyte chemoattractant protein-1




matrix metalloproteinase-9


nerve growth factor


neurotrophin 3


prostaglandin E2


pain transmission neurons STZ, streptozotocin


tumor necrosis factor


transient receptor potential



The work was supported in part by NIH grants NS40698, DE17794, and TW7180.


  1. Abbadie, C., Lindia, J.A., Cumiskey, A.M., Peterson, L.B., Mudgett, J.S., Bayne, E.K., DeMartino, J.A., MacIntyre, D.E., and Forrest, M.J. (2003). Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl. Acad. Sci. U.S.A. 100, 7947–7952.PubMedCrossRefGoogle Scholar
  2. Campbell, J.N. and Meyer, R.A. (2006). Mechanisms of neuropathic pain. Neuron 52, 77–92.PubMedCrossRefGoogle Scholar
  3. Chattopadhyay, M., Mata, M., and Fink, D.J. (2008). Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. J. Neurosci. 28, 6652–6658.PubMedCrossRefGoogle Scholar
  4. Clark, A.K., D'Aquisto, F., Gentry, C., Marchand, F., McMahon, S.B., and Malcangio, M. (2006). Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation. J. Neurochem. 99, 868–880.PubMedCrossRefGoogle Scholar
  5. Clark, A.K., Yip, P.K., Grist, J., Gentry, C., Staniland, A.A., Marchand, F., Dehvari, M., Wotherspoon, G., Winter, J., Ullah, J., Bevan, S., and Malcangio, M. (2007). Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. U.S.A. 104, 10655–10660.PubMedCrossRefGoogle Scholar
  6. Constantin, C.E., Mair, N., Sailer, C.A., Andratsch, M., Xu, Z.Z., Blumer, M.J., Scherbakov, N., Davis, J.B., Bluethmann, H., Ji, R.R., and Kress, M. (2008). Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. J. Neurosci. 28, 5072–5081.PubMedCrossRefGoogle Scholar
  7. Costigan, M., Befort, K., Karchewski, L., Griffin, R.S., D'Urso, D., Allchorne, A., Sitarski, J., Mannion, J.W., Pratt, R.E., and Woolf, C.J. (2002). Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC. Neurosci. 3, 16.PubMedCrossRefGoogle Scholar
  8. Coull, J.A., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M.W., and De Koninck, Y. (2005). BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021.PubMedCrossRefGoogle Scholar
  9. Coull, J.A., Boudreau, D., Bachand, K., Prescott, S.A., Nault, F., Sik, A., De Koninck, P., and De Koninck, Y. (2003). Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424, 938–942.PubMedCrossRefGoogle Scholar
  10. DeLeo, J.A. and Yezierski, R.P. (2001). The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 90, 1–6.PubMedCrossRefGoogle Scholar
  11. Devor, M. (1991). Neuropathic pain and injured nerve: peripheral mechanisms. Br. Med. Bull. 47, 619–630.Google Scholar
  12. Devor, M., Wall, P.D., and Catalan, N. (1992). Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. Pain 48, 261–268.PubMedCrossRefGoogle Scholar
  13. Djouhri, L., Koutsikou, S., Fang, X., McMullan, S., and Lawson, S.N. (2006). Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J. Neurosci. 26, 1281–1292.PubMedCrossRefGoogle Scholar
  14. Fukuoka, T., Kondo, E., Dai, Y., Hashimoto, N., and Noguchi, K. (2001). Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J. Neurosci. 21, 4891–4900.PubMedGoogle Scholar
  15. Hains, B.C. and Waxman, S.G. (2006). Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J. Neurosci. 26, 4308–4317.PubMedCrossRefGoogle Scholar
  16. Hokfelt, T., Zhang, X., and Wiesenfeld-Hallin, Z. (1994). Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci. 17, 22–30.PubMedCrossRefGoogle Scholar
  17. Hudmon, A., Choi, J.S., Tyrrell, L., Black, J.A., Rush, A.M., Waxman, S.G., and Dib-Hajj, S.D. (2008). Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. J. Neurosci. 28, 3190–3201.PubMedCrossRefGoogle Scholar
  18. Ji, R.R., Kawasaki, Y., Zhuang, Z.Y., Wen, Y.R., and Zhang, Y.Q. (2007). Protein kinases as potential targets for the treatment of pathological pain. Handb. Exp. Pharmacol. 359–389.Google Scholar
  19. Ji, R.R., Samad, T.A., Jin, S.X., Schmoll, R., and Woolf, C.J. (2002). p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36, 57–68.PubMedCrossRefGoogle Scholar
  20. Ji, R.R. and Strichartz, G. (2004). Cell signaling and the genesis of neuropathic pain. Sci. STKE. 2004, reE14.PubMedCrossRefGoogle Scholar
  21. Ji, R.R. and Suter, M.R. (2007). p38 MAPK, microglial signaling, and neuropathic pain. Mol. Pain 3, 33.PubMedCrossRefGoogle Scholar
  22. Ji, R.R. and Woolf, C.J. (2001). Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol. Dis. 8, 1–10.PubMedCrossRefGoogle Scholar
  23. Ji, R.R., Zhang, Q., Zhang, X., Piehl, F., Reilly, T., Pettersson, R.F., and Hokfelt, T. (1995). Prominent expression of bFGF in dorsal root ganglia after axotomy. Eur. J. Neurosci. 7, 2458–2468.PubMedCrossRefGoogle Scholar
  24. Jin, X. and Gereau, R.W. (2006). Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J. Neurosci. 26, 246–255.PubMedCrossRefGoogle Scholar
  25. Jin, S.X., Zhuang, Z.Y., Woolf, C.J., and Ji, R.R. (2003). 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.PubMedGoogle Scholar
  26. Kawasaki, Y., Zhang, L., Cheng, J.K., and Ji, R.R. (2008). 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. 28, 5189–5194.PubMedCrossRefGoogle Scholar
  27. Kehlet, H., Jensen, T.S., and Woolf, C.J. (2006). Persistent postsurgical pain: risk factors and prevention. Lancet 367, 1618–1625.PubMedCrossRefGoogle Scholar
  28. Kobayashi, K., Yamanaka, H., Fukuoka, T., Dai, Y., Obata, K., and Noguchi, K. (2008). P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J. Neurosci. 28, 2892–2902.PubMedCrossRefGoogle Scholar
  29. Kumar, S., Boehm, J., and Lee, J.C. (2003). p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat. Rev. Drug Discov. 2, 717–726.PubMedCrossRefGoogle Scholar
  30. Ma, C., Shu, Y., Zheng, Z., Chen, Y., Yao, H., Greenquist, K.W., White, F.A., and LaMotte, R.H. (2003). Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. J. Neurophysiol. 89, 1588–1602.PubMedCrossRefGoogle Scholar
  31. Ma, W., Zhang, Y., Bantel, C., and Eisenach, J.C. (2005). Medium and large injured dorsal root ganglion cells increase TRPV-1, accompanied by increased alpha2C-adrenoceptor co-expression and functional inhibition by clonidine. Pain 113, 386–394.PubMedCrossRefGoogle Scholar
  32. Moore, K.A., Kohno, T., Karchewski, L.A., Scholz, J., Baba, H., and Woolf, C.J. (2002). Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J. Neurosci. 22, 6724–6731.PubMedGoogle Scholar
  33. Obata, K., Katsura, H., Mizushima, T., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka, T., Tokunaga, A., Tominaga, M., and Noguchi, K. (2005). TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J. Clin. Invest 115, 2393–2401.PubMedCrossRefGoogle Scholar
  34. Obata, K., Yamanaka, H., Kobayashi, K., Dai, Y., Mizushima, T., Katsura, H., Fukuoka, T., Tokunaga, A., and Noguchi, K. (2004). Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J. Neurosci. 24, 10211–10222.PubMedCrossRefGoogle Scholar
  35. Pabbidi, R.M., Cao, D.S., Parihar, A., Pauza, M.E., and Premkumar, L.S. (2008). Direct role of streptozotocin in inducing thermal hyperalgesia by enhanced expression of transient receptor potential vanilloid 1 in sensory neurons. Mol. Pharmacol. 73, 995–1004.PubMedCrossRefGoogle Scholar
  36. Porreca, F., Ossipov, M.H., and Gebhart, G.F. (2002). Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319–325.PubMedCrossRefGoogle Scholar
  37. Raghavendra, V., Tanga, F., and DeLeo, J.A. (2003). Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 306, 624–630.PubMedCrossRefGoogle Scholar
  38. Rush, A.M., Dib-Hajj, S.D., Liu, S., Cummins, T.R., Black, J.A., and Waxman, S.G. (2006). A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. U.S.A. 103, 8245–8250.PubMedCrossRefGoogle Scholar
  39. Schafers, M., Lee, D.H., Brors, D., Yaksh, T.L., and Sorkin, L.S. (2003a). 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.PubMedGoogle Scholar
  40. Schafers, M., Svensson, C.I., Sommer, C., and Sorkin, L.S. (2003b). Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23, 2517–2521.PubMedGoogle Scholar
  41. Sung, C.S., Wen, Z.H., Chang, W.K., Chan, K.H., Ho, S.T., Tsai, S.K., Chang, Y.C., and Wong, C.S. (2005). Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1beta-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord. J. Neurochem. 94, 742–752.PubMedCrossRefGoogle Scholar
  42. Suter, M.R., Wen, Y.R., Decosterd, I., and Ji, R.R. (2007). Do glial cells control pain? Neuron Glia Biol. 3, 255–268.PubMedCrossRefGoogle Scholar
  43. Svensson, C.I., Fitzsimmons, B., Azizi, S., Powell, H.C., Hua, X.Y., and Yaksh, T.L. (2005a). Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J. Neurochem. 92, 1508–1520.PubMedCrossRefGoogle Scholar
  44. Svensson, C.I., Schafers, M., Jones, T.L., Powell, H., and Sorkin, L.S. (2005b). Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci. Lett. 379, 209–213.PubMedCrossRefGoogle Scholar
  45. Sweitzer, S.M., Schubert, P., and DeLeo, J.A. (2001). Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J. Pharmacol. Exp. Ther. 297, 1210–1217.PubMedGoogle Scholar
  46. Tang, H.B., Li, Y.S., Arihiro, K., and Nakata, Y. (2007). Activation of the neurokinin-1 receptor by substance P triggers the release of substance P from cultured adult rat dorsal root ganglion neurons. Mol. Pain 3, 42.PubMedCrossRefGoogle Scholar
  47. Trang, T., Beggs, S., Wan, X. and Salter, M.W., 2009. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci. 29, 3518–3528.Google Scholar
  48. Tsuda, M., Inoue, K., and Salter, M.W. (2005). Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. Trends Neurosci. 28, 101–107.PubMedCrossRefGoogle Scholar
  49. Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., Koizumi, S., and Inoue, K. (2004). Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 45, 89–95.PubMedCrossRefGoogle Scholar
  50. Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M.W., and Inoue, K. (2003). P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783.PubMedCrossRefGoogle Scholar
  51. Watkins, L.R., Martin, D., Ulrich, P., Tracey, K.J., and Maier, S.F. (1997). Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 71, 225–235.PubMedCrossRefGoogle Scholar
  52. Watkins, L.R., Milligan, E.D., and Maier, S.F. (2001). Glial activation: a driving force for pathological pain. Trends Neurosci. 24, 450–455.PubMedCrossRefGoogle Scholar
  53. Wen, Y.R., Suter, M.R., Kawasaki, Y., Huang, J., Pertin, M., Kohno, T., Berde, C.B., Decosterd, I., and Ji, R.R. (2007). Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model. Anesthesiology 107, 312–321.PubMedCrossRefGoogle Scholar
  54. White, F.A., Jung, H., and Miller, R.J. (2007). Chemokines and the pathophysiology of neuropathic pain. Proc. Natl. Acad. Sci. U.S.A. 104, 20151–20158.PubMedCrossRefGoogle Scholar
  55. Wilson-Gerwing, T.D., Dmyterko, M.V., Zochodne, D.W., Johnston, J.M., and Verge, V.M. (2005). Neurotrophin-3 suppresses thermal hyperalgesia associated with neuropathic pain and attenuates transient receptor potential vanilloid receptor-1 expression in adult sensory neurons. J. Neurosci. 25, 758–767.PubMedCrossRefGoogle Scholar
  56. Woolf, C.J. and Mannion, R.J. (1999). Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353, 1959–1964.PubMedCrossRefGoogle Scholar
  57. Wu, G., Ringkamp, M., Hartke, T.V., Murinson, B.B., Campbell, J.N., Griffin, J.W., and Meyer, R.A. (2001). Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J. Neurosci. 21, RC140.PubMedGoogle Scholar
  58. Xiao, H.S., Huang, Q.H., Zhang, F.X., Bao, L., Lu, Y.J., Guo, C., Yang, L., Huang, W.J., Fu, G., Xu, S.H., Cheng, X.P., Yan, Q., Zhu, Z.D., Zhang, X., Chen, Z., Han, Z.G., and Zhang, X. (2002). Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc. Natl. Acad. Sci. U.S.A. 99, 8360–8365.PubMedCrossRefGoogle Scholar
  59. Xu, J.T., Xin, W.J., Wei, X.H., Wu, C.Y., Ge, Y.X., Liu, Y.L., Zang, Y., Zhang, T., Li, Y.Y., and Liu, X.G. (2007). p38 activation in uninjured primary afferent neurons and in spinal microglia contributes to the development of neuropathic pain induced by selective motor fiber injury. Exp. Neurol. 204, 355–365.PubMedCrossRefGoogle Scholar
  60. Yamanaka, H., Obata, K., Kobayashi, K., Dai, Y., Fukuoka, T., and Noguchi, K. (2007). Activation of fibroblast growth factor receptor by axotomy, through downstream p38 in dorsal root ganglion, contributes to neuropathic pain. Neuroscience 150, 202–211.PubMedCrossRefGoogle Scholar
  61. Zhang, J., Shi, X.Q., Echeverry, S., Mogil, J.S., De Koninck, Y., and Rivest, S. (2007). Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J. Neurosci. 27, 12396–12406.PubMedCrossRefGoogle Scholar
  62. Zhuang, Z.Y., Gerner, P., Woolf, C.J., and Ji, R.R. (2005). 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.PubMedCrossRefGoogle Scholar
  63. Zhuang, Z.Y., Kawasaki, Y., Tan, P.H., Wen, Y.R., Huang, J., and Ji, R.R. (2007). 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.PubMedCrossRefGoogle Scholar
  64. Zhuang, Z.Y., Wen, Y.R., Zhang, D.R., Borsello, T., Bonny, C., Strichartz, G.R., Decosterd, I., and Ji, R.R. (2006). A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J. Neurosci. 26, 3551–3560.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Anesthesiology, Pain Research CenterBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

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