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P2X4R+ microglia drive neuropathic pain

Abstract

Neuropathic pain, the most debilitating of all clinical pain syndromes, may be a consequence of trauma, infection or pathology from diseases that affect peripheral nerves. Here we provide a framework for understanding the spinal mechanisms of neuropathic pain as distinct from those of acute pain or inflammatory pain. Recent work suggests that a specific microglia response phenotype characterized by de novo expression of the purinergic receptor P2X4 is critical for the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. Stimulating P2X4 receptors initiates a core pain signaling pathway mediated by release of brain-derived neurotrophic factor, which produces a disinhibitory increase in intracellular chloride in nociceptive (pain-transmitting) neurons in the spinal dorsal horn. The changes caused by signaling from P2X4R+ microglia to nociceptive transmission neurons may account for the main symptoms of neuropathic pain in humans, and they point to specific interventions to alleviate this debilitating condition.

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Figure 1: Microglia; microdomains and proliferation after nerve injury.
Figure 2: The P2X4R+ microglial phenotype mediates a core pain hypersensitivity cascade following peripheral nerve injury.

References

  1. Hanisch, U.-K. & Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387–1394 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Ulmann, L. et al. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J. Neurosci. 28, 11263–11268 (2008).

    Article  CAS  Google Scholar 

  4. Trang, T., Beggs, S., Wan, X. & Salter, M.W. 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 (2009).

    Article  CAS  Google Scholar 

  5. Nissl, F. Ueber einige Beziehungen zur Nervenzellenerkrankungen und gliosen Erscheinungen bei verschiedenen Psychosen. Arch. Psychiatr. 32, 656–676 (1899).

    Google Scholar 

  6. Cammermeyer, J. Juxtavascular karyokinesis and microglia cell proliferation during retrograde reaction in the mouse facial nucleus. Ergeb. Anat. Entwicklungsgesch. 38, 1–22 (1965).

    CAS  PubMed  Google Scholar 

  7. Gehrmann, J., Monaco, S. & Kreutzberg, G.W. Spinal cord microglial cells and DRG satellite cells rapidly respond to transection of the rat sciatic nerve. Restor. Neurol. Neurosci. 2, 181–198 (1991).

    CAS  PubMed  Google Scholar 

  8. Eriksson, N.P. et al. A quantitative analysis of the microglial cell reaction in central primary sensory projection territories following peripheral nerve injury in the adult rat. Exp. Brain Res. 96, 19–27 (1993).

    Article  CAS  Google Scholar 

  9. Graeber, M.B., Tetzlaff, W., Streit, W.J. & Kreutzberg, G.W. Microglial cells but not astrocytes undergo mitosis following rat facial nerve axotomy. Neurosci. Lett. 85, 317–321 (1988).

    Article  CAS  Google Scholar 

  10. Svensson, M., Eriksson, P., Persson, J., Liu, L. & Aldskogius, H. Functional properties of microglia following peripheral nerve injury. Neuropathol. Appl. Neurobiol. 20, 185–187 (1994).

    CAS  PubMed  Google Scholar 

  11. Kreutzberg, G.W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996).

    Article  CAS  Google Scholar 

  12. Liu, L., Persson, J.K., Svensson, M. & Aldskogius, H. Glial cell responses, complement, and clusterin in the central nervous system following dorsal root transection. Glia 23, 221–238 (1998).

    Article  CAS  Google Scholar 

  13. Rezaie, P. & Male, D. Mesoglia & microglia—a historical review of the concept of mononuclear phagocytes within the central nervous system. J. Hist. Neurosci. 11, 325–374 (2002).

    Article  Google Scholar 

  14. Penfield, W. Cytology & Cellular Pathology of the Nervous System (Hafner, 1965).

  15. 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).

    Article  Google Scholar 

  16. Honore, P. et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 98, 585–598 (2000).

    Article  CAS  Google Scholar 

  17. Lin, T. et al. Dissociation of spinal microglia morphological activation and peripheral inflammation in inflammatory pain models. J. Neuroimmunol. 192, 40–48 (2007).

    Article  CAS  Google Scholar 

  18. Tsuda, M. et al. Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays. Mol. Pain 5, 28 (2009).

    Article  Google Scholar 

  19. Zhang, J. et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J. Neurosci. 27, 12396–12406 (2007).

    Article  CAS  Google Scholar 

  20. Abbadie, C. et al. Chemokines and pain mechanisms. Brain Res. Rev. 60, 125–134 (2009).

    Article  CAS  Google Scholar 

  21. Toyomitsu, E. et al. CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. Purinergic Signal. 8, 301–310 (2012).

    Article  CAS  Google Scholar 

  22. Biber, K. et al. Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J. 30, 1864–1873 (2011).

    Article  CAS  Google Scholar 

  23. de Jong, E.K. et al. Vesicle-mediated transport and release of CCL21 in endangered neurons: a possible explanation for microglia activation remote from a primary lesion. J. Neurosci. 25, 7548–7557 (2005).

    Article  CAS  Google Scholar 

  24. de Jong, E.K. et al. Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles. FASEB J. 22, 4136–4145 (2008).

    Article  CAS  Google Scholar 

  25. Tsuda, M. et al. IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc. Natl. Acad. Sci. USA 106, 8032–8037 (2009).

    Article  CAS  Google Scholar 

  26. Tsuda, M. et al. Fibronectin/integrin system is involved in P2X4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury. Glia 56, 579–585 (2008).

    Article  Google Scholar 

  27. Nasu-Tada, K., Koizumi, S., Tsuda, M., Kunifusa, E. & Inoue, K. Possible involvement of increase in spinal fibronectin following peripheral nerve injury in upregulation of microglial P2X4, a key molecule for mechanical allodynia. Glia 53, 769–775 (2006).

    Article  Google Scholar 

  28. Tsuda, M., Toyomitsu, E., Kometani, M., Tozaki-Saitoh, H. & Inoue, K. Mechanisms underlying fibronectin-induced up-regulation of P2X4R expression in microglia: distinct roles of PI3K-Akt and MEK-ERK signalling pathways. J. Cell. Mol. Med. 13, 3251–3259 (2009).

    Article  Google Scholar 

  29. Tsuda, M. et al. Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury. Glia 56, 50–58 (2008).

    Article  Google Scholar 

  30. Yuan, H. et al. Role of mast cell activation in inducing microglial cells to release neurotrophin. J. Neurosci. Res. 88, 1348–1354 (2010).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Prescott, S.A., Sejnowski, T.J. & De Koninck, Y. Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain. Mol. Pain 2, 32 (2006).

    Article  Google Scholar 

  33. Knabl, J. et al. Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 451, 330–334 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  35. Keller, A.F., Beggs, S., Salter, M.W. & De Koninck, Y. Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Mol. Pain 3, 27 (2007).

    Article  Google Scholar 

  36. Jahr, C.E. & Jessell, T.M. ATP excites a subpopulation of rat dorsal horn neurones. Nature 304, 730–733 (1983).

    Article  CAS  Google Scholar 

  37. Fam, S.R., Gallagher, C.J. & Salter, M.W. P2Y1 purinoceptor-mediated Ca2+ signaling and Ca2+ wave propagation in dorsal spinal cord astrocytes. J. Neurosci. 20, 2800–2808 (2000).

    Article  CAS  Google Scholar 

  38. Foley, J.C., McIver, S.R. & Haydon, P.G. Gliotransmission modulates baseline mechanical nociception. Mol. Pain 7, 93 (2011).

    Article  CAS  Google Scholar 

  39. Salter, M.W., De Koninck, Y. & Henry, J.L. Physiological roles for adenosine and ATP in synaptic transmission in the spinal dorsal horn. Prog. Neurobiol. 41, 125–156 (1993).

    Article  CAS  Google Scholar 

  40. Suter, M.R., Berta, T., Gao, Y.-J., Decosterd, I. & Ji, R.-R. Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury. Mol. Pain 5, 53 (2009).

    Article  Google Scholar 

  41. Tozaki-Saitoh, H. et al. P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J. Neurosci. 28, 4949–4956 (2008).

    Article  CAS  Google Scholar 

  42. Kettenmann, H., Hanisch, U.-K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011).

    Article  CAS  Google Scholar 

  43. Rivest, S. Regulation of innate immune responses in the brain. Nat. Rev. Immunol. 9, 429–439 (2009).

    Article  CAS  Google Scholar 

  44. Milligan, E.D. & Watkins, L.R. Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 10, 23–36 (2009).

    Article  CAS  Google Scholar 

  45. Landry, R.P., Jacobs, V.L., Romero-Sandoval, E.A. & Deleo, J.A. 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. 234, 340–350 (2012).

    Article  CAS  Google Scholar 

  46. Watkins, L.R., Hutchinson, M.R. & Johnson, K.W. Commentary on Landry et al.: “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. 234, 351–353 (2012).

    Article  CAS  Google Scholar 

  47. Sorge, R.E. et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J. Neurosci. 31, 15450–15454 (2011).

    Article  CAS  Google Scholar 

  48. Beggs, S., Currie, G., Salter, M.W., Fitzgerald, M. & Walker, S.M. Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity. Brain 135, 404–417 (2012).

    Article  Google Scholar 

  49. Suleman, S., Beggs, S., Mogil,, J.S. & Salter,, M.W. Genetic correlation of microglial activation-associated proteins and pain-related behaviours across 12 inbred mouse strains. Proc. 12th World Congress on Pain. (IASP Press, 2008).

  50. Asiedu, M., Ossipov, M.H., Kaila, K. & Price, T.J. Acetazolamide and midazolam act synergistically to inhibit neuropathic pain. Pain 148, 302–308 (2010).

    Article  CAS  Google Scholar 

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Acknowledgements

The work of the authors is supported by grants from the Canadian Institutes of Health Research (MT-11219), the Krembil Foundation and the Ontario Research Fund Research Excellence Program. M.W.S. is supported by a Canada Research Chair (Tier I) in Neuroplasticity and Pain, and the Anne and Max Tanenbaum Chair in Molecular Medicine at the Hospital for Sick Children. T.T. was supported by a Canadian Institutes of Health Research fellowship.

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Beggs, S., Trang, T. & Salter, M. P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15, 1068–1073 (2012). https://doi.org/10.1038/nn.3155

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