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P2X4 purinoceptor signaling in chronic pain

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Abstract

ATP, acting via P2 purinergic receptors, is a known mediator of inflammatory and neuropathic pain. There is increasing evidence that the ATP-gated P2X4 receptor (P2X4R) subtype is a locus through which activity of spinal microglia and peripheral macrophages instigate pain hypersensitivity caused by inflammation or by injury to a peripheral nerve. The present article highlights the recent advances in our understanding of microglia–neuron interactions in neuropathic pain by focusing on the signaling and regulation of the P2X4R. We will also develop a framework for understanding converging lines of evidence for involvement of P2X4Rs expressed on macrophages in peripheral inflammatory pain.

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References

  1. Beggs S, Salter MW (2010) Microglia–neuronal signalling in neuropathic pain hypersensitivity 2.0. Curr Opin Neurobiol 20:474–480

    Article  PubMed  CAS  Google Scholar 

  2. Bernier LP, Ase AR, Boue-Grabot E, Seguela P (2012) P2X4 receptor channels form large noncytolytic pores in resting and activated microglia. Glia 60:728–737

    Google Scholar 

  3. Bernier LP, Ase AR, Chevallier S, Blais D, Zhao Q, Boue-Grabot E, Logothetis D, Seguela P (2008) Phosphoinositides regulate P2X4 ATP-gated channels through direct interactions. J Neurosci 28:12938–12945

    Article  PubMed  CAS  Google Scholar 

  4. Bianco F, Pravettoni E, Colombo A, Schenk U, Moller T, Matteoli M, Verderio C (2005) Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol 174:7268–7277

    PubMed  CAS  Google Scholar 

  5. Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K (2011) Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J 30(9):1864–1873

    Google Scholar 

  6. Bobanovic LK, Royle SJ, Murrell-Lagnado RD (2002) P2X receptor trafficking in neurons is subunit specific. J Neurosci 22:4814–4824

    PubMed  CAS  Google Scholar 

  7. Boucsein C, Zacharias R, Farber K, Pavlovic S, Hanisch UK, Kettenmann H (2003) Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur J Neurosci 17:2267–2276

    Article  PubMed  Google Scholar 

  8. Brone B, Moechars D, Marrannes R, Mercken M, Meert T (2007) P2X currents in peritoneal macrophages of wild type and P2X4−/− mice. Immunol Lett 113:83–89

    Article  PubMed  CAS  Google Scholar 

  9. Broom DC, Matson DJ, Bradshaw E, Buck ME, Meade R, Coombs S, Matchett M, Ford KK, Yu W, Yuan J, Sun SH, Ochoa R, Krause JE, Wustrow DJ, Cortright DN (2008) Characterization of N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-ben zamide, a P2X7 antagonist in animal models of pain and inflammation. J Pharmacol Exp Ther 327:620–633

    Article  PubMed  CAS  Google Scholar 

  10. Brough D, Le Feuvre RA, Iwakura Y, Rothwell NJ (2002) Purinergic (P2X7) receptor activation of microglia induces cell death via an interleukin-1-independent mechanism. Mol Cell Neurosci 19:272–280

    Article  PubMed  CAS  Google Scholar 

  11. Burnstock G (2006) Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol Rev 58:58–86

    Article  PubMed  CAS  Google Scholar 

  12. Burnstock G (2006) Purinergic P2 receptors as targets for novel analgesics. Pharmacol Ther 110:433–454

    Article  PubMed  CAS  Google Scholar 

  13. Chakfe Y, Seguin R, Antel JP, Morissette C, Malo D, Henderson D, Seguela P (2002) ADP and AMP induce interleukin-1beta release from microglial cells through activation of ATP-primed P2X7 receptor channels. J Neurosci 22:3061–3069

    PubMed  Google Scholar 

  14. Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114:386–396

    Article  PubMed  CAS  Google Scholar 

  15. Clark AK, Wodarski R, Guida F, Sasso O, Malcangio M (2010) Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia 58:1710–1726

    Article  PubMed  Google Scholar 

  16. Collo G, Neidhart S, Kawashima E, Kosco-Vilbois M, North RA, Buell G (1997) Tissue distribution of the P2X7 receptor. Neuropharmacology 36:1277–1283

    Article  PubMed  CAS  Google Scholar 

  17. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De KY (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021

    Article  PubMed  CAS  Google Scholar 

  18. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De KP, De KY (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942

    Article  PubMed  CAS  Google Scholar 

  19. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758

    Article  PubMed  CAS  Google Scholar 

  20. de Jong EK, Dijkstra IM, Hensens M, Brouwer N, van Amerongen M, Liem RS, Boddeke HW, Biber K (2005) 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

    Article  PubMed  Google Scholar 

  21. DeLeo JA, Yezierski RP (2001) The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 90:1–6

    Article  PubMed  CAS  Google Scholar 

  22. Dell'Antonio G, Quattrini A, Cin ED, Fulgenzi A, Ferrero ME (2002) Relief of inflammatory pain in rats by local use of the selective P2X7 ATP receptor inhibitor, oxidized ATP. Arthritis Rheum 46:3378–3385

    Article  PubMed  Google Scholar 

  23. Di VF (2006) Purinergic signalling between axons and microglia. Novartis Found Symp 276:253–258

    Article  Google Scholar 

  24. Donnelly-Roberts D, McGaraughty S, Shieh CC, Honore P, Jarvis MF (2008) Painful purinergic receptors. J Pharmacol Exp Ther 324:409–415

    Article  PubMed  CAS  Google Scholar 

  25. Farber K, Kettenmann H (2005) Physiology of microglial cells. Brain Res Brain Res Rev 48:133–143

    Article  PubMed  Google Scholar 

  26. Ferrari D, Chiozzi P, Falzoni S, Dal SM, Melchiorri L, Baricordi OR, Di VF (1997) Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol 159:1451–1458

    PubMed  CAS  Google Scholar 

  27. Ferrari D, Chiozzi P, Falzoni S, Hanau S, Di VF (1997) Purinergic modulation of interleukin-1 beta release from microglial cells stimulated with bacterial endotoxin. J Exp Med 185:579–582

    Article  PubMed  CAS  Google Scholar 

  28. Ferrari D, Villalba M, Chiozzi P, Falzoni S, Ricciardi-Castagnoli P, Di VF (1996) Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. J Immunol 156:1531–1539

    PubMed  CAS  Google Scholar 

  29. Fountain SJ, North RA (2006) A C-terminal lysine that controls human P2X4 receptor desensitization. J Biol Chem 281:15044–15049

    Article  PubMed  CAS  Google Scholar 

  30. Fujii K, Young MT, Harris KD (2011) Exploiting powder X-ray diffraction for direct structure determination in structural biology: the P2X4 receptor trafficking motif YEQGL. J Struct Biol (in press)

  31. Grace PM, Rolan PE, Hutchinson MR (2011) Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain. Brain Behav Immun (in press)

  32. Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9:1512–1519

    Article  PubMed  CAS  Google Scholar 

  33. Honore P, Donnelly-Roberts D, Namovic M, Zhong C, Wade C, Chandran P, Zhu C, Carroll W, Perez-Medrano A, Iwakura Y, Jarvis MF (2009) The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1alphabeta knockout mice. Behav Brain Res 204:77–81

    Article  PubMed  CAS  Google Scholar 

  34. Honore P, Donnelly-Roberts D, Namovic MT, Hsieh G, Zhu CZ, Mikusa JP, Hernandez G, Zhong C, Gauvin DM, Chandran P, Harris R, Medrano AP, Carroll W, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF (2006) A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J Pharmacol Exp Ther 319:1376–1385

    Article  PubMed  CAS  Google Scholar 

  35. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW (2008) Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. J Cell Biol 180:905–914

    Article  PubMed  CAS  Google Scholar 

  36. Inoue K, Tsuda M (2006) The role of microglia and ATP receptors in a mechanism of neuropathic pain. Nippon Yakurigaku Zasshi 127:14–17

    Article  PubMed  CAS  Google Scholar 

  37. Itoh K, Chiang CY, Li Z, Lee JC, Dostrovsky JO, Sessle BJ (2011) Central sensitization of nociceptive neurons in rat medullary dorsal horn involves purinergic P2X7 receptors. Neuroscience 192:721–731

    Article  PubMed  CAS  Google Scholar 

  38. Jaiswal JK, Andrews NW, Simon SM (2002) Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells. J Cell Biol 159:625–635

    Article  PubMed  CAS  Google Scholar 

  39. Jarvis MF (2010) The neural-glial purinergic receptor ensemble in chronic pain states. Trends Neurosci 33:48–57

    Article  PubMed  CAS  Google Scholar 

  40. Jin SX, Zhuang ZY, Woolf CJ, Ji RR (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

    PubMed  CAS  Google Scholar 

  41. Kawate T, Michel JC, Birdsong WT, Gouaux E (2009) Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature 460:592–598

    Article  PubMed  CAS  Google Scholar 

  42. Keller AF, Beggs S, Salter MW, De KY (2007) Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Mol Pain 3:27

    Article  PubMed  Google Scholar 

  43. Kobayashi K, Takahashi E, Miyagawa Y, Yamanaka H, Noguchi K (2011) Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model. Neurosci Lett 504:57–61

    Article  PubMed  CAS  Google Scholar 

  44. Kobayashi K, Yamanaka H, Fukuoka T, Dai Y, Obata K, Noguchi K (2008) P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J Neurosci 28:2892–2902

    Article  PubMed  CAS  Google Scholar 

  45. Kurpius D, Nolley EP, Dailey ME (2007) Purines induce directed migration and rapid homing of microglia to injured pyramidal neurons in developing hippocampus. Glia 55:873–884

    Article  PubMed  Google Scholar 

  46. Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10:895–926

    Article  PubMed  Google Scholar 

  47. Maeda M, Tsuda M, Tozaki-Saitoh H, Inoue K, Kiyama H (2010) Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn. Glia 58:1838–1846

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. McGaraughty S, Chu KL, Namovic MT, Donnelly-Roberts DL, Harris RR, Zhang XF, Shieh CC, Wismer CT, Zhu CZ, Gauvin DM, Fabiyi AC, Honore P, Gregg RJ, Kort ME, Nelson DW, Carroll WA, Marsh K, Faltynek CR, Jarvis MF (2007) P2X7-related modulation of pathological nociception in rats. Neuroscience 146:1817–1828

    Article  PubMed  CAS  Google Scholar 

  50. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36

    Article  PubMed  CAS  Google Scholar 

  51. Monif M, Reid CA, Powell KL, Smart ML, Williams DA (2009) The P2X7 receptor drives microglial activation and proliferation: a trophic role for P2X7R pore. J Neurosci 29:3781–3791

    Article  PubMed  CAS  Google Scholar 

  52. Nasu-Tada K, Koizumi S, Tsuda M, Kunifusa E, Inoue K (2006) 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

    Article  PubMed  Google Scholar 

  53. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    Article  PubMed  CAS  Google Scholar 

  54. Perez-Medrano A, Donnelly-Roberts DL, Honore P, Hsieh GC, Namovic MT, Peddi S, Shuai Q, Wang Y, Faltynek CR, Jarvis MF, Carroll WA (2009) Discovery and biological evaluation of novel cyanoguanidine P2X(7) antagonists with analgesic activity in a rat model of neuropathic pain. J Med Chem 52:3366–3376

    Article  PubMed  CAS  Google Scholar 

  55. Portanova JP, Zhang Y, Anderson GD, Hauser SD, Masferrer JL, Seibert K, Gregory SA, Isakson PC (1996) Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. J Exp Med 184:883–891

    Article  PubMed  CAS  Google Scholar 

  56. Qureshi OS, Paramasivam A, Yu JC, Murrell-Lagnado RD (2007) Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis. J Cell Sci 120:3838–3849

    Article  PubMed  CAS  Google Scholar 

  57. Reddy A, Caler EV, Andrews NW (2001) Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes. Cell 106:157–169

    Article  PubMed  CAS  Google Scholar 

  58. Ren K, Dubner R (2010) Interactions between the immune and nervous systems in pain. Nat Med 16:1267–1276

    Article  PubMed  CAS  Google Scholar 

  59. Royle SJ, Bobanovic LK, Murrell-Lagnado RD (2002) Identification of a non-canonical tyrosine-based endocytic motif in an ionotropic receptor. J Biol Chem 277:35378–35385

    Article  PubMed  CAS  Google Scholar 

  60. Samad TA, Sapirstein A, Woolf CJ (2002) Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med 8:390–396

    Article  PubMed  CAS  Google Scholar 

  61. Sasaki Y, Hoshi M, Akazawa C, Nakamura Y, Tsuzuki H, Inoue K, Kohsaka S (2003) Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain. Glia 44:242–250

    Article  PubMed  Google Scholar 

  62. Scholz J, Woolf CJ (2002) Can we conquer pain? Nat Neurosci 5(Suppl):1062–1067

    Article  PubMed  CAS  Google Scholar 

  63. Seil M, El OM, Fontanils U, Etxebarria IG, Pochet S, Dal MG, Marino A, Dehaye JP (2010) Ivermectin-dependent release of IL-1beta in response to ATP by peritoneal macrophages from P2X(7)-KO mice. Purinergic Signal 6:405–416

    Article  PubMed  CAS  Google Scholar 

  64. Shinozaki Y, Sumitomo K, Tsuda M, Koizumi S, Inoue K, Torimitsu K (2009) Direct observation of ATP-induced conformational changes in single P2X4 receptors. PLoS Biol 7:e103

    Article  PubMed  Google Scholar 

  65. Sorge RE, Trang T, Dorfman R, Smith SB, Beggs S, Ritchie J, Austin JS, Zaykin DV, Meulen HV, Costigan M, Herbert TA, Yarkoni-Abitbul M, Tichauer D, Livneh J, Gershon E, Zheng M, Tan K, John SL, Slade GD, Jordan J, Woolf CJ, Peltz G, Maixner,W, Diatchenko L, Seltzer Z, Salter MW, Mogil JS (2012) Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med doi:10.1038/nm.2710

  66. Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, Schuchman E, Tabas I, Andrews NW (2010) Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J Cell Biol 189:1027–1038

    Article  PubMed  CAS  Google Scholar 

  67. Toulme E, Soto F, Garret M, Boue-Grabot E (2006) Functional properties of internalization-deficient P2X4 receptors reveal a novel mechanism of ligand-gated channel facilitation by ivermectin. Mol Pharmacol 69:576–587

    Article  PubMed  CAS  Google Scholar 

  68. Toyomitsu E, Tsuda M, Yamashita T, Tozaki-Saitoh H, Tanaka Y, Inoue K (2012) CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. Purinergic Signal (in press)

  69. Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K (2008) P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci 28:4949–4956

    Article  PubMed  CAS  Google Scholar 

  70. Trang T, Beggs S, Wan X, Salter MW (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

    Article  PubMed  CAS  Google Scholar 

  71. Tsuda M, Inoue K, Salter MW (2005) Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci 28:101–107

    Article  PubMed  CAS  Google Scholar 

  72. Tsuda M, Kuboyama K, Inoue T, Nagata K, Tozaki-Saitoh H, Inoue K (2009) Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays. Mol Pain 5:28

    Article  PubMed  Google Scholar 

  73. Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K (2009) IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci U S A 106:8032–8037

    Article  PubMed  CAS  Google Scholar 

  74. Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, 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

    Article  PubMed  Google Scholar 

  75. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783

    Article  PubMed  CAS  Google Scholar 

  76. Tsuda M, Toyomitsu E, Komatsu T, Masuda T, Kunifusa E, Nasu-Tada K, Koizumi S, Yamamoto K, Ando J, Inoue K (2008) Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury. Glia 56:579–585

    Article  PubMed  Google Scholar 

  77. Tsuda M, Toyomitsu E, Kometani M, Tozaki-Saitoh H, Inoue K (2009) 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

    Article  PubMed  Google Scholar 

  78. Tsuda M, Tozaki-Saitoh H, Masuda T, Toyomitsu E, Tezuka T, Yamamoto T, Inoue K (2008) Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury. Glia 56:50–58

    Article  PubMed  Google Scholar 

  79. Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F (2008) Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci 28:11263–11268

    Article  PubMed  CAS  Google Scholar 

  80. Ulmann L, Hirbec H, Rassendren F (2010) P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain. EMBO J 29:2290–2300

    Article  PubMed  CAS  Google Scholar 

  81. Watkins LR, Maier SF (2003) Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2:973–985

    Article  PubMed  CAS  Google Scholar 

  82. Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24:450–455

    Article  PubMed  CAS  Google Scholar 

  83. Woolf CJ (2004) Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci 74:2605–2610

    Article  PubMed  CAS  Google Scholar 

  84. Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1769

    Article  PubMed  CAS  Google Scholar 

  85. Yuan H, Zhu X, Zhou S, Chen Q, Zhu X, Ma X, He X, Tian M, Shi X (2010) Role of mast cell activation in inducing microglial cells to release neurotrophin. J Neurosci Res 88:1348–1354

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  87. Zhao J, Seereeram A, Nassar MA, Levato A, Pezet S, Hathaway G, Morenilla-Palao C, Stirling C, Fitzgerald M, McMahon SB, Rios M, Wood JN (2006) Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol Cell Neurosci 31(3):539–548

    Google Scholar 

  88. Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR (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

    Article  PubMed  CAS  Google Scholar 

  89. Zimmermann M (2001) Pathobiology of neuropathic pain. Eur J Pharmacol 429:23–37

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The work of the authors is supported by grants from the Canadian Institutes of Health Research (CIHR; grant number MT-11219), the Krembil Foundation, and the Ontario Research Fund Research Excellence Program. MWS holds a Canada Research Chair (Tier I) in Neuroplasticity and Pain, and is the Anne and Max Tanenbaum Chair in Molecular Medicine at the Hospital for Sick Children. TT was supported by a CIHR fellowship. We thank Ms. Janice Hicks and Dr. Simon Beggs for helpful comments and revisions on the manuscript.

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  1. Program in Neurosciences & Mental Health, Hospital for Sick Children, University of Toronto Centre for the Study of Pain, Toronto, Ontario, M5G 1X8, Canada

    Tuan Trang & Michael W. Salter

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  1. Tuan Trang
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Correspondence to Michael W. Salter.

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Trang, T., Salter, M.W. P2X4 purinoceptor signaling in chronic pain. Purinergic Signalling 8, 621–628 (2012). https://doi.org/10.1007/s11302-012-9306-7

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