Abstract
Since new roles of nucleotides as neurotransmitters were proposed by Geoffrey Burnstock, the roles of ATP and P2 receptors (P2Rs) have been extensively studied in pain signaling. Chronic pain is a debilitating condition that often occurs following peripheral tissue inflammation and nerve injury. Especially neuropathic pain is a significant clinical problem because there are few clinically effective drugs. This review summarizes the findings for the role of ATP signaling through P2X3Rs and P2X2/3Rs in primary afferent neurons and through P2X4Rs, P2X7Rs, and P2Y12R in spinal microglia in chronic pain to discuss the therapeutic potentials with considering active situation of drug development of P2R compounds.
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References
Todd AJ (2010) Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11:823–836
Moehring F, Halder P, Seal RP, Cheryl Stucky L (2018) Uncovering the cells and circuits of touch in normal and pathological settings. Neuron 100:349–360
Burnstock G (1972) Purinergic nerves. Pharmacol Rev 24:509–581
Khakh BS, North RA (2006) P2X receptors as cell-surface ATP sensors in health and disease. Nature 442:527–532
Burnstock G (2008) Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discov 7:575–590
Idzko M, Ferrari D, Eltzschig HK (2014) Nucleotide signalling during inflammation. Nature 509:310–317
Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1769
Kuner R, Flor H (2017) Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci 18:113
Peirs C, Seal RP (2016) Neural circuits for pain: recent advances and current views. Science 354:578–584
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
McMahon SB, Malcangio M (2009) Current challenges in glia-pain biology. Neuron 64:46–54
Salter MW, Beggs S (2014) Sublime microglia: expanding roles for the guardians of the CNS. Cell 158:15–24
Inoue K, Tsuda M (2018) Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 19:138–152
Ji RR, Donnelly CR, Nedergaard M (2019) Astrocytes in chronic pain and itch. Nat Rev Neurosci 20:667–685
Burnstock G (2016) Purinergic mechanisms and pain. Adv Pharmacol 75:91–137
Chen CC, Akopian AN, Sivilotti L, Colquhoun D, Burnstock G, Wood JN (1995) A P2X purinoceptor expressed by a subset of sensory neurons. Nature 377:428–431
Lewis C, Neidhart S, Holy C, North RA, Buell G, Surprenant A (1995) Coexpression of P2X2 and P2X3 receptor subunits can account for ATP- gated currents in sensory neurons. Nature 377:432–435
Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW (1997) Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387:505–508
Vulchanova L, Riedl MS, Shuster SJ, Buell G, Surprenant A, North RA, Elde R (1997) Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals. Neuropharmacology 36:1229–1242
Eriksson J, Bongenhielm U, Kidd E, Matthews B, Fried K (1998) Distribution of P2X3 receptors in the rat trigeminal ganglion after inferior alveolar nerve injury. Neurosci Lett 254:37–40
Vulchanova L, Riedl MS, Shuster SJ, Stone LS, Hargreaves KM, Buell G, Surprenant A, North RA, Elde R (1998) P2X3 is expressed by DRG neurons that terminate in inner lamina II. Eur J Neurosci 10:3470–3478
Guo A, Vulchanova L, Wang J, Li X, Elde R (1999) Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J Neurosci 11:946–958
Bradbury EJ, Burnstock G, McMahon SB (1998) The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 12:256–268
Krishtal OA, Marchenko SM, Pidoplichko VI (1983) Receptor for ATP in the membrane of mammalian sensory neurones. Neurosci Lett 35:41–45
Krishtal OA, Marchenko SM, Obukhov AG (1988) Cationic channels activated by extracellular ATP in rat sensory neurons. Neuroscience 27:995–1000
Bean BP (1990) ATP-activated channels in rat and bullfrog sensory neurons: concentration dependence and kinetics. J Neurosci 10:1–10
Khakh BS, Humphrey PP, Surprenant A (1995) Electrophysiological properties of P2X-purinoceptors in rat superior cervical, nodose and guinea-pig coeliac neurones. J Physiol 484(Pt 2):385–395
Gu JG, MacDermott AB (1997) Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature 389:749–753
Rae MG, Rowan EG, Kennedy C (1998) Pharmacological properties of P2X3-receptors present in neurones of the rat dorsal root ganglia. Br J Pharmacol 124:176–180
Burgard EC, Niforatos W, van Biesen T, Lynch KJ, Touma E, Metzger RE, Kowaluk EA, Jarvis MF (1999) P2X receptor-mediated ionic currents in dorsal root ganglion neurons. J Neurophysiol 82:1590–1598
Ueno S, Tsuda M, Iwanaga T, Inoue K (1999) Cell type-specific ATP-activated responses in rat dorsal root ganglion neurons. Br J Pharmacol 126:429–436
Tsuda M, Koizumi S, Kita A, Shigemoto Y, Ueno S, Inoue K (2000) Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-insensitive primary afferent neurons. J Neurosci 20:RC90
Tsuzuki K, Ase A, Seguela P, Nakatsuka T, Wang CY, She JX, Gu JG (2003) TNP-ATP-resistant P2X ionic current on the central terminals and somata of rat primary sensory neurons. J Neurophysiol 89:3235–3242
Tsuda M, Ueno S, Inoue K (1999) In vivo pathway of thermal hyperalgesia by intrathecal administration of alpha, beta-methylene ATP in mouse spinal cord: involvement of the glutamate-NMDA receptor system. Br J Pharmacol 127:449–456
Nakatsuka T, Mena N, Ling J, Gu JG (2001) Depletion of substance P from rat primary sensory neurons by ATP, an implication of P2X receptor-mediated release of substance P. Neuroscience 107:293–300
Jahr CE, Jessell TM (1983) ATP excites a subpopulation of rat dorsal horn neurones. Nature 304:730–733
Cockayne DA, Dunn PM, Zhong Y, Rong W, Hamilton SG, Knight GE, Ruan HZ, Ma B, Yip P, Nunn P, McMahon SB, Burnstock G, Ford AP (2005) P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol 567:621–639
Bo X, Alavi A, Xiang Z, Oglesby I, Ford A, Burnstock G (1999) Localization of ATP-gated P2X2 and P2X3 receptor immunoreactive nerves in rat taste buds. NeuroReport 10:1107–1111
Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford AP (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407:1011–1015
Sawynok J, Reid A (1997) Peripheral adenosine 5’-triphosphate enhances nociception in the formalin test via activation of a purinergic p2X receptor. Eur J Pharmacol 330:115–121
Jarvis MF, Wismer CT, Schweitzer E, Yu H, van Biesen T, Lynch KJ, Burgard EC, Kowaluk EA (2001) Modulation of BzATP and formalin induced nociception: attenuation by the P2X receptor antagonist, TNP-ATP and enhancement by the P2X(3) allosteric modulator, cibacron blue. Br J Pharmacol 132:259–269
McGaraughty S, Wismer CT, Zhu CZ, Mikusa J, Honore P, Chu KL, Lee CH, Faltynek CR, Jarvis MF (2003) Effects of A-317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration. Br J Pharmacol 140:1381–1388
Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, Suzuki R, Carpenter K, Dickenson A, Boyce S, Hill R, Nebenuis-Oosthuizen D, Smith AJ, Kidd EJ, Wood JN (2000) Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407:1015–1017
Honore P, Kage K, Mikusa J, Watt AT, Johnston JF, Wyatt JR, Faltynek CR, Jarvis MF, Lynch K (2002) Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain 99:11–19
Tsuda M, Shigemoto-Mogami Y, Ueno S, Koizumi S, Ueda H, Iwanaga T, Inoue K (2002) Downregulation of P2X3 receptor-dependent sensory functions in A/J inbred mouse strain. Eur J Neurosci 15:1444–1450
Li P, Calejesan AA, Zhuo M (1998) ATP P2x receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats. J Neurophysiol 80:3356–3360
Nakatsuka T, Tsuzuki K, Ling JX, Sonobe H, Gu JG (2003) Distinct roles of P2X receptors in modulating glutamate release at different primary sensory synapses in rat spinal cord. J Neurophysiol 89:3243–3252
Okada M, Nakagawa T, Minami M, Satoh M (2002) Analgesic effects of intrathecal administration of P2Y nucleotide receptor agonists UTP and UDP in normal and neuropathic pain model rats. J Pharmacol Exp Ther 303:66–73
Fukuhara N, Imai Y, Sakakibara A, Morita K, Kitayama S, Tanne K, Dohi T (2000) Regulation of the development of allodynia by intrathecally administered P2 purinoceptor agonists and antagonists in mice. Neurosci Lett 292:25–28
Tsuda M, Koizumi S, Inoue K (2001) Role of endogenous ATP at the incision area in a rat model of postoperative pain. NeuroReport 12:1701–1704
Morita K, Morioka N, Abdin J, Kitayama S, Nakata Y, Dohi T (2004) Development of tactile allodynia and thermal hyperalgesia by intrathecally administered platelet-activating factor in mice. Pain 111:351–359
Zheng JH, Chen J (2000) Modulatory roles of the adenosine triphosphate P2x-purinoceptor in generation of the persistent nociception induced by subcutaneous bee venom injection in the conscious rat. Neurosci Lett 278:41–44
Hamilton SG, McMahon SB, Lewin GR (2001) Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin. J Physiol 534:437–445
Bleehen T, Keele CA (1977) Observations on the algogenic actions of adenosine compounds on the human blister base preparation. Pain 3:367–377
Coutts AA, Jorizzo JL, Eady RA, Greaves MW, Burnstock G (1981) Adenosine triphosphate-evoked vascular changes in human skin: mechanism of action. Eur J Pharmacol 76:391–401
Hamilton SG, Warburton J, Bhattacharjee A, Ward J, McMahon SB (2000) ATP in human skin elicits a dose-related pain response which is potentiated under conditions of hyperalgesia. Brain 123(Pt 6):1238–1246
Ryan LM, Rachow JW, McCarty DJ (1991) Synovial fluid ATP: a potential substrate for the production of inorganic pyrophosphate. J Rheumatol 18:716–720
Park W, Masuda I, Cardenal-Escarcena A, Palmer DL, McCarty DJ (1996) Inorganic pyrophosphate generation from adenosine triphosphate by cell-free human synovial fluid. J Rheumatol 23:665–671
Wang C, Li GW, Huang LY (2007) Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons. Mol Pain 3:22
Jarvis MF, Burgard EC, McGaraughty S, Honore P, Lynch K, Brennan TJ, Subieta A, Van Biesen T, Cartmell J, Bianchi B, Niforatos W, Kage K, Yu H, Mikusa J, Wismer CT, Zhu CZ, Chu K, Lee CH, Stewart AO, Polakowski J, Cox BF, Kowaluk E, Williams M, Sullivan J, Faltynek C (2002) 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
Dai Y, Fukuoka T, Wang H, Yamanaka H, Obata K, Tokunaga A, Noguchi K (2004) Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons. Pain 108:258–266
Barclay J, Patel S, Dorn G, Wotherspoon G, Moffatt S, Eunson L, Abdel’al S, Natt F, Hall J, Winter J, Bevan S, Wishart W, Fox A, Ganju P (2002) Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. J Neurosci 22:8139–8147
Xu GY, Huang LY (2002) Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 22:93–102
Fukuoka T, Tokunaga A, Tachibana T, Dai Y, Yamanaka H, Noguchi K (2002) VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation. Pain 99:111–120
Tsuzuki K, Kondo E, Fukuoka T, Yi D, Tsujino H, Sakagami M, Noguchi K (2001) Differential regulation of P2X(3) mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory ganglia. Pain 91:351–360
Kim C, Chung JM, Chung K (2003) Changes in the gene expression of six subtypes of P2X receptors in rat dorsal root ganglion after spinal nerve ligation. Neurosci Lett 337:81–84
Nakatsuka T, Gu JG (2001) 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
Jo YH, Schlichter R (1999) Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat Neurosci 2:241–245
Fam SR, Gallagher CJ, Salter MW (2000) P2Y(1) purinoceptor-mediated Ca(2+) signaling and Ca(2+) wave propagation in dorsal spinal cord astrocytes. J Neurosci 20:2800–2808
Liu T, Tracey DJ (2000) ATP P2X receptors play little role in the maintenance of neuropathic hyperalgesia. NeuroReport 11:1669–1672
Ramer MS, Thompson SW, McMahon SB (1999) Causes and consequences of sympathetic basket formation in dorsal root ganglia. Pain Suppl 6:S111-120
Burnstock G, Wood JN (1996) Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr Opin Neurobiol 6:526–532
Dunn PM, Zhong Y, Burnstock G (2001) P2X receptors in peripheral neurons. Prog Neurobiol 65:107–134
Xu M, Petraschka M, McLaughlin JP, Westenbroek RE, Caron MG, Lefkowitz RJ, Czyzyk TA, Pintar JE, Terman GW, Chavkin C (2004) Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci 24:4576–4584
Hasegawa S, Kohro Y, Tsuda M, Inoue K (2009) Activation of cytosolic phospholipase A2 in dorsal root ganglion neurons by Ca2+/calmodulin-dependent protein kinase II after peripheral nerve injury. Mol Pain 5:22
Hasegawa S, Kohro Y, Shiratori M, Ishii S, Shimizu T, Tsuda M, Inoue K (2010) Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain. PLoS ONE 5:e10467
Schafers M, Svensson CI, Sommer C, Sorkin LS (2003) 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
Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14:331–336
Prinz M, Jung S, Priller J (2019) Microglia biology: one century of evolving concepts. Cell 179:292–311
Masuda T, Sankowski R, Staszewski O, Prinz M (2020) Microglia heterogeneity in the single-cell era. Cell Rep 30:1271–1281
Kohno K, Kitano J, Kohro Y, Tozaki-Saitoh H, Inoue K, Tsuda M (2018) Temporal kinetics of microgliosis in the spinal dorsal horn after peripheral nerve injury in rodents. Biol Pharm Bull 41:1096–1102
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
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 USA 106:8032–8037
Narita M, Usui A, Narita M, Niikura K, Nozaki H, Khotib J, Nagumo Y, Yajima Y, Suzuki T (2005) Protease-activated receptor-1 and platelet-derived growth factor in spinal cord neurons are implicated in neuropathic pain after nerve injury. J Neurosci 25:10000–10009
Masuda J, Tsuda M, Tozaki-Saitoh H, Inoue K (2009) Intrathecal delivery of PDGF produces tactile allodynia through its receptors in spinal microglia. Mol Pain 5:23
Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C, Vaman S, Guan AK, Evans-Reinsch Z, Braz J, Devor M, Abboud-Werner SL, Lanier LL, Lomvardas S, Basbaum AI (2016) Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 19:94–101
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
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
Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021
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
Masuda T, Ozono Y, Mikuriya S, Kohro Y, Tozaki-Saitoh H, Iwatsuki K, Uneyama H, Ichikawa R, Salter MW, Tsuda M, Inoue K (2016) Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat Commun 7:12529
Biber K, TsudaM T-S, 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 30:1864–1873
Masuda T, Tsuda M, Yoshinaga R, Tozaki-Saitoh H, Ozato K, Tamura T, Inoue K (2012) IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Rep 1:334–340
Masuda T, Iwamoto S, Yoshinaga R, Tozaki-Saitoh H, Nishiyama A, Mak TW, Tamura T, Tsuda M, Inoue K (2014) Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. Nat Commun 5:3771
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 P2X(4), a key molecule for mechanical allodynia. Glia 53:769–775
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
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
Salter MW, Kalia LV (2004) Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci 5:317–328
Tsuda M, Toyomitsu E, Kometani M, Tozaki-Saitoh H, Inoue K (2009) Mechanisms underlying fibronectin-induced upregulation of P2XR expression in microglia: distinct roles of PI3K-Akt and MEK-ERK signaling pathways. J Cell Mol Med 13:3251–3259
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
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. Purine Signal 8:301–310
Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, Ben-Yehuda H, David E, Zelada Gonzalez F, Perrin P, Keren-Shaul H, Gury M, Lara-Astaiso D, Thaiss CA, Cohen M, Bahar Halpern K, Baruch K, Deczkowska A, Lorenzo-Vivas E, Itzkovitz S, Elinav E, Sieweke MH, Schwartz M, Amit I (2016) Microglia development follows a stepwise program to regulate brain homeostasis. Science 353:8670
Tozaki-Saitoh H, Masuda J, Kawada R, Kojima C, Yoneda S, Masuda T, Inoue K, Tsuda M (2019) Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development. Glia 67:729–740
Imai TNE, Inoue K (2012) Inhibition of P2X4 receptor on spinal microglia attenuates mechanical allodynia in experimental autoimmune neuritis rats. Pain Res 27:27–36
Zhang Z, Zhang ZY, Fauser U, Schluesener HJ (2008) Mechanical allodynia and spinal up-regulation of P2X4 receptor in experimental autoimmune neuritis rats. Neuroscience 152:495–501
Nagata K, Imai T, Yamashita T, Tsuda M, Tozaki-Saitoh H, Inoue K (2009) Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief. Mol Pain 5:20
Loeser JD (1986) Herpes zoster and postherpetic neuralgia. Pain 25:149–164
Sasaki A, Inomata Y, Serizawa K, Andoh T, Kuraishi Y (2013) Contribution of sensory C-fiber neuron injury to mechanical dynamic allodynia in a murine model of postherpetic neuralgia. NeuroReport 24:137–141
Takasaki I, Andoh T, Shiraki K, Kuraishi Y (2000) Allodynia and hyperalgesia induced by herpes simplex virus type-1 infection in mice. Pain 86:95–101
Takasaki I, Taniguchi K, Komatsu F, Sasaki A, Andoh T, Nojima H, Shiraki K, Hsu DK, Liu FT, Kato I, Hiraga K, Kuraishi Y (2012) Contribution of spinal galectin-3 to acute herpetic allodynia in mice. Pain 153:585–592
Matsumura Y, Yamashita T, Sasaki A, Nakata E, Kohno K, Masuda T, Tozaki-Saitoh H, Imai T, Kuraishi Y, Tsuda M, Inoue K (2016) A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain. Sci Rep 6:32461
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
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
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
He WJ, Cui J, Du L, Zhao YD, Burnstock G, Zhou HD, Ruan HZ (2012) Spinal P2X(7) receptor mediates microglia activation-induced neuropathic pain in the sciatic nerve injury rat model. Behav Brain Res 226:163–170
Ferrari D, Chiozzi P, Falzoni S, Hanau S, Di Virgilio F (1997) Purinergic modulation of interleukin-1 beta release from microglial cells stimulated with bacterial endotoxin. J Exp Med 185:579–582
Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, Nakata Y (2000) Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J Neurochem 75:965–972
Shigemoto-Mogami Y, Koizumi S, Tsuda M, Ohsawa K, Kohsaka S, Inoue K (2001) Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5. J Neurochem 78:1339–1349
Ikeda H, Tsuda M, Inoue K, Murase K (2007) Long-term potentiation of neuronal excitation by neuron-glia interactions in the rat spinal dorsal horn. Eur J Neurosci 25:1297–1306
Kawasaki Y, Zhang L, Cheng JK, Ji RR (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
Clark AK, Staniland AA, Marchand F, Kaan TK, McMahon SB, Malcangio M (2010) P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J Neurosci 30:573–582
Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S (2017) The P2X7 Receptor in Infection and Inflammation. Immunity 47:15–31
Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25:5071–5082
Bravo D, Maturana CJ, Pelissier T, Hernandez A, Constandil L (2015) Interactions of pannexin 1 with NMDA and P2X7 receptors in central nervous system pathologies: Possible role on chronic pain. Pharmacol Res 101:86–93
Iglesias R, Locovei S, Roque A, Alberto AP, Dahl G, Spray DC, Scemes E (2008) P2X7 receptor-Pannexin1 complex: pharmacology and signaling. Am J Physiol Cell Physiol 295:C752-760
Bravo D, Ibarra P, Retamal J, Pelissier T, Laurido C, Hernandez A, Constandil L (2014) Pannexin 1: a novel participant in neuropathic pain signaling in the rat spinal cord. Pain 155:2108–2115
Mousseau M, Burma NE, Lee KY, Leduc-Pessah H, Kwok CHT, Reid AR, O’Brien M, Sagalajev B, Stratton JA, Patrick N, Stemkowski PL, Biernaskie J, Zamponi GW, Salo P, McDougall JJ, Prescott SA, Matyas JR, Trang T (2018) Microglial pannexin-1 channel activation is a spinal determinant of joint pain. Sci Adv 4:eaas846
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
Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, Bevan S, Malcangio M (2007) Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci USA 104:10655–10660
Clark AK, Malcangio M (2014) Fractalkine/CX3CR1 signaling during neuropathic pain. Front Cell Neurosci 8:121
Clark AK, Gruber-Schoffnegger D, Drdla-Schutting R, Gerhold KJ, Malcangio M, Sandkuhler J (2015) Selective activation of microglia facilitates synaptic strength. J Neurosci 35:4552–4570
Kataoka A, Tozaki-Saitoh H, Koga Y, Tsuda M, Inoue K (2009) Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT. J Neurochem 108:115–125
Shiratori M, Tozaki-Saitoh H, Yoshitake M, Tsuda M, Inoue K (2010) P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways. J Neurochem 114:810–819
Kiguchi N, Kobayashi Y, Maeda T, Saika F, Kishioka S (2010) CC-chemokine MIP-1alpha in the spinal cord contributes to nerve injury-induced neuropathic pain. Neurosci Lett 484:17–21
Ochi-Ishi R, Nagata K, Inoue T, Tozaki-Saitoh H, Tsuda M, Inoue K (2014) Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia. Mol Pain 10:53
Di Cesare ML, Pacini A, Micheli L, Tani A, Zanardelli M, Ghelardini C (2014) Glial role in oxaliplatin-induced neuropathic pain. Exp Neurol 261:22–33
Matsushita K, Tozaki-Saitoh H, Kojima C, Masuda T, Tsuda M, Inoue K, Hoka S (2014) Chemokine (C-C motif) receptor 5 is an important pathological regulator in the development and maintenance of neuropathic pain. Anesthesiology 120:1491–1503
Burnstock G, Knight GE (2018) The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression. Purinergic Signal 14:1–18
Zhang WJ, Zhu ZM, Liu ZX (2020) The role and pharmacological properties of the P2X7 receptor in neuropathic pain. Brain Res Bull 155:19–28
Hutchinson MR, Shavit Y, Grace PM, Rice KC, Maier SF, Watkins LR (2011) Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol Rev 63:772–810
Wang Z, Ma W, Chabot JG, Quirion R (2009) Cell-type specific activation of p38 and ERK mediates calcitonin gene-related peptide involvement in tolerance to morphine-induced analgesia. Faseb J 23:2576–2586
Fukagawa H, Koyama T, Kakuyama M, Fukuda K (2013) Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4. J Anesth 27:93–97
Leduc-Pessah H, Weilinger NL, Fan CY, Burma NE, Thompson RJ, Trang T (2017) Site-Specific Regulation of P2X7 Receptor Function in Microglia Gates Morphine Analgesic Tolerance. J Neurosci 37:10154–10172
Horvath RJ, Romero-Sandoval EA, De Leo JA (2010) Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2. Pain 150:401–413
Zhou D, Chen ML, Zhang YQ, Zhao ZQ (2010) Involvement of spinal microglial P2X7 receptor in generation of tolerance to morphine analgesia in rats. J Neurosci 30:8042–8047
Ferrini F, Trang T, Mattioli TA, Laffray S, Del’Guidice T, Lorenzo L-E, Castonguay A, Doyon N, Zhang W, Godin AG, Mohr D, Beggs S, Vandal K, Beaulieu J-M, Cahill CM, Salter MW, De Koninck Y (2013) Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis. Nat Neurosci 16:183–192
Burma NE, Bonin RP, Leduc-Pessah H, Baimel C, Cairncross ZF, Mousseau M, Shankara JV, Stemkowski PL, Baimoukhametova D, Bains JS, Antle MC, Zamponi GW, Cahill CM, Borgland SL, De Koninck Y, Trang T (2017) Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. Nat Med 23:355–360
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
Pausch MH, Lai M, Tseng E, Paulsen J, Bates B, Kwak S (2004) Functional expression of human and mouse P2Y12 receptors in Saccharomyces cerevisiae. Biochem Biophys Res Commun 324:171–177
Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y(12) receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9:1512–1519
Kobayashi K, Fukuoka T, Yamanaka H, Dai Y, Obata K, Tokunaga A, Noguchi K (2006) Neurons and glial cells differentially express P2Y receptor mRNAs in the rat dorsal root ganglion and spinal cord. J Comp Neurol 498:443–454
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
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
Honda S, Sasaki Y, Ohsawa K, Imai Y, Nakamura Y, Inoue K, Kohsaka S (2001) Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J Neurosci 21:1975–1982
Ohsawa K, Irino Y, Nakamura Y, Akazawa C, Inoue K, Kohsaka S (2007) Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. Glia 55:604–616
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
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
Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446:1091–1095
Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Decosterd I (2006) Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol 2:259–269
Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR (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
Katsura H, Obata K, Miyoshi K, Kondo T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Sakagami M, Noguchi K (2008) Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. Glia 56:723–733
Salter MW, Hicks JL (1994) ATP-evoked increases in intracellular calcium in neurons and glia from the dorsal spinal cord. J Neurosci 14:1563–1575
Tashima R, Koga K, Sekine M, Kanehisa K, Kohro Y, Tominaga K, Matsushita K, Tozaki-Saitoh H, Fukazawa Y, Inoue K, Yawo H, Furue H, Tsuda M (2018) Optogenetic activation of non-nociceptive Aβ fibers induces neuropathic pain-like sensory and emotional behaviors after nerve injury in rats. eNeuro 5: ENEURO.0450–17.2018
Zhanga W-J, Zhua Z-M, Liub Z-X (2020) The role of P2X4 receptor in neuropathic pain and its pharmacological properties. Pharmacol Res 158:104875
Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, Thompson R, Thackray-Nocera S, Wright C (2019) The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J 54:1900439
Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, Smith JA (2015) P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 385:1198–1205
Richards D, Gever JR, Ford AP, Fountain SJ (2019) Action of MK-7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation. Br J Pharmacol 176:2279–2291
Igawa T, Higashi S, Abe Y, Ohkuri T, Tanaka H, Morimoto S, Yamashita T, Tsuda M, Inoue K, Ueda T (2013) Preparation and characterization of a monoclonal antibody against the refolded and functional extracellular domain of rat P2X4 receptor. J Biochem 153:275–282
Igawa T, Kishikawa S, Abe Y, Yamashita T, Nagai S, Shiroishi M, Shinozaki C, Tanaka H, Tozaki-Saitoh H, Tsuda M, Inoue K, Ueda T (2019) Evidence for detection of rat P2X4 receptor expressed on cells by generating monoclonal antibodies recognizing the native structure. Purinergic Signal 15:27–35
Williams WA, Linley JE, Jones CA, Shibata Y, Snijder A, Button J, Hatcher JP, Huang L, Taddese B, Thornton P, Schofield DJ, Thom G, Popovic B, Dosanjh B, Wilkinson T, Hughes J, Dobson CL, Groves MA, Webster CI, Billinton A, Vaughan TJ, Chessell I (2019) Antibodies binding the head domain of P2X4 inhibit channel function and reverse neuropathic pain. Pain 160:1989–2003
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
Mansoor SE, Lu W, Oosterheert W, Shekhar M, Tajkhorshid E, Gouaux E (2016) X-ray structures define human P2X(3) receptor gating cycle and antagonist action. Nature 538:66–71
Wang J, Wang Y, Cui WW, Huang Y, Yang Y, Liu Y, Zhao WS, Cheng XY, Sun WS, Cao P, Zhu MX, Wang R, Hattori M, Yu Y (2018) Druggable negative allosteric site of P2X3 receptors. Proc Natl Acad Sci U S A 115:4939–4944
Karasawa A, Kawate T (2016) Structural basis for subtype-specific inhibition of the P2X7 receptor. eLife 5
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Inoue, K. The Role of ATP Receptors in Pain Signaling. Neurochem Res 47, 2454–2468 (2022). https://doi.org/10.1007/s11064-021-03516-6
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DOI: https://doi.org/10.1007/s11064-021-03516-6