In pursuit of P2X3 antagonists: Novel therapeutics for chronic pain and afferent sensitization

Purinergic Signalling

Volumn 8, Issue SUPPL. 1, 2012, Pages 3-26

  Ford, Anthony P ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Analgesic; Anti hyperalgesic; Joint pain; Neuropathic pain; P2X2 3 receptor; P2X3 antagonist; P2X3 receptor; Visceral pain

Indexed keywords

EID: 84856298187     PISSN: 15739538     EISSN: 15739546     Source Type: Journal    
DOI: 10.1007/s11302-011-9271-6     Document Type: Article

References (184)

1. Burnstock G, Fredholm BB, North RA, Verkhratsky A (2010) The birth and postnatal development of purinergic signalling. Acta Physiol 199(2): 93-147.
2. Gunosewoyo H, Kassiou M (2010) P2X purinergic receptor ligands: recently patented compounds. Expert Opin Ther Pat 20: 625-646.
3. Gunosewoyo H, Coster MJ, Kassiou M (2007) Molecular probes for P2X7 receptor studies. Curr Med Chem 14(14): 1505-1523.
4. Romagnoli R, Baraldi PG, Cruz-Lopez O et al (2008) The P2X7 receptor as a therapeutic target. Expert Opin Ther Targets 12(5): 647-661.
5. Carroll WA, Donnelly-Roberts DL, Jarvis MF (2009) Selective P2X7 receptor antagonists for chronic inflammation and pain. Purinergic Signal 5: 63-73.
6. McInnes IB, Snell NJ, Perrett JH, Parmar H, Wang MM, Astbury C (2007) Results of a Phase II clinical trial of a novel P2X7 receptor antagonist, AZD-9056, in patients with active rheumatoid arthritis (CREATE study) Abstracts of the 2007 American College of Rheumatology Annual Meeting. Presentation 2085.
7. Keystone EC, Wang MM, Layton M, Hollis S, McInnes IB (2011) Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis (in press).
8. Burnstock G (2009) Purinergic receptors and pain. Curr Pharm Des 15(15): 1717-1735.
9. Holton P (1959) The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol 145: 494-504.
10. 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(6548): 428-431.
11. 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.
12. Burnstock G (2001) Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 22(4): 182-188.
13. Ford AP, Gever JR, Nunn PA, Zhong Y, Cefalu JS, Dillon MP, Cockayne DA (2006) Purinoceptors as therapeutic targets for lower urinary tract dysfunction. Br J Pharmacol 147: S132-S143.
14. Jarvis MF (2003) Contributions of P2X3 homomeric and heteromeric channels to acute and chronic pain. Expert Opin Ther Targets 7(4): 513-522.
15. 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.
16. 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(4-5): 256-268.
17. Dunn PM, Zhong Y, Burnstock G (2001) P2X receptors in peripheral neurons. Prog Neurobiol 65(2): 107-134.
18. Gu JG, MacDermott AB (1997) Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature 389(6652): 749-753.
19. 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.
20. Nakatsuka T (2001) 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(17): 6522-6531.
21. 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(2): 293-300.
22. 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(6): 3243-3252.
23. Sun Y, Chai TC (2004) Up-regulation of P2X3 receptor during stretch of bladder urothelial cells from patients with interstitial cystitis. J Urol 171: 448-452.
24. Yao ST, Barden JA, Lawrence AJ (2001) On the immunohistochemical distribution of ionotropic P2X receptors in the nucleus tractus solitarius of the rat. Neuroscience 108(4): 673-685.
25. Collier HO, James GW, Schneider C (1966) Antagonism by aspirin and fenamates of bronchoconstriction and nociception induced by adenosine-5'-triphosphate. Nature 212(5060): 411-412.
26. Bleehen T, Hobbiger F, Keele CA (1976) Identification of algogenic substances in human erythrocytes. J Physiol (Lond) 262: 131-149.
27. Bleehen T, Keele CA (1977) Observations on the algogenic actions of adenosine compounds on the human skin blister base preparation. Pain 3: 367-377.
28. 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(6): 1238-1246.
29. Hilliges M, Weidner C, Schmelz M, Schmidt R, Orstavik K, Torebjork E, Handwerker H (2002) ATP responses in human C nociceptors. Pain 98: 59-68.
30. Mork H, Ashina M, Bendtsen L, Olesen J, Jensen R (2003) Experimental muscle pain and tenderness following infusion of endogenous substances in humans. Eur J Pain 7: 145-153.
31. Tsuda M, Ueno S, Inoue K (1999) Evidence for the involvement of spinal endogenous ATP and P2X receptors in nociceptive responses caused by formalin and capsaicin in mice. Br J Pharmacol 128: 1497-1504.
32. Tsuda M, Ueno S, Inoue K (1999) In vivo pathway of thermal hyperalgesia by intrathecal administration of α, β-methylene ATP in mouse spinal cord: Involvement of the glutamate-NMDA receptor system. Br J Pharmacol 127: 449-456.
33. 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 P2X3 allosteric modulator, cibacron blue. Br J Pharmacol 132(1): 259-269.
34. 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(1-2): 11-19.
35. Ueno S, Moriyama T, Honda K, Kamiya H, Sakurada T, Katsuragi T (2003) Involvement of P2X2 and P2X3 receptors in neuropathic pain in a mouse model of chronic constriction injury. Drug Dev Res 59: 104-111.
36. 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(26): 17179-17184.
37. 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(8): 1381-1388.
38. 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.
39. 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 APDW (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.
40. Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, Suzuki R, Carpenter K, Dickenson A, Boyce S, Hill R, Nebenius-Oosthuizen D, Smith AJH, Kidd EJ, Wood JN (2000) Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407: 1015-1017.
41. 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.
42. Inoue K, Tsuda M, Koizumi S (2003) ATP induced three types of pain behaviors, including allodynia. Drug Dev Res 59: 56-63.
43. Dorn G, Patel S, Wotherspoon G, Hemmings-Mieszczak M, Barclay J, Natt FJC, Martin P, Bevan S, Fox A, Ganju P, Wishart W, Hall J (2004) siRNA relieves chronic neuropathic pain. Nucleic Acids Res 32: e49.
44. Di Virgilio F (2005) Purinergic mechanism in the immune system: a signal of danger for dendritic cells. Purinergic Signal 1(3): 205-209.
45. Burnstock G (2006) Purinergic signalling-an overview. Novartis Found Symp 276: 26-48, discussion 48-57, 275-281.
46. Bours MJ, Dagnelie PC, Giuliani AL, Wesselius A, Di Virgilio F (2011) P2 receptors and extracellular ATP: a novel homeostatic pathway in inflammation. Front Biosci (Schol Ed) 3: 1443-1456.
47. Varani K, De Mattei M, Vincenzi F, Tosi A, Gessi S, Merighi S, Pellati A, Masieri F, Ongaro A, Borea PA (2008) Pharmacological characterization of P2X1 and P2X3 purinergic receptors in bovine chondrocytes. Osteoarthritis Cartilage 16(11): 1421-1429.
48. Varani K, De Mattei M, Vincenzi F, Tosi A, Targa M, Masieri FF, Pellati A, Massari L, Borea PA (2010) P2X1 and P2X3 purinergic receptors differentially modulate the inflammatory response in human osteoarthritic synovial fibroblasts. Cell Physiol Biochem 25(2-3): 325-336.
49. McGaraughty S, Jarvis MF (2005) Antinociceptive properties of a non-nucleotide P2X3/P2X2/3 receptor antagonist. Drug News Perspect 18(8): 501-507.
50. Oliveira MC, Pelegrini-da-Silva A, Tambeli CH, Parada CA (2009) Peripheral mechanisms underlying the essential role of P2X3, 2/3 receptors in the development of inflammatory hyperalgesia. Pain 141(1-2): 127-134.
51. Teixeira JM, Oliveira MC, Nociti FH, Clemente-Napimoga JT, Pelegrini-da-Silva A, Parada CA, Tambeli CH (2010) Involvement of temporomandibular joint P2X3 and P2X2/3 receptors in carrageenan-induced inflammatory hyperalgesia in rats. Eur J Pharmacol 645: 79-85.
52. Xiang Z, Xiong Y, Yan N, Li X, Mao Y, Ni X, He C, LaMotte RH, Burnstock G, Sun J (2008) Functional up-regulation of P2X 3 receptors in the chronically compressed dorsal root ganglion. Pain 140(1): 23-34.
53. Liu P, Okun A, Ren J, Guo RC, Ossipov MH, Xie J, King T, Porreca F (2011) Ongoing pain in the MIA model of osteoarthritis. Neurosci Lett 493(3): 72-75.
54. Gordon JL (1986) Extracellular ATP: effects, sources and fate. Biochem J 233(2): 309-319.
55. Dowd E, McQueen DS, Chessell IP, Humphrey PP (1998) P2X receptor-mediated excitation of nociceptive afferents in the normal and arthritic rat knee joint. Br J Pharmacol 125(2): 341-346.
56. Ryan LM, Rachow JW, McCarty DJ (1991) Synovial fluid ATP: a potential substrate for the production of inorganic pyrophosphate. J Rheumatol 18: 716-720.
57. 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(4): 665-671.
58. Pellegatti P, Raffaghello L, Bianchi G, Piccardi F, Pistoia V, Di VF (2008) Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS One 3: e2599.
59. Kumahashi N, Naitou K, Nishi H, Oae K, Watanabe Y, Kuwata S, Ochi M, Ikeda M, Uchio Y (2011) Correlation of changes in pain intensity with synovial fluid adenosine triphosphate levels after treatment of patients with osteoarthritis of the knee with high-molecular-weight hyaluronic acid. Knee 18(3): 160-164.
60. Bove SE, Calcaterra SL, Brooker RM, Huber CM, Guzman RE, Juneau PL, Schrier DJ, Kilgore KS (2003) Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. OsteoArthritis and Cartilage 11: 821-830.
61. Gever JR, Soto R, Henningsen RA, Martin RS, Hackos DH, Panicker S, Rubas W, Oglesby IB, Dillon MP, Milla ME, Burnstock G, Ford AP (2010) AF-353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist. Br J Pharmacol 160: 1387-1398.
62. Jimenez-Andrade JM, Mantyh WG, Bloom AP, Ferng AS, Geffre CP, Mantyh PW (2010) Bone cancer pain. Ann N Y Acad Sci 1198: 173-181.
63. Mantyh WG, Jimenez-Andrade JM, Stake JI, Bloom AP, Kaczmarska MJ, Taylor RN, Freeman KT, Ghilardi JR, Kuskowski MA, Mantyh PW (2010) Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain. Neuroscience 171(2): 588-598.
64. Gilchrist LS, Cain DM, Harding-Rose C, Kov AN, Wendelschafer-Crabb G, Kennedy WR, Simone DA (2005) Re-organization of P2X3 receptor localization on epidermal nerve fibers in a murine model of cancer pain. Brain Res 1044(2): 197-205.
65. Nagamine K, Ozaki N, Shinoda M, Asai H, Nishiguchi H, Mitsudo K, Tohnai I, Ueda M, Sugiura Y (2006) Mechanical allodynia and thermal hyperalgesia induced by experimental squamous cell carcinoma of the lower gingiva in rats. J Pain 7(9): 659-670.
66. Kaan TK, Yip PK, Patel S, Davies M, Marchand F, Cockayne DA, Nunn PA, Dickenson AH, Ford AP, Zhong Y, Malcangio M, McMahon SB (2010) Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain 133(9): 2549-2564.
67. Fujita M, Andoh T, Sasaki A, Saiki I, Kuraishi Y (2010) Involvement of peripheral adenosine 5'-triphosphate and P2X purinoceptor in pain-related behavior produced by orthotopic melanoma inoculation in mice. Eur J Neurosci 31(9): 1629-1636.
68. Yu XH, Pare M, Martino G, Grazzini E, Projean D, Cantin LD, McIntosh F, Perkins MN, Tomaszewski M (2010) P2X3 Selective antagonist demonstrates antinociceptive effect in a rat inflammatory pain model via peripheral site of action. Proceedings of 13th World Congress on Pain (IASP), Abstract PH374.
69. Burnstock G (1999) Release of vasoactive substances from endothelial cells by sheer stress and purinergic mechanosensory transduction. J Anat 194: 335-342.
70. Burnstock G (2009) Purinergic mechanosensory transduction and visceral pain. Mol Pain 5: 69-80.
71. Nazif O, Teichman JM, Gebhart GF (2007) Neural upregulation in interstitial cystitis. Urology 69(4 Suppl): 24-33.
72. Yiangou Y, Facer P, Ford A, Brady C, Wiseman O, Fowler CJ, Anand P (2001) Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU Int 87: 774-779.
73. Facer P, Knowles CH, Tam PK, Ford AP, Dyer N, Baecker PA, Anand P (2004) Novel capsaicin (VR1) and purinergic (P2X3) receptors in Hirschsprung's intestine. J Pediatr Surg 36(11): 1679-1684.
74. Brady CM, Apostolidis A, Yiangou Y, Baecker PA, Ford AP, Freeman A, Jacques TS, Fowler CJ, Anand P (2004) P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol 46(2): 247-253.
75. Zhong Y, Banning AS, Cockayne DA, Ford APDW, Burnstock G, McMahon SB (2003) Bladder and cutaneous sensory neurons of the rat express different functional P2X receptors. Neuroscience 120: 667-675.
76. Vlaskovska M, Kasakov L, Rong W, Bodin P, Bardini M, Cockayne DA, Ford AP, Burnstock G (2001) P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci 21: 5670-5677.
77. Rong W, Spyer KM, Burnstock G (2002) Activation and sensitisation of low and high threshold afferent fibres mediated by P2X receptors in the mouse urinary bladder. J Physiol 541: 591-600.
78. Rong W, Burnstock G (2004) Activation of ureter nociceptors by exogenous and endogenous ATP in guinea pig. Neuropharmacology 47: 1093-1101.
79. Lu S, Fraser M, Chancellor M, Sun L, de Groat WC (2002) Evaluation of voiding dysfunction and purinergic mechanism in awake long-term spinal cord injured rats: Comparison of metabolism cage and cystometrogram measurements. J Urol 167: 276.
80. Lu SH, Groat WC, Lin AT, Chen KK, Chang LS (2007) Evaluation of purinergic mechanism for the treatment of voiding dysfunction: a study in conscious spinal cord-injured rats. J Chin Med Assoc 70: 439-444.
81. Brederson JD, Jarvis MF (2008) Homomeric and heteromeric P2X3 receptors in peripheral sensory neurons. Curr Opin Inv Drugs 9(7): 716-725.
82. Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP (2004) Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int 45: 987-993.
83. Salas NA, Somogyi GT, Gangitano DA, Boone TB, Smith CP (2007) Receptor activated bladder and spinal ATP release in neurally intact and chronic spinal cord injured rats. Neurochem Int 50: 345-350.
84. Smith CP, Gangitano DA, Munoz A, Salas NA, Boone TB, Aoki KR, Francis J, Somogyi GT (2008) Botulinum toxin type A normalizes alterations in urothelial ATP and NO release induced by chronic spinal cord injury. Neurochem Int 52(6): 1068-1075.
85. Ito K, Iwami A, Katsura H, Ikeda M (2008) Therapeutic effects of the putative P2X3/P2X2/3 antagonist A-317491 on cyclophosphamide-induced cystitis in rats. Naunyn Schmiedebergs Arch Pharmacol 377: 483-490.
86. Ford AP, Cockayne DA (2011) ATP and P2X purinoceptors in urinary tract disorders. Handb Exp Pharmacol (202): 485-526.
87. Bardoni R, Goldstein PA, Lee CJ, Gu JG, MacDermott AB (1997) ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. J Neurosci 17(14): 5297-5304.
88. Kaan TK, Yip PK, Grist J, Cefalu JS, Nunn PA, Ford AP, Zhong Y, McMahon SB (2010) Endogenous purinergic control of bladder activity via presynaptic P2X3 and P2X2/3 receptors in the spinal cord. J Neurosci 30: 4503-4507.
89. Grundy D (2004) What activates visceral afferents? Gut 53(Suppl 2): ii5-ii8.
90. Rong W, Keating C, Sun B, Dong L, Grundy D (2009) Purinergic contribution to small intestinal afferent hypersensitivity in a murine model of post-infectious bowel disease. Neurogastroenterol Motil 21(6): 665-671.
91. Shinoda M, La JH, Bielefeldt K, Gebhart GF (2010) Altered purinergic signaling in colorectal dorsal root ganglion neurons contributes to colorectal hypersensitivity. J Neurophysiol 104(6): 3113-3123.
92. Brumovsky PR, Gebhart GF (2010) Visceral organ cross-sensitization-an integrated perspective. Auton Neurosci 153(1-2): 106-115.
93. Gold MS, Gebhart GF (2010) Nociceptor sensitization in pain pathogenesis. Nat Med 16(11): 1248-1257.
94. 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(1): 37-40.
95. Novakovic SD, Kassotakis LC, Oglesby IB, Smith JA, Eglen RM, Ford AP, Hunter JC (1999) Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain 80(1-2): 273-282.
96. Shinoda M, Kawashima K, Ozaki N, Asai H, Nagamine K, Sugiura Y (2007) P2X3 receptor mediates heat hyperalgesia in a rat model of trigeminal neuropathic pain. J Pain 8(7): 588-597.
97. Zhang A, Gao Y, Zhong X, Xu C, Li G, Liu S, Lin J, Li X, Zhang Y, Liu H, Linag S (2010) Effect of sodium ferulate on the hyperalgesia mediated by P2X3 receptor in neuropathic pain rats. Brain Res 1313: 215-221.
98. Wang Y, Zhang X, Guo QL, Zou WY, Huang CS, Yan JQ (2010) Cyclooxygenase inhibitors suppress the expression of P2X3 receptors in the DRG and attenuate hyperalgesia following chronic constriction injury in rats. Neurosci Lett 478(2): 77-81.
99. Lin J, Li G, Den X, Xu C, Liu S, Gao Y, Liu H, Zhang J, Li X, Liang S (2010) VEGF and its receptor-2 involved in neuropathic pain transmission mediated by P2X2/3 receptor of primary sensory neurons. Brain Res Bull 83(5): 284-291.
100. Ou S, Zhao YD, Xiao Z, Wen HZ, Cui J, Ruan HZ (2011) Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion. Neurochem Int 58(5): 564-573.
101. Beneng K, Yilmaz Z, Yiangou Y, McParland H, Anand P, Renton T (2010) Sensory purinergic receptor P2X3 is elevated in burning mouth syndrome. Int J Oral Maxillofac Surg 39(8): 815-819.
102. Kage K, Niforatos W, Zhu CZ, Lynch KJ, Honore P, Jarvis MF (2002) Alteration of dorsal root ganglion P2X3 receptor expression and function following spinal nerve ligation in the rat. Exp Brain Res 147(4): 511-519.
103. Peleshok JC, Ribeiro-da-Silva A (2011) Delayed reinnervation by nonpeptidergic nociceptive afferents of the glabrous skin of the rat hindpaw in a neuropathic pain model. J Comp Neurol 519(1): 49-63.
104. Taylor AM, Ribeiro-da-Silva A (2011) GDNF levels in the lower lip skin in a rat model of trigeminal neuropathic pain: implications for nonpeptidergic fiber reinnervation and parasympathetic sprouting. Pain 152(7): 1502-1510.
105. Biggs JE, Yates JM, Loescher AR, Clayton NM, Robinson PP, Boissonade FM (2008) P2X(3) expression is not altered by lingual nerve injury. Neurosci Lett 441(1): 110-114.
106. 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(3): 351-360.
107. Chen Y, Li GW, Wang C, Gu Y, Huang LY (2005) Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state. Pain 119(1-3): 38-48.
108. Tsuda M, Hasegawa S, Inoue K (2007) P2X receptors-mediated cytosolic phospholipase A2 activation in primary afferent sensory neurons contributes to neuropathic pain. J Neurochem 103(4): 1408-1416.
109. Meisner JG, Reid AR, Sawynok J (2008) Adrenergic regulation of P2X3 and TRPV1 receptors: differential effects of spared nerve injury. Neurosci Lett 444(2): 172-175.
110. Mo G, Grant R, O'Donnell D, Ragsdale DS, Cao CQ, Séguéla S (2011) Neuropathic Nav1. 3-mediated sensitization to P2X activation is regulated by protein kinase C. Mol Pain 7: 14.
111. Sharp CJ, Reeve AJ, Collins SD, Martindale JC, Summerfield SG, Sargent BS, Bate ST, Chessell IP (2006) Investigation into the role of P2X(3)/P2X(2/3) receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiological study. Br J Pharmacol 148(6): 845-852.
112. Kwong K, Kollarik M, Nassenstein C, Ru F, Undem BJ (2008) P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus. Am J Physiol Lung Cell Mol Physiol 292: L858-L865.
113. Undem BJ, Nassenstein C (2009) Airway nerves and dyspnea associated with inflammatory airway disease. Respir Physiol Neurobiol 167(1): 36-44.
114. Brouns I, Adriaensen D, Burnstock G, Timmermans JP (2000) Intraepithelial vagal sensory nerve terminals in rat pulmonary neuroepithelial bodies express P2X3 receptors. Am J Respir Cell Mol Biol 23(1): 52-61.
115. Muroi Y, Undem BJ (2011) Targeting peripheral afferent nerve terminals for cough and dyspnea. Curr Opin Pharmacol 11(3): 254-264.
116. Kamei J, Takahashi Y, Yoshikawa Y, Saitoh A (2005) Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity. Eur J Pharmacol 528(1-3): 158-161.
117. Kamei J, Takahashi Y (2006) Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs. Eur J Pharmacol 547(1-3): 160-164.
118. Weigand LA, Undem BJ (2011) A role for ATP in the mechanical activation of nodose C-fibers in guinea pig lungs. FASEB J 25: 1077. 4.
119. Pelleg A, Hurt CM (1996) Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. J Physiol 490(1): 265-275.
120. Basoglu OK, Pelleg A, Essilfie-Quaye S, Brindicci C, Barnes PJ, Kharitonov SA (2005) Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma. Chest 128(4): 1905-1909.
121. Beijer S, Gielisse EA, Hupperets PS, van den Borne BE, van den Beuken-Van EM, Nijziel MR, van Henten AM, Dagnelie PC (2007) Intravenous ATP infusions can be safely administered in the home setting: a study in pre-terminal cancer patients. Invest New Drugs 25: 571-579.
122. Mortaz E, Folkerts G, Nijkamp FP, Henricks PA (2010) ATP and the pathogenesis of COPD. Eur J Pharmacol 638: 1-4.
123. Lommatzsch M, Cicko S, Müller T, Lucattelli M, Bratke K, Stoll P, Grimm M, Dürk T, Zissel G, Ferrari D, Di Virgilio F, Sorichter S, Lungarella G, Virchow JC, Idzko M (2010) Extracellular adenosine triphosphate and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 181(9): 928-934.
124. Zylka MJ, Dong X, Southwell AL, Anderson DJ (2003) Atypical expansion in mice of the sensory neuron-specific Mrg G-protein-coupled receptor family. Proc Natl Acad Sci USA 100: 10043-10048.
125. Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45: 17-25.
126. Chen CL, Broom DC, Liu Y, de Nooij JC, Cen C, Samad OA, Jessell TM, Woolf CJ, Ma Q (2006) Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron 40: 365-377.
127. Dussor G, Zylka MJ, Anderson DJ, McCleskey EW (2008) Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors. J Neurophysiol 99: 1581-1589.
128. Loken LS, Wessberg J, Morrison I, McGlone F, Olausson H (2009) Coding of pleasant touch by unmyelinated afferents in humans. Nat Neurosci 12: 547-548.
129. Morrison I, Loken LS, Minde J, Wessberg J, Perini I, Nennesmo I, Olausson H (2011) Reduced C-afferent fibre density affects perceived pleasantness and empathy for touch. Brain 134: 1116-1126.
130. Xu C, Li G, Gao Y, Liu S, Lin J, Zhang J, Li X, Liu H, Liang S (2009) Effect of puerarin on P2X3 receptor involved in hyperalgesia after burn injury in the rat. Brain Res Bull 80(6): 341-346.
131. Gao Y, Xu C, Yu K, Li G, Wan F, Liu S, Lin J, Liu H, Zhang J, Li X, Liang S (2010) Effect of tetramethylpyrazine on DRG neuron P2X3 receptor involved in transmitting pain after burn. Burns 36(1): 127-134.
132. Burnstock G, McMahon SB, Humphrey PPA, Hamilton SG (2000) ATP (P2X) receptors and pain. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Z (eds) Proceedings of the 9th World Congress on Pain. Progress in pain research and management vol. 16. IASP Press, Seattle, pp 63-76.
133. Housley GD, Bringmann A, Reichenbach A (2009) Purinergic signaling in special senses. Trends Neurosci 32(3): 128-141.
134. Shigematsu Y, Shimoda Y, Kaneda M (2007) Distribution of immunoreactivity for P2X3, P2X5, and P2X6-purinoceptors in mouse retina. J Mol Histol 38: 369-371.
135. Puthussery T, Fletcher EL (2007) Neuronal expression of P2X3 purinoceptors in the rat retina. Neuroscience 146: 403-414.
136. Hegg CC, Greenwood D, Huang W, Han P, Lucero MT (2003) Activation of purinergic receptor subtypes modulates odor sensitivity. J Neurosci 23(23): 8291-8301.
137. Telang RS, Paramananthasivam V, Vlajkovic SM, Munoz DJB, Housley GD, Thorne PR (2010) Reduced P2X2 receptor-mediated regulation of endocochlear potential in the ageing mouse cochlea. Purinergic Signalling 6: 263-272.
138. Huang LC, Greenwood D, Thorne PR, Housley GD (2005) Developmental regulation of neuron-specific P2X3 receptor expression in the rat cochlea. J Comp Neurol 484: 133-143.
139. Huang LC, Ryan AF, Cockayne DA, Housley GD (2006) Developmentally regulated expression of the P2X3 receptor in the mouse cochlea. Histochem Cell Biol 125: 681-692.
140. Greenwood D, Jagger DJ, Huang LC, Hoya N, Thorne PR, Wildman SS, King BF, Pak K, Ryan AF, Housley GD (2007) P2X receptor signaling inhibits BDNF-mediated spiral ganglion neuron development in the neonatal rat cochlea. Development 134: 1407-1417.
141. Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, Hellekant G, Kinnamon SC (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310: 1495-1499.
142. Eddy MC, Eschle BK, Barrows J, Hallock RM, Finger TE, Delay ER (2009) Double P2X2/P2X3 purinergic receptor knockout mice do not taste NaCl or the artificial sweetener SC45647. Chem Senses 34(9): 789-797.
143. Roper SD, Huang YA, Stone LM, Pereira E, Finger TE, Kinnamon SC (2008) Knocking out P2X receptors prevents ATP release from taste buds. ISOT Abstract #P339. Chem Senses 33(8): S127.
144. Rong W, Burnstock G, Spyer KM (2001) P2X purinoceptor-mediated excitation of trigeminal lingual nerve terminals in an in vitro intra-arterially perfused rat tongue preparation. J Physiol 524(3): 891-902.
145. Jiang J, Gu J (2002) Expression of adenosine triphosphate P2X3 receptors in rat molar pulp and trigeminal ganglia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94(5): 622-626.
146. Ichikawa H, Sugimoto T (2004) The co-expression of P2X3 receptor with VR1 and VRL-1 in the rat trigeminal ganglion. Brain Res 998(1): 130-135.
147. Ambalavanar R, Moritani M, Dessem D (2005) Trigeminal P2X3 receptor expression differs from dorsal root ganglion and is modulated by deep tissue inflammation. Pain 117(3): 280-291.
148. Fabbretti E, D'Arco M, Fabbro A, Simonetti M, Nistri A, Giniatullin R (2006) Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J Neurosci 26(23): 6163-6171.
149. Staikopoulos V, Sessle BJ, Furness JB, Jennings EA (2007) Localization of P2X2 and P2X3 receptors in rat trigeminal ganglion neurons. Neuroscience 144(1): 208-216.
150. Yang Z, Cao Y, Wang Y, Luo W, Hua X, Lu Y, Liao Z, Lai W, Zhao Z (2009) Behavioural responses and expression of P2X3 receptor in trigeminal ganglion after experimental tooth movement in rats. Arch Oral Biol 54(1): 63-70.
151. Dessem D, Ambalavanar R, Evancho M, Moutanni A, Yallampalli C, Bai G (2010) Eccentric muscle contraction and stretching evoke mechanical hyperalgesia and modulate CGRP and P2X(3) expression in a functionally relevant manner. Pain 149(2): 284-295.
152. Adachi K, Shimizu K, Hu JW, Suzuki I, Sakagami H, Koshikawa N, Sessle BJ, Shinoda M, Miyamoto M, Honda K, Iwata K (2010) Purinergic receptors are involved in tooth-pulp evoked nocifensive behavior and brainstem neuronal activity. Mol Pain 6: 59.
153. D'Arco M, Giniatullin R, Simonetti M, Fabbro A, Nair A, Nistri A, Fabbretti E (2007) Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. J Neurosci 27(31): 8190-8201.
154. Giniatullin R, Nistri A, Fabbretti E (2008) Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol Neurobiol 37(1): 83-90.
155. Simonetti M, Giniatullin R, Fabbretti E (2008) Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. J Biol Chem 283(27): 18743-18752.
156. Nair A, Simonetti M, Birsa N, Ferrari MD, van den Maagdenberg AM, Giniatullin R, Nistri A, Fabbretti E (2010) Familial hemiplegic migraine Ca(v)2. 1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Mol Pain 6: 48.
157. Bodin P, Burnstock G (1995) Synergistic effect of acute hypoxia on flow-induced release of ATP from cultured endothelial cells. Experientia 51(3): 256-259.
158. Bodin P, Burnstock G (1996) ATP-stimulated release of ATP by human endothelial cells. J Cardiovasc Pharmacol 27(6): 872-875.
159. Wood RE, Wishart C, Walker PJ, Askew CD, Stewart IB (2009) Plasma ATP concentration and venous oxygen content in the forearm during dynamic handgrip exercise. BMC Physiol 9: 24.
160. Clarke TC, Williams OJ, Martin PE, Evans WH (2009) ATP release by cardiac myocytes in a simulated ischaemia model: inhibition by a connexin mimetic and enhancement by an antiarrhythmic peptide. Eur J Pharmacol 605(1-3): 9-14.
161. Birdsong WT, Fierro L, Williams FG, Spelta V, Naves LA, Knowles M, Marsh-Haffner J, Adelman JP, Almers W, Elde RP, McCleskey EW (2010) Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels. Neuron 68(4): 739-749.
162. Mortensen SP, Thaning P, Nyberg M, Saltin B, Hellsten Y (2011) Local release of ATP into the arterial inflow and venous drainage of human skeletal muscle: insight from ATP determination with the intravascular microdialysis technique. J Physiol 589(Pt 7): 1847-1857.
163. Xu J, Kussmaul W, Kurnik PB, Al-Ahdav M, Pelleg A (2005) Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. V. Role of purinergic receptors. Am J Physiol Regul Integr Comp Physiol 288(3): R651-R655.
164. Shao LJ, Liang SD, Li GL, Xu CS, Zhang CP (2007) Exploration of P2X3 in the rat stellate ganglia after myocardial ischemia. Acta Histochem 109(4): 330-337.
165. Wang Y, Li G, Yu K, Liang S, Wan F, Xu C, Gao Y, Liu S, Lin J (2009) Expression of P2X2 and P2X3 receptors in rat nodose neurons after myocardial ischemia injury. Auton Neurosci 145(1-2): 71-75.
166. Zhang C, Li G, Liang S, Xu C, Zhu G, Wang Y, Zhang A, Wan F (2008) Myocardial ischemic nociceptive signaling mediated by P2X3 receptor in rat stellate ganglion neurons. Brain Res Bull 75(1): 77-82.
167. Wang Y, Li G, Liang S, Zhang A, Xu C, Gao Y, Zhang C, Wan F (2008) Role of P2X3 receptor in myocardial ischemia injury and nociceptive sensory transmission. Auton Neurosci 139(1-2): 30-37.
168. Li G, Liu S, Zhang J, Yu K, Xu C, Lin J, Li X, Liang S (2010) Increased sympathoexcitatory reflex induced by myocardial ischemic nociceptive signaling via P2X2/3 receptor in rat superior cervical ganglia. Neurochem Int 56(8): 984-990.
169. Fu LW, Longhurst JC (2010) A new function for ATP: activating cardiac sympathetic afferents during myocardial ischemia. Am J Physiol Heart Circ Physiol 299(6): H1762-H1771.
170. Lujan HL, Palani G, Zhang L, DiCarlo SE (2010) Targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced sustained ventricular tachycardia in conscious rats. Am J Physiol Heart Circ Physiol 298(5): H1330-H1339.
171. Smith SA, Mitchell JH, Garry MG (2006) Neural control of the circulation during exercise: the mammalian exercise pressor reflex in health and disease. Exp Physiol 91(1): 89-102.
172. Delaney EP, Greaney JL, Edwards DG, Rose WC, Fadel PJ, Farquhar WB (2010) Exaggerated sympathetic and pressor responses to handgrip exercise in older hypertensive humans: role of the muscle metaboreflex. Am J Physiol Heart Circ Physiol 299(5): H1318-H1327.
173. Cui J, Leuenberger UA, Blaha C, King NC, Sinoway LI (2011) Effect of P2 receptor blockade with pyridoxine on sympathetic response to exercise pressor reflex in humans. J Physiol 589(Pt 3): 685-695.
174. McCord JL, Tsuchimochi H, Kaufman MP (2010) P2X2/3 and P2X3 receptors contribute to the metaboreceptor component of the exercise pressor reflex. J Appl Physiol 109(5): 1416-1423.
175. Liu J, Li JD, Lu J, Xing J, Li J (2011) Contribution of nerve growth factor to upregulation of P2X3 expression in DRG neurons of rats with femoral artery occlusion. Am J Physiol Heart Circ Physiol (in press).
176. Wang HJ, Li YL, Gao L, Zucker IH, Wang W (2010) Alteration in skeletal muscle afferents in rats with chronic heart failure. J Physiol 588(Pt 24): 5033-5047.
177. Paton JFR (2011) Perspective-exercise with angina and cramp? J Physiol 589(2): 261-262.
178. Lee CH, Perner RJ, Larson DP, Koenig JR, Gomtsyan AR, Zheng GZ, Didomenico S, Stewart AO, Bayburt EK, Abbott Laboratories (2002) Preparation of trisubstituted N-[(1S)-1, 2, 3, 4-tetrahydro-1-naphthalenyl] benzamides as inhibitors of P2X3 and P2X2/P2X3 containing receptors for treating pain, urinary incontinence and bladder overactivity. Patent WO2002094767.
179. Brotherton-Pleiss CE, Dillon MP, Ford AP, Gever JR, Carter DS, Gleason SK, Lin CJ, Moore AG, Thompson AW, Villa M, Zhai Y (2010) Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist. Bioorg Med Chem Lett 20: 1031-1103.
180. Carter DS, Alam M, Cai H, Dillon MP, Ford AP, Gever JR, Jahangir A, Lin C, Moore AG, Wagner PJ, Zhai Y (2009) Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X3/P2X2/3 antagonist for the treatment of pain. Bioorg Med Chem Lett 19: 1628-1631.
181. Jahangir A, Alam M, Carter DS, Dillon MP, Bois DJ, Ford AP, Gever JR, Lin C, Wagner PJ, Zhai Y, Zira J (2009) Identification and SAR of novel diaminopyrimidines. Part 2: the discovery of RO-51, a potent and selective, dual P2X(3)/P2X(2/3) antagonist for the treatment of pain. Bioorg Med Chem Lett 19: 1632-1635.
182. Chen L, Dillon MP, Feng L, Hawley RC, Yang M, Hoffmann-La Roche AG (2008) Tetrazole-substituted arylamides as P2X3 and P2X2/3 receptor antagonists and their preparation, pharmaceutical compositions and use in the treatment of diseases. Patent WO2008000645.
183. Chen L, Dillon MP, Feng L, Hawley RC, Yang M, Hoffmann-La Roche AG (2009) Triazole-substituted arylamide derivatives and their use as P2X3 and or P2X2/3 purinergic receptor antagonists. Patent WO2009077366.
184. Burgey CS, Nguyen D, Deng Z, Paone DV, Potteiger CM, Vacca JP, Merck (2008) P2X3 receptor antagonists for treatment of pain. US Patent 20100266714.