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 |
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Authors: | Jarvis Michael F Burgard Edward C McGaraughty Steve Honore Prisca Lynch Kevin Brennan Timothy J Subieta Alberto Van Biesen Tim Cartmell Jayne Bianchi Bruce Niforatos Wende Kage Karen Yu Haixia Mikusa Joe Wismer Carol T Zhu Chang Z Chu Katharine Lee Chih-Hung Stewart Andrew O Polakowski James Cox Bryan F Kowaluk Elizabeth Williams Michael Sullivan James Faltynek Connie |
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Affiliation: | Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. michael.jarvis@abbott.com |
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Abstract: | P2X3 and P2X2/3 receptors are highly localized on peripheral and central processes of sensory afferent nerves, and activation of these channels contributes to the pronociceptive effects of ATP. A-317491 is a novel non-nucleotide antagonist of P2X3 and P2X2/3 receptor activation. A-317491 potently blocked recombinant human and rat P2X3 and P2X2/3 receptor-mediated calcium flux (Ki = 22-92 nM) and was highly selective (IC50 >10 microM) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ganglion neurons. Blockade of P2X3 containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and P2X2/3 receptors. A-317491 dose-dependently (ED50 = 30 micromolkg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED50 = 10-15 micromolkg s.c.) in attenuating both thermal hyperalgesia and mechanical allodynia after chronic nerve constriction injury. The R-enantiomer, A-317344, was inactive in these chronic pain models. Although active in chronic pain models, A-317491 was ineffective (ED50 >100 micromolkg s.c.) in reducing nociception in animal models of acute pain, postoperative pain, and visceral pain. The present data indicate that a potent and selective antagonist of P2X3 and P2X2/3 receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X3 and P2X2/3 receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain. |
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