Journal Article

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

Bryan F. Cox, Elizabeth Kowaluk, Prisca Honore, Haixia Yu, Karen Kage, Chang Z. Zhu, Katharine Chu, James Sullivan, Bruce Bianchi, Joe Mikusa, Jayne Cartmell, Carol T. Wismer, Connie Faltynek, Kevin Lynch, Edward C. Burgard, Chih-Hung Lee, Tim van Biesen, Steve McGaraughty, Michael F. Jarvis, Alberto Subieta, James Polakowski, Timothy J. Brennan, Wende Niforatos, Michael Williams, Andrew O. Stewart

2002

نظرة عامة

P2X 3 and P2X 2/3 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 P2X 3 and P2X 2/3 receptor activation. A-317491 potently blocked recombinant human and rat P2X 3 and P2X 2/3 receptor-mediated calcium flux ( K i = 22–92 nM) and was highly selective (IC 50 >10 μM) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X 3 and P2X 2/3 receptors in rat dorsal root ganglion neurons. Blockade of P2X 3 containing channels was stereospecific because the R -enantiomer (A-317344) of A-317491 was significantly less active at P2X 3 and P2X 2/3 receptors. A-317491 dose-dependently (ED 50 = 30 μmol/kg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED 50 = 10–15 μmol/kg 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 (ED 50 >100 μmol/kg 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 P2X 3 and P2X 2/3 receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X 3 and P2X 2/3 receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain.

• الناشر: National Acad Sciences,National Academy of Sciences
• موضوع: Analgesics, Non-Narcotic - pharmacology / Animal models / Animals / Anti-Inflammatory Agents, Non-Steroidal - pharmacology / Biological Sciences / Brain - drug effects / Brain - physiology / Dose-Response Relationship, Drug / Hemodynamics - drug effects / Male / Motor Activity - drug effects / Pain management / Pharmacology / Phenols - pharmacology / Polycyclic Compounds - pharmacology / Purinergic P2 Receptor Antagonists / Rats / Rats, Sprague-Dawley / Receptors, Purinergic P2X2 / Receptors, Purinergic P2X3 / Rodents