A-317491, a Novel Potent and Selective Non-Nucleotide Antagonist of P2X3and P2X2/3Receptors, Reduces Chronic Inflammatory and Neuropathic Pain in the Rat

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-12, Vol.99 (26), p.17179-17184
• Main 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
• Format: Article
• Language: English
• Subjects: Agonists; Analgesics; Animal models; Biological Sciences; Electric current; Hyperalgesia; Nerves; Neurons; Pain; Rats; Receptors
• ISSN: 0027-8424

P2X3and P2X2/3receptors 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 P2X3and P2X2/3receptor activation. A-317491 potently blocked recombinant human and rat P2X3and P2X2/3receptor-mediated calcium flux (Ki= 22-92 nM) and was highly selective$(IC_{50} > 10\;\mu M)$over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3and P2X2/3receptors in rat dorsal root ganglion neurons. Blockade of P2X3containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3and P2X2/3receptors. A-317491 dose-dependently (ED50= 30 μ mol/kg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED50= 10-15 μ mol/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$(ED_{50} > 100\;\mu mol/kg\;s.c.)$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 P2X3and P2X2/3receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X3and P2X2/3receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain.