A-317491, a selective P2X3/P2X2/3 receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at peripheral receptors in rats.

Abstract

The effect of A-317491 (5-([(3-Phenoxybenzyl)[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl)-1,2,4-benzenetricarboxylic acid), a recently described selective P2X3 and P2X(2/3) receptor antagonist, on inflammatory mechanical hyperalgesia was examined. In the rat Freund's complete adjuvant model of inflammatory pain, s.c. administration of A-317491 dose-dependently reversed mechanical hyperalgesia. Maximum percent reversal (72%) was seen 3 h after administration at 10 mg/kg. Substantial plasma concentrations were measured for A-317491 after s.c. dosing 3, 10 and 30 mg/kg. However, the brain-to-plasma concentration ratio, determined 1 h after a 10 mg/kg s.c. dose, indicated limited penetration of A-317491 into the central nervous system. As revealed by neural activity recorded from single C-fiber nociceptive afferent in a Freund's complete adjuvant-inflamed rat skin-nerve preparation, topical application of A-317491 completely blocked afferent activation and mechanical sensitization induced by alpha,beta-methylene ATP, a P2X agonist. These results suggest that A-317491 is a peripherally acting P2X blocker. Its efficacy demonstrates the importance of peripheral P2X3/P2X(2/3) receptors in mediating ATP-associated mechanical hyperalgesia following inflammation, confirming previous suggestions of a significant role for P2X(2/3).

• Authors: Gang Wu, Garth T Whiteside, Gary Lee, Scott Nolan, Mark Niosi, Michelle S Pearson, Victor I Ilyin
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 504 Issue 1-2 Pg. 45-53 (Nov 03 2004) ISSN: 0014-2999 [Print] Netherlands
• PMID: 15507220 (Publication Type: Comparative Study, Journal Article)

Chemical References

• A-317491
• Anti-Inflammatory Agents, Non-Steroidal
• P2rx2 protein, rat
• P2rx3 protein, rat
• Phenols
• Polycyclic Compounds
• Purinergic P2 Receptor Antagonists
• Receptors, Purinergic P2
• Receptors, Purinergic P2X2
• Receptors, Purinergic P2X3

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Hyperalgesia (drug therapy, pathology)
• Male
• Pain Measurement (drug effects, methods)
• Phenols (pharmacology, therapeutic use)
• Physical Stimulation (methods)
• Polycyclic Compounds (pharmacology, therapeutic use)
• Purinergic P2 Receptor Antagonists
• Rats
• Rats, Sprague-Dawley
• Receptors, Purinergic P2 (physiology)
• Receptors, Purinergic P2X2
• Receptors, Purinergic P2X3