Received for publication January 24, 2005.
Revised April 13, 2005.
Accepted for publication April 14, 2005.

A-425619, a Novel TRPV1 Receptor Antagonist, Relieves Pathophysiological Pain Associated with Inflammation and Tissue Injury in Rats

Abstract

The vanilloid receptor 1 (VR1, TRPV1) which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N-arachidonoyl-dopamine (NADA). A-425619 is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose-dependently reduced capsaicin-induced mechanical hyperalgesia (ED₅₀ = 45 µmol/kg, p.o.). A-425619 was also effective in models of inflammatory pain and post-operative pain. A-425619 potently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration (ED₅₀ = 40 µmol/kg, p.o.) and was also effective after either intrathecal administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the post-operative pain model after twice daily dosing p.o. for five days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 µmol/kg, p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and post-operative pain.

Key words: TRPV1, capsaicin, hyperalgesia, inflammation, pain, vanilliod receptor

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