1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea (A-425619), a novel, potent, and selective transient receptor potential type V1 (TRPV1) antagonist, attenuates pain associated with inflammation and tissue injury in rats. A-425619 was found to potently block capsaicin-evoked increases in intracellular calcium concentrations in HEK293 cells expressing recombinant human TRPV1 receptors (IC50 = 5 nM). A-425619 showed similar potency (IC50 = 3-4 nM) to block TRPV1 receptor activation by anandamide and N-arachidonoyl-dopamine. Electrophysiological experiments showed that A-425619 also potently blocked the activation of native TRPV1 channels in rat dorsal root ganglion neurons (IC50 = 9 nM). In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 umol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 umol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 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 micromol/kg p.o.). A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.