The orally administered selective TRPV1 antagonist,JTS-653,attenuates chronic pain refractory to non-steroidal anti-inflammatory drugs in rats and mice including post-herpetic pain

Chronic pain refractory to non-steroidal anti-inflammatory drugs (nsaids) is a major problem and drugs for such pain are needed. many studies suggest that transient receptor potential vanilloid type 1 (trpv1) is associated with nsaid-refractory chronic pain. therefore,we investigated the involvement of trpv1 in nsaid-refractory chronic pain using experimental models for nsaid-refractory chronic pain reflecting severe arthritic and postherpetic pain. the selective trpv1 antagonist jts-653 {(3s)-3-(hydroxymethyl)-4-(5- methylpyridin-2-yl)-n- [6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2h- benzo[b][1,4]oxazine-8-carboxamide} reversed mechanical hyperalgesia on day 7 after injection of complete-freund-adjuvant into the hindpaw in rats at 0.3 mg/kg,whereas indomethacin showed no effect. jts-653 reduced chronic pain at 0.3 mg/kg in herpes simplex virus-1-inoculated mice that has been reported as nsaidrefractory pain. jts-653 partially attenuated mechanical hyperalgesia in the l5 spinal nerve ligation model in rats at 0.3 mg/kg,whereas indomethacin showed no effect. both jts-653 and indomethacin reduced formalin-induced pain in the second phase,whereas they showed no effect in the first phase. jts-653 did not affect the nociception of noxious thermal and mechanical stimuli and motor coordination in normal rats. these findings demonstrate the trpv1 involvement in nsaid-refractory chronic pain reflecting severe arthritic and postherpetic pain. trpv1 antagonists would be useful for the treatment of nsaid-refractory chronic pain. © 2013 the japanese pharmacological society.