title: 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.
abstract: 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 NSAID-refractory 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.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan. yoshihiro.kitagawa@jt.com
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Isao
authors.initials: I
authors.lastname: Tamai
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hamada
authors.forename: Kenji
authors.initials: K
authors.lastname: Usui
authors.forename: Masashi
authors.initials: M
authors.lastname: Wada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakata
authors.forename: Mutsuyoshi
authors.initials: M
authors.lastname: Matsushita
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D048588:Benzoxazines / Q000008:administration & dosage* / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D051474:Neuralgia, Postherpetic / Q000188:drug therapy* / Q000235:genetics*; D010146:Pain / Q000188:drug therapy* / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: C576953:3-(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; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D048588:Benzoxazines; D011725:Pyridines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat