title: Antinociceptive properties of FR140423 mediated through spinal delta-, but not mu- and kappa-, opioid receptors.
abstract: We investigated the antinociceptive effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl] pyrazole, in the tail-pinch test in mice, and evaluated the mechanism of action using various opioid receptor antagonists. P.o. and i.t. injection of FR140423 exerted dose-dependent antinociceptive activities with ED50 values of 21 mg/kg and 3.1 microg/mouse, respectively. However, i.c.v. injection of FR140423 did not show an antinociceptive effect. The antinociceptive effects of FR140423 were completely abolished by naloxone and naltrindole but not by naloxonazine, beta-funaltrexamine and nor-binaltorphimine. FR140423 did not affect any opioid receptor binding in mouse spinal membranes at concentrations up to 100 microM in vitro. Naloxone-induced jumping and diarrhea tests for morphine-like physical dependence of FR140423 gave negative results. These results suggest that FR140423 can induce antinociception by acting on the spinal but not the supraspinal site, and that spinal delta-opioid systems indirectly play a role in the antinociception produced by FR140423 in mice.
authors.affiliation: Department of Immunology and Inflammation, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ochi
authors.forename: T
authors.initials: T
authors.lastname: Fujii
authors.forename: Y
authors.initials: Y
authors.lastname: Motoyama
authors.forename: T
authors.initials: T
authors.lastname: Goto
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013454:Sulfoxides
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009292:Narcotic Antagonists; D011720:Pyrazoles; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013454:Sulfoxides; C108904:3-(difluoromethyl)-1-(4-methoxyphenyl)-5-(4-(methylsulfinyl)phenyl)pyrazole; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; C024524:beta-funaltrexamine; C034643:naloxonazine; C055382:naltrindole