Antinociceptive properties of FR140423 mediated through spinal delta-, butnot mu- and kappa-, opioid receptors

We investigated the antinociceptive effect of FR140423, 3-(difluoromethyl)- 1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl] pyrazole, in the tail-pinc h test in mice, and evaluated the mechanism of action using various opioid receptor antagonists. P.o. and i.t. injection of FR140423 exerted dose-depe ndent antinociceptive activities with ED50 values of 21 mg/kg and 3.1 mu g/ mouse, respectively. However, i.c.v. injection of FR140423 did not show an antinociceptive effect. The antinociceptive effects of FR140423 were comple tely abolished by naloxone and naltrindole but not by naloxonazine, beta-fu naltrexamine and nor-binaltorphimine. FR140423 did not affect any opioid re ceptor binding in mouse spinal membranes at concentrations up to 100 mu M i n vitro. Naloxone-induced jumping and diarrhea tests for morphine-like phys ical dependence of FR140423 gave negative results. These results suggest th at FR140423 can induce antinociception by acting on the spinal but not the supraspinal site, and that spinal delta-opioid systems indirectly play a ro le in the antinociception produced by FR140423 in mice. (C) 1999 Elsevier S cience B.V. All rights reserved.