Facilitation of enkephalins catabolism inhibitor-induced antinociception by drugs classically used in pain management

The aim of this study was to investigate the facilitatory effects of subana lgesic or low doses of different drugs (acetylsalicylic acid, ibuprofen and morphine) on the antinociceptive responses induced by the endogenous opioi d peptides, enkephalins, protected from their catabolism by the dual enkeph alin-degrading enzymes inhibitor RB101. According to the analgesic profile of the three studied compounds different antinociceptive assays were used: the hot plate and formalin tests in mice, and the tail flick and paw pressu re tests on inflamed paws in rats and polyarthritic rats. Facilitatory effe cts of subanalgesic doses of acetylsalicylic acid and ibuprofen on RB101-in duced antinociceptive responses were observed in the early and late phases of the formalin test, respectively. In the hot plate, tail flick and paw pr essure tests, the dose-dependent analgesic effects of RB101 were strongly p otentiated by subanalgesic doses of morphine (0.5 mg/kg), while in these te sts, acetylsalicylic acid and ibuprofen were unable to modify the RB101-ind uced antinociceptive responses. The synergism in antinociceptive effects ob served with the combination of RB101 and morphine supported by isobolograph ic analysis, may have interesting clinical implications, considering both t he lack of opiate drawbacks observed with RB101 and the high potentiation o f its antinociceptive effects with very low doses of morphine. (C) 2001 Pub lished by Elsevier Science Ltd.