Identification of opioid receptor subtypes in antinociceptive actions of supraspinally-administered mitragynine in mice

Mitragynine (MG), a major alkaloidal constituent extracted from the plant Mitragyna speciosa Korth, is known to exert an opioid-like activity. Our previous study showed the involvement of opioid systems in the antinociceptive activity of MG in the tail-pinch and hot-plate tests in mice. In the present study, to clarify the opioid receptor subtypes involved in the antinociceptive action of MG, we investigated the effects of selective antagonists for mu-, delta- and kappa- opioid receptors on antinociception caused by the intracerebroventricular (i.c.v.) injection of MG in the tail-pinch and hot-plate tests in mice. The coadministration of a selective mu-opioid antagonist, cyprodime (1-10 mu g, i.c.v.) and the pretreatment with a selective mu 1-opioid antagonist naloxonazine (1-3 mu g, i.c.v.) significantly antagonized the antinociceptive activities of MG (10 mu g, i.c.v.) and morphine (MOR, 3 mu g, i.c.v.) in the tail-pinch and hot-plate tests. Naltrindole (1-5 ng, i.c.v.), a selective delta-opioid antagonist, also blocked the effects of MG (10 mu g, i.c.v.) without affecting MOR (3 mu g, i.c.v.) antinociception. Nor-binaltorphimine, a selective kappa-opioid antagonist, significantly attenuated MG(10 mu g, i.c.v.) antinociception in the tail-pinch test but not in the hot-plate test at the dose (1 mu g, i.c.v.) that antagonized the antinociceptive effects of the selective kappa-opioid agonist U50,488H in both tests, while it had no effect on MOR antinociception in either tests. These results suggest that antinociception caused by i.c.v. MG is dominantly mediated by mu- and delta-opioid receptor subtypes, and that the selectivity of MG for the supraspinal opioid receptor subtypes differs from that of MOR in mice.