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 μ-, δ- and κ-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 μ-opioid antagonist, cyprodime (1-10 μg, i.c.v.) and the pretreatment with a selective μ1-opioid antagonist naloxonazine (1-3 μg, i.c.v.) significantly antagonized the antinociceptive activities of MG (10 μg, i.c.v.) and morphine (MOR, 3 μg, i.c.v.) in the tail-pinch and hot-plate tests. Naltrindole (1-5 ng, i.c.v.), a selective δ-opioid antagonist, also blocked the effects of MG (10 μg, i.c.v.) without affecting MOR (3 μg, i.c.v.) antinociception. Nor-binaltorphimine, a selective κ-opioid antagonist, significantly attenuated MG (10 μg, i.c.v.) antinociception in the tail-pinch test but not in the hot-plate test at the dose (1 μg, i.c.v.) that antagonized the antinociceptive effects of the selective κ-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 μ- and δ-opioid receptor subtypes, and that the selectivity of MG for the supraspinal opioid receptor subtypes differs from that of MOR in mice.