Suppressive effect of mitragynine on the 5-methoxy-N,N-dimethyltryptamine-induced head-twitch response in mice

We investigated the effects of mitragynine, a major alkaloid isolated from the leaves of Mitragyna speciosa Korth (Rubiaceae), on the 5-HT2A receptor-mediated head-twitch response in mice. Intraperitoneal injection of mitragynine (5-30 mg/kg), as well as intraperitoneal injection of 5-HT2A receptor antagonist ritanserin, inhibited the 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT: 16 mg/kg, IP)-induced head-twitch response in a dose-dependent manner. In contrast, mitragynine affected neither head-weaving caused by 5-MeO-DMT, nor drug-free spontaneous motor activity. Pretreatment of mice with reserpine (5 mg/kg, IP), p-chlorophenylalanine (p-CPA, 300 mg/kg x 3 times, IP), or 6-hydroxydopamine (6-OHDA, 50 micrograms/mouse, ICV) plus nomifensine (5 mg/kg, IP) did not change the suppressant effect of mitragynine on the head-twitch response caused by 5-MeO-DMT. On the other hand, the alpha 2-adrenoceptor antagonists yohimbine (0.5 mg/kg, IP), and idazoxan (0.2 mg/kg, IP), significantly attenuated the suppressant effect of mitragynine. Lesion of central noradrenergic systems by 6-OHDA plus nomifensine did not alter the effect of idazoxan (0.2 mg/kg) on mitragynine-induced suppression of the head-twitch response. These results indicate that stimulation of postsynaptic alpha 2-adrenoceptor, blockade of 5-HT2A receptors, or both, are involved in suppression of 5-HT2A receptor-mediated head-twitch response by mitragynine.