The Mitragyna speciosa (kratom) alkaloid mitragynine: Analysis of adrenergic α2 receptor activity in vitro and in vivo.

ABSTRACT

Mitragynine, an alkaloid present in the leaves of Mitragyna speciosa (kratom), has a complex pharmacology that includes low efficacy agonism at µ-opioid receptors (MORs). This study examined the activity of mitragynine at adrenergic α2 receptors (Aα2Rs) in vitro and in vivo. Mitragynine displaced a radiolabeled Aα2R antagonist ([3H]RX821002) from human Aα2ARs in vitro with lower affinity (Ki = 1260 nM) than the agonists (-)-epinephrine (Ki = 263 nM) or lofexidine (Ki = 7.42 nM). Mitragynine did not significantly stimulate [35S]GTPγS binding at Aα2ARs in vitro, but in rats trained to discriminate 32 mg/kg mitragynine from vehicle (intraperitoneally administered; i.p.), mitragynine exerted an Aα2R agonist-like effect. Both α2R antagonists (atipamezole and yohimbine) and MOR antagonists (naloxone and naltrexone) produced rightward shifts in mitragynine discrimination dose-effect function and Aα2R agonists lofexidine and clonidine produced leftward shifts. In the mitragynine trained rats, Aα2R agonists also produced leftward shifts in discrimination dose-effect functions for morphine and fentanyl. In a separate rat cohort trained to discriminate 3.2 mg/kg i.p. morphine from vehicle, naltrexone produced a rightward shift, but neither an Aα2R agonist or antagonist affected morphine discrimination. In a hypothermia assay, both lofexidine and clonidine produced marked effects antagonized by yohimbine. Mitragynine did not produce hypothermia. Together, these data demonstrate that mitragynine acts in vivo like an Aα2R agonist, although its failure to induce hypothermia or stimulate [35S]GTPγS binding in vitro, suggests that mitragynine maybe a low efficacy Aα2R agonist.