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

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 Aα_2ARs in vitro with lower affinity (K_i = 1260 nM) than the agonists (−)-epinephrine (K_i = 263 nM) or lofexidine (K_i = 7.42 nM). Mitragynine did not significantly stimulate [³⁵S]GTPγS binding at Aα_2ARs 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.