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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 α 2 receptors (Aα 2 Rs) in vitro and in vivo. Mitragynine displaced a radiolabeled Aα 2 R antagonist ([ 3 H]RX821002) from human Aα 2A Rs 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 [ 35 S]GTPγS binding at Aα 2A Rs in vitro, but in rats trained to discriminate 32 mg/kg mitragynine from vehicle (intraperitoneally administered; i.p.), mitragynine exerted an Aα 2 R agonist-like effect. Both α 2 R antagonists (atipamezole and yohimbine) and MOR antagonists (naloxone and naltrexone) produced rightward shifts in mitragynine discrimination dose-effect function and Aα 2 R agonists lofexidine and clonidine produced leftward shifts. In the mitragynine trained rats, Aα 2 R 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 Aα 2 R 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 Aα 2 R agonist, although its failure to induce hypothermia or stimulate [ 35 S]GTPγS binding in vitro, suggests that mitragynine maybe a low efficacy Aα 2 R agonist., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at µ -opioid receptors (MORs) and adrenergic- α 2 receptors (A α 2 Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). A α 2 R and MOR agonists can produce antinociceptive synergism. Here, contributions of both receptors to produce mitragynine-related effects were assessed by measuring receptor binding in cell membranes and, in rats, pharmacological behavioral effect antagonism studies. Mitragynine displayed binding affinity at both receptors, whereas 7-hydroxymitragynine only displayed MOR binding affinity. Compounds were tested for their capacity to decrease food-maintained responding and rectal temperature and to produce antinociception in a hotplate test. Prototypical MOR agonists and 7-hydroxymitragynine, but not mitragynine, produced antinociception. MOR agonist and 7-hydroxymitragynine rate-deceasing and antinociceptive effects were antagonized by the opioid antagonist naltrexone but not by the A α 2 R antagonist yohimbine. Hypothermia only resulted from reference A α 2 R agonists. The rate-deceasing and hypothermic effects of reference A α 2 R agonists were antagonized by yohimbine but not naltrexone. Neither naltrexone nor yohimbine antagonized the rate-decreasing effects of mitragynine. Mitragynine and 7-hydroxymitragynine increased the potency of the antinociceptive effects of A α 2 R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference A α 2 R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with A α 2 R and MOR agonists. When combined with A α 2 R agonists, mitragynine could also produce hypothermic synergism. SIGNIFICANCE STATEMENT: Mitragynine is proposed to target the µ-opioid receptor (MOR) and adrenergic-α 2 receptor (Aα 2 R) and to produce behavioral effects through conversion to its MOR agonist metabolite 7-hydroxymitragynine. Isobolographic analyses indicated supra-additivity in some dose ratio combinations. This study suggests mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα 2 R and MOR agonists. When combined with Aα 2 R agonists, mitragynine could also produce hypothermic synergism., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)