Interactive Effects of m-Opioid and Adrenergic-a₂ Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine

The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at m-opioid receptors (MORs) and adrenergic-a₂ receptors (Aa₂Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). Aa₂R 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 Aa₂R antagonist yohimbine. Hypothermia only resulted from reference Aa₂R agonists. The rate-deceasing and hypothermic effects of reference Aa₂R agonists were antagonized by yohimbine but not naltrexone. Neither naltrexone nor yohimbine antagonized the rate-decreasing effects of mitragynine. Mitragynine and 7-hydroxymitra-gynine increased the potency of the antinociceptive effects of Aa₂R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference Aa₂R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aa₂R and MOR agonists. When combined with Aa₂R agonists, mitragynine could also produce hypothermic synergism. SIGNIFICANCE STATEMENT Mitragynine is proposed to target the m-opioid receptor (MOR) and adrenergic-a₂ receptor (Aa₂R) 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 Aa₂R and MOR agonists. When combined with Aa₂ R agonists, mitragynine could also produce hypothermic synergism.