Interactive Effects of μ-Opioid and Adrenergic-α2 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 mu-opioid receptors (MORs) and adrenergic-alpha(2) receptors (A alpha(2)Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). A alpha R-2 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 alpha R-2 antagonist yohimbine. Hypothermia only resulted from reference A alpha R-2 agonists. The rate-deceasing and hypothermic effects of reference A alpha R-2 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 alpha R-2 but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference A alpha R-2 and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with A alpha R-2 and MOR agonists. When combined with A alpha R-2 agonists, mitragynine could also produce hypothermic synergism. SIGNIFICANCE STATEMENT Mitragynine is proposed to target the m-opioid receptor (MOR) and adrenergic-alpha(2) receptor (A alpha R-2) 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 A alpha R-2 and MOR agonists. When combined with A alpha(2) R agonists, mitragynine could also produce hypothermic synergism.

Automated summary

The primary kratom alkaloid mitragynine and its metabolite 7-hydroxymitragynine may produce antinociceptive effects through synergistic actions with adrenergic-alpha(2) receptor (A alpha R-2) and m-opioid receptor (MOR) agonists. Additionally, when combined with A alpha R-2 agonists, mitragynine may also produce hypothermic effects.