Interactive Effects of µ-Opioid and Adrenergic-α2 Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynines

• Published in: The Journal of pharmacology and experimental therapeutics 2022-12, Vol.383 (3), p.182-198
• Main Authors: Obeng, Samuel, Leon, Francisco, Patel, Avi, Zuarth Gonzalez, Julio D., Chaves Da Silva, Lucas, Restrepo, Luis F., Gamez-Jimenez, Lea R., Ho, Nicholas P., Guerrero Calvache, Maria P., Pallares, Victoria L.C., Helmes, Justin A., Shiomitsu, Sakura K., Soto, Paul L., Hampson, Aidan J., McCurdy, Christopher R., McMahon, Lance R., Wilkerson, Jenny L., Hiranita, Takato
• Format: Article
• Language: English
• ISSN: 0022-3565
• DOI: 10.1124/jpet.122.001192

The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at µ-opioid receptors (MORs) and adrenergic-α2 receptors (A α2Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). A α2R 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 α2R antagonist yohimbine. Hypothermia only resulted from reference A α2R agonists. The rate-deceasing and hypothermic effects of reference A α2R 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 α2R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference A α2R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with A α2R and MOR agonists. When combined with A α2R agonists, mitragynine could also produce hypothermic synergism. Mitragynine is proposed to target the µ-opioid receptor (MOR) and adrenergic-α2 receptor (Aα2R) 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 Aα2R and MOR agonists. When combined with Aα2R agonists, mitragynine could also produce hypothermic synergism.