PT - JOURNAL ARTICLE AU - Samuel Obeng AU - Francisco León AU - Avi Patel AU - Julio D. Zuarth Gonzalez AU - Lucas Chaves Da Silva AU - Luis F. Restrepo AU - Lea R Gamez-Jimenez AU - Nicholas P Ho AU - Maria P. Guerrero Calvache AU - Victoria LC Pallares AU - Justin A. Helmes AU - Sakura K. Shiomitsu AU - Paul L. Soto AU - Christopher R. McCurdy AU - Lance R. McMahon AU - Jenny L. Wilkerson AU - Takato Hiranita TI - Interactive Effects of µ-Opioid and Adrenergic-α<sub>2</sub> Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine AID - 10.1124/jpet.122.001192 DP - 2022 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - JPET-AR-2022-001192 4099 - http://jpet.aspetjournals.org/content/early/2022/09/24/jpet.122.001192.short 4100 - http://jpet.aspetjournals.org/content/early/2022/09/24/jpet.122.001192.full AB - The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at µ-opioid (MORs), 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 the hot plate 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-hydroxymitragynine increased the potency of the antinociceptive effects of Aa2R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolar 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 µ-opioid (MOR) and adrenergic-a2 receptor (Aa2R) and to produce behavioral effects through conversion to its MOR agonist metabolite 7-hydroxymitragynine. Isobolar 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 Aa2R agonists, mitragynine could also produce hypothermic synergism.