TY - JOUR T1 - Interactive Effects of <em>µ</em>-Opioid and Adrenergic-<em>α</em><sub>2</sub> Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 182 LP - 198 DO - 10.1124/jpet.122.001192 VL - 383 IS - 3 AU - Samuel Obeng AU - Francisco Leon 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 L.C. Pallares AU - Justin A. Helmes AU - Sakura K. Shiomitsu AU - Paul L. Soto AU - Aidan J. Hampson AU - Christopher R. McCurdy AU - Lance R. McMahon AU - Jenny L. Wilkerson AU - Takato Hiranita Y1 - 2022/12/01 UR - http://jpet.aspetjournals.org/content/383/3/182.abstract N2 - The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at µ-opioid receptors (MORs) and adrenergic-α2 receptors (Aα2Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). Aα2R 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 Aα2R antagonist yohimbine. Hypothermia only resulted from reference Aα2R agonists. The rate-deceasing and hypothermic effects of reference Aα2R 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 Aα2R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference Aα2R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα2R and MOR agonists. When combined with Aα2R agonists, mitragynine could also produce hypothermic synergism.SIGNIFICANCE STATEMENT 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. ER -