TY - JOUR
T1 - Interactive Effects of m-Opioid and Adrenergic-a2 Receptor Agonists in Rats
T2 - Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine
AU - Obeng, Samuel
AU - Leon, Francisco
AU - Patel, Avi
AU - Zuarth Gonzalez, Julio D.
AU - da Silva, Lucas Chaves
AU - Restrepo, Luis F.
AU - Gamez-Jimenez, Lea R.
AU - Ho, Nicholas P.
AU - Guerrero Calvache, Maria P.
AU - Pallares, Victoria L.C.
AU - Helmes, Justin A.
AU - Shiomitsu, Sakura K.
AU - Soto, Paul L.
AU - McCurdy, Christopher R.
AU - McMahon, Lance R.
AU - Wilkerson, Jenny L.
AU - Hiranita, Takato
N1 - Publisher Copyright:
© 2022 American Society for Pharmacology and Experimental Therapy. All rights reserved.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.122.001192
DO - 10.1124/jpet.122.001192
M3 - Article
C2 - 36153006
AN - SCOPUS:85141939224
SN - 0022-3565
VL - 383
SP - 182
EP - 198
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -