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 - Funding Information:
The present study was supported by National Institutes of Health National Institute on Drug Abuse [Grants R01-DA025267 and UG3-DA048353-01] (to C.R.M. and L.R.M.), University of Florida Foundation and University of Florida Department of Pharmacodynamics Funding. No author has an actual or perceived conflict of interest with the contents of this article. 1Current affiliation: Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas. dx.doi.org/10.1124/jpet.122.001192. S This article has supplemental material available at jpet.aspetjournals.org.
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 -