The Mitragyna speciosa (kratom) alkaloid mitragynine: Analysis of adrenergic α 2 receptor activity in vitro and in vivo.

Autor: Obeng S; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Crowley ML; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Mottinelli M; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., León F; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Zuarth Gonzalez JD; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Chen Y; Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Atlanta, GA, 30341, USA., Gamez-Jimenez LR; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Restrepo LF; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Ho NP; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Patel A; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Martins Rocha J; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Alvarez MA; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Thadisetti AM; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Park CR; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Pallares VLC; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Milner MJ; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Canal CE; Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Atlanta, GA, 30341, USA., Hampson AJ; Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, 20892, USA., McCurdy CR; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA; Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA; Translational Drug Development Core, Clinical and Translational Sciences Institute, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., McMahon LR; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Wilkerson JL; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA. Electronic address: Jenny.Wilkerson@ttuhsc.edu., Hiranita T; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA. Electronic address: hiranita@uthscsa.edu.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Oct 05; Vol. 980, pp. 176863. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1016/j.ejphar.2024.176863
Abstrakt: Mitragynine, an alkaloid present in the leaves of Mitragyna speciosa (kratom), has a complex pharmacology that includes low efficacy agonism at μ-opioid receptors (MORs). This study examined the activity of mitragynine at adrenergic α 2 receptors (Aα 2 Rs) in vitro and in vivo. Mitragynine displaced a radiolabeled Aα 2 R antagonist ([ 3 H]RX821002) from human Aα 2A Rs in vitro with lower affinity (K i  = 1260 nM) than the agonists (-)-epinephrine (K i  = 263 nM) or lofexidine (K i  = 7.42 nM). Mitragynine did not significantly stimulate [ 35 S]GTPγS binding at Aα 2A Rs in vitro, but in rats trained to discriminate 32 mg/kg mitragynine from vehicle (intraperitoneally administered; i.p.), mitragynine exerted an Aα 2 R agonist-like effect. Both α 2 R antagonists (atipamezole and yohimbine) and MOR antagonists (naloxone and naltrexone) produced rightward shifts in mitragynine discrimination dose-effect function and Aα 2 R agonists lofexidine and clonidine produced leftward shifts. In the mitragynine trained rats, Aα 2 R agonists also produced leftward shifts in discrimination dose-effect functions for morphine and fentanyl. In a separate rat cohort trained to discriminate 3.2 mg/kg i.p. morphine from vehicle, naltrexone produced a rightward shift, but neither an Aα 2 R agonist or antagonist affected morphine discrimination. In a hypothermia assay, both lofexidine and clonidine produced marked effects antagonized by yohimbine. Mitragynine did not produce hypothermia. Together, these data demonstrate that mitragynine acts in vivo like an Aα 2 R agonist, although its failure to induce hypothermia or stimulate [ 35 S]GTPγS binding in vitro, suggests that mitragynine maybe a low efficacy Aα 2 R agonist.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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