Oxidative Metabolism as a Modulator of Kratom’s Biological Actions
Soumen Chakraborty, Rajendra Uprety, Samuel T. Slocum, Takeshi Irie, Valerie Le Rouzic, Xiaohai Li, Lisa Wilson, Brittany Scouller, Amy F. Alder, Andrew C. Kruegel, Michael Ansonoff, András Váradi, Shainnel O. Eans, Amanda Hunkele, Abdullah Allaoa, Sanjay Kalra, Jin Xu, Ying‐Xian Pan, John E. Pintar, Bronwyn M. Kivell, Gavril W. Pasternak, Michael D. Cameron, Jay P. McLaughlin, Dalibor Sameš, Susruta Majumdar
Abstract
The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom’s major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.