TY - JOUR
T1 - The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice
T2 - A Pharmacokinetic and Pharmacodynamic Study
AU - Berthold, Erin C.
AU - Kamble, Shyam H.
AU - Raju, Kanumuri S.
AU - Kuntz, Michelle A.
AU - Senetra, Alexandria S.
AU - Mottinelli, Marco
AU - León, Francisco
AU - Restrepo, Luis F.
AU - Patel, Avi
AU - Ho, Nicholas P.
AU - Hiranita, Takato
AU - Sharma, Abhisheak
AU - McMahon, Lance R.
AU - McCurdy, Christopher R.
N1 - Funding Information:
No author has an actual or perceived conflict of interest with the contents of this article. This work was supported by National Institutes of Health National Institute of Drug Abuse [Grants UG3 DA048353, UH3 DA048353, R01 DA047855]; the University of Florida Clinical and Translational Science Institute, which is supported in part by National Institutes of Health National Center for Advancing Translational Sciences [UL1TR001427]; and the University of Florida Foundation and University of Florida Department of Pharmacodynamics Funding. 1Current affiliation: Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina dx.doi.org/10.1124/dmd.121.000640. S This article has supplemental material available at dmd.aspetjournals.org.
Publisher Copyright:
Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - Kratom (Mitragyna speciosa), a Southeast Asian tree, has been used for centuries in pain relief and mitigation of opium withdrawal symptoms. Mitragynine (MTG), the major kratom alkaloid, is being investigated for its potential to provide analgesia without the deleterious effects associated with typical opioids. Concerns have been raised regarding the active metabolite of MTG, 7- hydroxymitragynine (7HMG), which has higher affinity and efficacy at m-opioid receptors than MTG. Here we investigated the hotplate antinociception, pharmacokinetics, and tissue distribution of MTG and 7HMG at equianalgesic oral doses in male and female C57BL/6 mice to determine the extent to which 7HMG metabolized from MTG accounts for the antinociceptive effects of MTG and investigate any sex differences. The mechanism of action was examined by performing studies with the opioid receptor antagonist naltrexone. A population pharmacokinetic/pharmacodynamic model was developed to predict the behavioral effects after administration of various doses of MTG and 7HMG. When administered alone, 7HMG was 2.8-fold more potent than MTG to produce antinociception. At equivalent effective doses of MTG and 7HMG, there was a marked difference in the maximum brain concentration of 7HMG achieved, i.e., 11-fold lower as a metabolite of MTG. The brain concentration of 7HMG observed 4 hours post administration, producing an analgesic effect <10%, was still 1.5-fold higher than the maximum concentration of 7HMG as a metabolite of MTG. These results provide strong evidence that 7HMG has a negligible role in the antinociceptive effects of MTG in mice.
AB - Kratom (Mitragyna speciosa), a Southeast Asian tree, has been used for centuries in pain relief and mitigation of opium withdrawal symptoms. Mitragynine (MTG), the major kratom alkaloid, is being investigated for its potential to provide analgesia without the deleterious effects associated with typical opioids. Concerns have been raised regarding the active metabolite of MTG, 7- hydroxymitragynine (7HMG), which has higher affinity and efficacy at m-opioid receptors than MTG. Here we investigated the hotplate antinociception, pharmacokinetics, and tissue distribution of MTG and 7HMG at equianalgesic oral doses in male and female C57BL/6 mice to determine the extent to which 7HMG metabolized from MTG accounts for the antinociceptive effects of MTG and investigate any sex differences. The mechanism of action was examined by performing studies with the opioid receptor antagonist naltrexone. A population pharmacokinetic/pharmacodynamic model was developed to predict the behavioral effects after administration of various doses of MTG and 7HMG. When administered alone, 7HMG was 2.8-fold more potent than MTG to produce antinociception. At equivalent effective doses of MTG and 7HMG, there was a marked difference in the maximum brain concentration of 7HMG achieved, i.e., 11-fold lower as a metabolite of MTG. The brain concentration of 7HMG observed 4 hours post administration, producing an analgesic effect <10%, was still 1.5-fold higher than the maximum concentration of 7HMG as a metabolite of MTG. These results provide strong evidence that 7HMG has a negligible role in the antinociceptive effects of MTG in mice.
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U2 - 10.1124/dmd.121.000640
DO - 10.1124/dmd.121.000640
M3 - Article
C2 - 34759012
AN - SCOPUS:85123812594
SN - 0090-9556
VL - 50
SP - 158
EP - 167
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 2
ER -