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The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine

Hill, Rob; Kruegel, Andrew C.; Javitch, Jonathan A.; Lane, J. Robert; Canals, Meritxell

The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine Thumbnail


Authors

Rob Hill

Andrew C. Kruegel

Jonathan A. Javitch

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor



Abstract

Background and Purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A-dependent oxidation of mitragynine yields the metabolite 7-OH mitragynine, a more efficacious μ receptor agonist. While both mitragynine and 7-OH mitragynine can induce anti-nociception in mice, recent evidence suggests that 7-OH mitragynine formed as a metabolite is sufficient to explain the anti-nociceptive effects of mitragynine. However, the ability of 7-OH mitragynine to induce μ receptor-dependent respiratory depression has not yet been studied. Experimental Approach: Respiration was measured in awake, freely moving, male CD-1 mice, using whole body plethysmography. Anti-nociception was measured using the hot plate assay. Morphine, mitragynine, 7-OH mitragynine and the CYP3A inhibitor ketoconazole were administered orally. Key Results: The respiratory depressant effects of mitragynine showed a ceiling effect, whereby doses higher than 10 mg·kg−1 produced the same level of effect. In contrast, 7-OH mitragynine induced a dose-dependent effect on mouse respiration. At equi-depressant doses, both mitragynine and 7-OH mitragynine induced prolonged anti-nociception. Inhibition of CYP3A reduced mitragynine-induced respiratory depression and anti-nociception without affecting the effects of 7-OH mitragynine. Conclusions and Implications: Both the anti-nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7-OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built-in ceiling effect of the mitragynine-induced respiratory depression. These data suggest that such ‘metabolic saturation’ at high doses may underlie the improved safety profile of mitragynine as an opioid analgesic.

Journal Article Type Article
Acceptance Date Mar 7, 2022
Online Publication Date Mar 16, 2022
Publication Date 2022-07
Deposit Date Mar 21, 2022
Publicly Available Date Mar 29, 2022
Journal British Journal of Pharmacology
Print ISSN 0007-1188
Electronic ISSN 1476-5381
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 179
Issue 14
Pages 3875-3885
DOI https://doi.org/10.1111/bph.15832
Keywords Pharmacology
Public URL https://nottingham-repository.worktribe.com/output/7616753
Publisher URL https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15832

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