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.