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CYP3A\u2010dependent oxidation of mitragynine yields the metabolite 7\u2010OH mitragynine, a more efficacious \u03bc receptor agonist. While both mitragynine and 7\u2010OH mitragynine can induce anti\u2010nociception in mice, recent evidence suggests that 7\u2010OH mitragynine formed as a metabolite is sufficient to explain the anti\u2010nociceptive effects of mitragynine. However, the ability of 7\u2010OH mitragynine to induce \u03bc receptor\u2010dependent respiratory depression has not yet been studied.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Respiration was measured in awake, freely moving, male CD\u20101 mice, using whole body plethysmography. Anti\u2010nociception was measured using the hot plate assay. Morphine, mitragynine, 7\u2010OH mitragynine and the CYP3A inhibitor ketoconazole were administered orally.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      The respiratory depressant effects of mitragynine showed a ceiling effect, whereby doses higher than 10\u2009mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      produced the same level of effect. In contrast, 7\u2010OH mitragynine induced a dose\u2010dependent effect on mouse respiration. At equi\u2010depressant doses, both mitragynine and 7\u2010OH mitragynine induced prolonged anti\u2010nociception. Inhibition of CYP3A reduced mitragynine\u2010induced respiratory depression and anti\u2010nociception without affecting the effects of 7\u2010OH mitragynine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Both the anti\u2010nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7\u2010OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built\u2010in ceiling effect of the mitragynine\u2010induced respiratory depression. These data suggest that such \u2018metabolic saturation\u2019 at high doses may underlie the improved safety profile of mitragynine as an opioid analgesic.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15832","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:11:35Z","timestamp":1647475895000},"page":"3875-3885","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["The respiratory depressant effects of mitragynine are limited by its conversion to 7\u2010OH mitragynine"],"prefix":"10.1111","volume":"179","author":[{"given":"Rob","family":"Hill","sequence":"first","affiliation":[{"name":"Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre University of Nottingham  Nottingham UK"},{"name":"Centre of Membrane Proteins and Receptors Universities of Nottingham and Birmingham  Midlands UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Kruegel","sequence":"additional","affiliation":[{"name":"Department of Chemistry Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Javitch","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry and Molecular Pharmacology and Therapeutics Columbia University Vagelos College of Physicians and Surgeons  New York New York USA"},{"name":"Division of Molecular Therapeutics New York State Psychiatric Institute  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7361-7875","authenticated-orcid":false,"given":"J. 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