The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study
| Autor: | Takato Hiranita, Kanumuri Siva Rama Raju, Shyam H. Kamble, Michelle A Kuntz, Alexandria S Senetra, Francisco León, Lance R. McMahon, Marco Mottinelli, Christopher R. McCurdy, Erin C. Berthold, Luis F. Restrepo, Nicholas P. Ho, Avi Patel, Abhisheak Sharma |
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| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.drug_class Mitragyna speciosa Population Pharmaceutical Science Pharmacology Southeast asian Naltrexone chemistry.chemical_compound Mice Opioid receptor Medicine Animals education Active metabolite education.field_of_study biology business.industry Articles biology.organism_classification Secologanin Tryptamine Alkaloids Analgesics Opioid Mice Inbred C57BL chemistry Mitragynine 7-Hydroxymitragynine Female business medicine.drug |
| Zdroj: | Drug Metab Dispos |
| ISSN: | 1521-009X |
| Popis: | Kratom (Mitragyna speciosa), a Southeast Asian tree, has been used for centuries in pain relief and mitigation of opium withdrawal symptoms. Mitragynine, 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 mitragynine, 7-hydroxymitragynine, which has higher affinity and efficacy at µ-opioid receptors than mitragynine. Here we investigated the hotplate antinociception, pharmacokinetics, and tissue distribution of mitragynine and 7-hydroxymitragynine at equianalgesic oral doses in male and female C57BL/6 mice to determine the extent to which 7-hydroxymitragynine metabolized from mitragynine accounts for the antinociceptive effects of mitragynine 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 mitragynine and 7-hydroxymitragynine. When administered alone, 7-hydroxymitragynine was 2.8-fold more potent than mitragynine to produce antinociception. At equivalent effective doses of mitragynine and 7-hydroxymitragynine, there was a marked difference in the maximum brain concentration of 7-hydroxymitragynine achieved, i.e, 11-fold lower as a metabolite of mitragynine. The brain concentration of 7-hydroxymitragynine observed 4 hr post administration, producing an analgesic effect < 10%, was still 1.5-fold higher than the maximum concentration of 7-hydroxymitragynine as a metabolite of mitragynine. These results provide strong evidence that 7-hydroxymitragynine has a negligible role in the antinociceptive effects of mitragynine in mice. Significance Statement Mitragynine is being investigated for its potential to aid in pain relief and opioid use disorder, but the active metabolite of mitragynine, 7-hydroxymitragynine, has been shown to have abuse potential and has been implicated in the opioid-like analgesic effect after mitragynine administration. The present results suggest a lack of involvement of 7-hydroxymitragyine to the antinociceptive effects of mitragynine in mice. |
| Databáze: | OpenAIRE |
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