Pharmacological comparison of mitragynine and 7-hydroxymitragynine: In vitro affinity and efficacy for μ-opioid receptor and opioid-like behavioral effects in rats

Samuel Obeng, Jenny L. Wilkerson, Francisco León, Morgan E. Reeves, Luis F. Restrepo, Lea R. Gamez-Jimenez, Avi Patel, Anna E. Pennington, Victoria A. Taylor, Nicholas P. Ho, Tobias Braun, John D. Fortner, Morgan L. Crowley, Morgan R. Williamson, Victoria L.C. Pallares, Marco Mottinelli, Carolina Lopera-Londoño, Christopher R. McCurdy, Lance R. McMahon, Takato Hiranita

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Relationships between m-opioid receptor (MOR) efficacy and effects of mitragynine and 7-hydroxymitragynine are not fully established. We assessed in vitro binding affinity and efficacy and discriminative stimulus effects together with antinociception in rats. The binding affinities of mitragynine and 7-hydroxymitragynine at MOR (Ki values 77.9 and 709 nM, respectively) were higher than their binding affinities at k-opioid receptor (KOR) or d-opioid receptor (DOR). [35S] guanosine 59-O-[g-thio]triphosphate stimulation at MOR demonstrated that mitragynine was an antagonist, whereas 7-hydroxymitragynine was a partial agonist (Emax = 41.3%). In separate groups of rats discriminating either morphine (3.2 mg/kg) or mitragynine (32 mg/kg), mitragynine produced a maximum of 72.3% morphine-lever responding, and morphine produced a maximum of 65.4% mitragynine-lever responding. Other MOR agonists produced high percentages of drug-lever responding in the morphine and mitragynine discrimination assays: 7-hydroxymitragynine (99.7% and 98.1%, respectively), fentanyl (99.7% and 80.1%, respectively), buprenorphine (99.8% and 79.4%, respectively), and nalbuphine (99.4% and 98.3%, respectively). In the morphine and mitragynine discrimination assays, the KOR agonist U69,593 produced maximums of 72.3% and 22.3%, respectively, and the DOR agonist SNC 80 produced maximums of 34.3% and 23.0%, respectively. 7-Hydroxymitragynine produced antinociception; mitragynine did not. Naltrexone antagonized all of the effects of morphine and 7-hydroxymitragynine; naltrexone antagonized the discriminative stimulus effects of mitragynine but not its rate-decreasing effects. Mitragynine increased the potency of the morphine discrimination yet decreased morphine antinociception. Here we illustrate striking differences in MOR efficacy, with mitragynine having less than 7-hydroxymitragynine.

Original languageEnglish (US)
Pages (from-to)410-427
Number of pages18
JournalJournal of Pharmacology and Experimental Therapeutics
Volume376
Issue number3
DOIs
StatePublished - Mar 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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