RT Journal Article
SR Electronic
T1 Pharmacological Comparison of Mitragynine and 7-Hydroxymitragynine: In Vitro Affinity and Efficacy for Mu-Opioid Receptor and Opioid-Like Behavioral Effects in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2020-000189
DO 10.1124/jpet.120.000189
A1 Samuel Obeng
A1 Jenny L. Wilkerson
A1 Francisco León
A1 Morgan E Reeves
A1 Luis F Restrepo
A1 Lea R Gamez-Jimenez
A1 Avi Patel
A1 Anna E Pennington
A1 Victoria A Taylor
A1 Nicholas P Ho
A1 Tobias Braun
A1 John D Fortner
A1 Morgan L Crowley
A1 Morgan R Williamson
A1 Victoria LC Pallares
A1 Marco Mottinelli
A1 Carolina Lopera-Londoño
A1 Christopher R. McCurdy
A1 Lance R. McMahon
A1 Takato Hiranita
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/12/31/jpet.120.000189.abstract
AB Relationships between μ-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 - κ (KOR) or δ-opioid receptors (DOR). [35S]GTPγS 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. Significance Statement At human MOR in vitro, mitragynine has low affinity and is an antagonist, whereas 7-hydroxymitragynine has 9-fold higher affinity than mitragynine and is a MOR partial agonist. In rats, intraperitoneal mitragynine exhibits a complex pharmacology including MOR agonism; 7-hydroxymitragynine has higher MOR potency and efficacy than mitragynine. These results are consistent with 7-hydroxymitragynine being a highly selective MOR agonist, and with mitragynine having a complex pharmacology that combines low efficacy MOR agonism with activity at non-opioid receptors.