| Autor: |
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 |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
J Pharmacol Exp Ther |
| ISSN: |
1521-0103 |
| Popis: |
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 (K(i) values 77.9 and 709 nM, respectively) were higher than their binding affinities at κ-opioid receptor (KOR) or δ-opioid receptor (DOR). [(35)S]guanosine 5′-O-[γ-thio]triphosphate stimulation at MOR demonstrated that mitragynine was an antagonist, whereas 7-hydroxymitragynine was a partial agonist (E(max) = 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 µ-opioid receptor (MOR) in vitro, mitragynine has low affinity and is an antagonist, whereas 7-hydroxymitragynine has 9-fold higher affinity than mitragynine and is an 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 nonopioid receptors. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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