In Vitro and In Vivo Pharmacological Comparison of Mu‐Opioid Receptor Activity of the Kratom (Mitragyna speciosa) Alkaloid Mitragynine and its Metabolite 7‐Hydroxymitragynine

Abstract

AbstractBackgroundThe µ‐opioid receptor (MOR) pharmacology of mitragynine and its 7‐hydroxy metabolite have not been fully established.MethodFor both we assessed binding affinity and efficacy in vitro, as well as discriminative stimulus and antinociceptive effects in rats.ResultBoth mitragynine (MG) and 7‐hydroxymitragynine (7‐MG) had higher binding affinities at human MOR (Ki values 77.9 and 709 nM, respectively) than at the human k‐ (KOR) or d‐opioid receptors (DOR). MG was identified as a MOR antagonist while 7‐MG was identified as a MOR partial agonist (Emax=41%) using the [35S]GTPγS functional assay. In Sprague Dawley rats trained to discriminate 3.2 mg/kg morphine from vehicle (i.p.), MG produced a maximum of 72% morphine‐lever responding. Whereas morphine produced a maximum of 65% MG‐lever responding in a separate group of rats trained to discriminate 32 mg/kg MG from vehicle (i.p.), other MOR agonists (i.p.) produced high percentages of morphine‐lever and MG‐lever responding (respectively): 7‐MG (100% and 98%), fentanyl (100% and 80%), buprenorphine (100% and 79%), and nalbuphine (99% and 98%). MG (up to 56 mg/kg, i.p.) did not produce significant antinociception, whereas 7‐MG (17.8 mg/kg, i.p.) produced robust antinociception in the hotplate assay with the temperature set at 52 °C. Naltrexone (0.032 mg/kg, i.p.) antagonized the discriminative stimulus, rate‐decreasing, and antinociceptive effects of morphine and 7‐MG. Conversly, naltrexone (0.032 mg/kg, i.p.) antagonized the discriminative stimulus effects of MG, but not its rate‐decreasing effects. Pretreatment with MG (5.6 mg/kg, i.p.) potentiated the discriminative‐stimulus effects of morphine but antagonized the antinociceptive effects of morphine.ConclusionStriking differences in MOR efficacy in vitro are consistent with 7‐MG having greater MOR efficacy than MG in vivo. MG exerts both MOR antagonist and agonist activity depending on the MOR efficacy required.