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Effects of Mitragynine and its Active Metabolites on the Reinforcing Effects of Remifentanil and Cocaine in Rats Self‐Administering Remifentanil

Kratom is being developed as a pharmacotherapy to mitigate withdrawal symptoms from opioids; however, the presence of active metabolites of the primary kratom alkaloid mitragynine (MG) at mu‐opioid receptors [(MORs), 7‐hydoxymitragynine (7‐OH‐MG) and mitragynine pseudoindoxyl (MG‐P)] may limit effectiveness due to their abuse potential. Yue et al (2018) indicated specificity of the antagonizing effects of MG for the reinforcing effects of the MOR agonist heroin relative to the non‐opioid methamphetamine. Using an intravenous drug self‐administration assay, the present study compared abuse potential of MG and its metabolites, and assessed specificity of MG to antagonize the reinforcing effects of the MOR agonist remifentanil and the non‐opioid cocaine in rats. In rats self‐administering remifentanil (0.1‐3.2 µg/kg/injection), reference MOR agonists (methadone and buprenorphine) and the dopamine uptake inhibitor cocaine maintained self‐administration responding above extinction (no injection) levels whereas antagonists at MOR (naltrexone and naloxone) did not. Self‐administration responding above extinction was maintained by 7‐OH‐MG (1.0‐10 µg/kg/injection) and MGP (0.32 µg/kg/injection), but not MG (up to 3.2 mg/kg/injection) when substituted for remifentanil. Self administration of remifentanil, cocaine, 7‐OH‐MG, and MG‐P was decreased by naltrexone (3.2 mg/kg, i.p.). Self administration of remifentanil was also decreased by MG, 7‐OH‐MG, and MG‐P (ED50 values: 34.5, 4.35, and 2.66 mg/kg, respectively). Self administration of cocaine was also decreased by MG, 7‐OH‐MG, and MG‐P (ED50 values: 59.2, 5.12, and 5.17 mg/kg, respectively). Despite the abuse potential of active metabolites of MG, these results suggest less abuse potential of MG than that of its metabolites in rats. The lack of obvious reinforcing effects of MG also suggests if any low contribution of 7‐OH‐MG and MGP to the in vivo MOR activity of MG in rats. Though MG was least potent to decrease the reinforcing effects of remifentanil and cocaine, the comparable ED50 values per compound suggest a lack of specificity of the antagonizing effects of MG and its metabolites in rats with opioid history. These results also indicate that drug history could affect the antagonizing effects of MG on the reinforcing effects of stimulants.