Mitragynine and naltrexone alone and in combination reduce alcohol self-administration in female Sprague Dawley rats

Background: Mitragynine (MG), an alkaloid found in leaves of Mitragyna speciosa (kratom), is used for pain and opioid withdrawal. MG’s effects are thought to be mediated through opioid receptors. The mu opioid antagonist naltrexone (NTX), indicated for the treatment of alcohol use disorder (AUD), reduces alcohol self-administration in animals. MG also alters alcohol consumption and alleviates alcohol withdrawal. Therefore, we tested MG, NTX, and both combined on alcohol self-administration in rats. Methods: MG (0.3–3.0 mg/kg, IP) and NTX (0.3–3.0 mg/kg, IP) alone and the combinations of equal drug doses were evaluated in female Sprague Dawley rats lever pressing for alcohol (10%, w/v) under a fixed ratio 2 schedule of reinforcement. Numbers of active and inactive lever presses and estimated alcohol consumed were analyzed. Locomotor activity was assessed in separate groups of rats following MG, NTX (3.0 mg/kg), or its combination and their brains processed to determine cFos expression using immunohistochemistry. Results: Both MG and NTX decreased alcohol self-administration, yet the combination had a greater effect than either alone and did not depress locomotor activity. Similarly, MG and NTX combined enhanced cFos expression in several brain regions more than either drug alone. Conclusions: MG decreased alcohol reinforcement more than NTX but the combination of the two was more impactful than either alone and engendered no adverse effects suggesting decreases in alcohol self-administration were not due to non-specific depression of activity levels. These data suggest that MG has a complex pharmacology that may involve mechanisms other than the mu opioid system.