Mitragynine improves cognitive performance in morphine-withdrawn rats

Rationale The treatment of opiate addiction is an unmet medical need. Repeated exposure to opiates disrupts cognitive performance. Opioid substitution therapy, with, e.g., methadone, may further exacerbate the cognitive deficits. Growing evidence suggests that mitragynine, the primary alkaloid from the Kratom (Mitragyna speciosa) leaves, may serve as a promising alternative therapy for opiate addiction. However, the knowledge of its health consequences is still limited. Objectives We aimed to examine the cognitive effects of mitragynine substitution in morphine-withdrawn rats. Furthermore, we asked whether neuronal addiction markers like the brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent kinase II alpha (alpha CaMKII) might mediate the observed effects. Methods Male Sprague-Dawley rats were given morphine at escalating doses before treatment was discontinued to induce a spontaneous morphine withdrawal. Then, vehicle or mitragynine (5 mg/kg, 15 mg/kg, or 30 mg/kg) substitution was given for 3 days. A vehicle-treated group was used as a control. Withdrawal signs were scored after 24 h, 48 h, and 72 h, while novel object recognition (NOR) and attentional set-shifting (ASST) were tested during the substitution period. Results Discontinuation of morphine significantly induced morphine withdrawal signs and cognitive deficit in the ASST. The substitution with mitragynine was able to alleviate the withdrawal signs. Mitragynine did not affect the recognition memory in the NOR but significantly improved the reversal learning deficit in the morphine-withdrawn rats. Conclusions These data support the idea that mitragynine could be used as safe medication therapy to treat opiate addiction with beneficial effects on cognitive deficits.

Automated summary

The study aimed to examine the cognitive effects of mitragynine substitution in morphine-withdrawn rats and investigate whether neuronal addiction markers such as brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent kinase II alpha (alpha CaMKII) might mediate the observed effects. Results showed that mitragynine substitution was able to alleviate morphine withdrawal signs and improve cognitive deficits, suggesting its potential as a safe medication therapy for opiate addiction.