Maresin1 mitigates morphine analgesic tolerance via the Lgr6 pathway

Repeated morphine administration leads to analgesic tolerance, reducing its pain-relief effectiveness and increasing overdose risks. However, the changes in endogenous levels of specialized pro-resolving mediators and their relationship with the mu-opioid receptor, as well as their role in analgesic tolerance during extended morphine use, have yet to be fully understood. Our study demonstrates that chronic morphine exposure reduces maresin1 levels in mice, correlating with morphine dosage in tolerant patients. Systemic or intrathecal administration of maresin1 alleviates morphine tolerance, but intracerebroventricular administration does not. Additionally, Lgr6 expression decreases in the dorsal root ganglia of morphine-tolerant mice, and reducing Lgr6 expression in dorsal root ganglia via AAV injection negates the protective effects of maresin1. Maresin1 works by preventing β-arrestin2 recruitment and mu-opioid receptor internalization, preserving morphine's pain-relief effects. In conclusion, this study elucidates the functions of maresin1 in the modulation of morphine tolerance, suggesting it as a potential target to improve opioid effectiveness.