Activation of Wnt3a Signaling Rescues the Analgesic Efficacy of Morphine by Regulating Microglial Reactivation in the Spinal Cord

Repetitive opioid treatment promotes analgesic tolerance through mechanisms involving opioid‐induced neuroinflammation. Here, we report that Wnt signaling activation can rescue opioid analgesic effects and suppress neuroinflammation by regulating microglial cells in the spinal cord. We used prolonged repetitive morphine treatment (10 mg/kg, daily) to induce morphine analgesic tolerance in adult C57BL/6J mice. Experiments were performed in mice and in the BV‐2 microglial cell line to determine the potential cellular mechanisms underlying the effects of recombinant Wnt3a on microglial reactive states. Our in vivo studies showed that repetitive morphine treatment suppressed the level of Wnt ligands and β‐catenin activity in the spinal cord. After 4 days of repetitive morphine treatment, intrathecal administration of Wnt3a rescued the analgesic effect of morphine. Ablation of the microglial population by PLX5622 revealed that microglial cells were required for Wnt3a to restore the analgesic efficacy of morphine. In vitro results indicated that exogenous Wnt3a inhibited neuroinflammation and regulated the reactive states of microglial cells by suppressing the activity of NF‐κB and increasing the nuclear expression of STAT3. These findings demonstrate that Wnt3a signaling activation can rescue the analgesic effect of morphine and suppress morphine tolerance‐induced neuroinflammation by regulating microglial reactivation in the spinal cord. This study provides mechanistic insights into the pathophysiology of morphine tolerance and potential therapeutic targets to control morphine‐induced neuroinflammation.