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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\u2009mg\/kg, daily) to induce morphine analgesic tolerance in adult C57BL\/6J mice. Experiments were performed in mice and in the BV\u20102 microglial cell line to determine the potential cellular mechanisms underlying the effects of recombinant Wnt3a on microglial reactive states. Our in\u00a0vivo studies showed that repetitive morphine treatment suppressed the level of Wnt ligands and \u03b2\u2010catenin activity in the spinal cord. After 4\u2009days 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\u00a0vitro results indicated that exogenous Wnt3a inhibited neuroinflammation and regulated the reactive states of microglial cells by suppressing the activity of NF\u2010\u03baB 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\u2010induced 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\u2010induced neuroinflammation.<\/jats:p>","DOI":"10.1002\/glia.70122","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T08:04:48Z","timestamp":1765613088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of\n                    <scp>Wnt3a<\/scp>\n                    Signaling Rescues the Analgesic Efficacy of Morphine by Regulating Microglial Reactivation in the Spinal Cord"],"prefix":"10.1002","volume":"74","author":[{"given":"Cheng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medical Neuroscience School of Medicine, Southern University of Science and Technology  Shenzhen China"},{"name":"SUSTech Center for Pain Medicine, Southern University of Science and Technology  Shenzhen 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