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Epigenetic modifications, particularly N\n                      <jats:sup>6<\/jats:sup>\n                      \u2010methyladenosine (m\n                      <jats:sup>6<\/jats:sup>\n                      A), have garnered increasing research interest. AlkB homologue 5 (ALKBH5), a key m\n                      <jats:sup>6<\/jats:sup>\n                      A demethylase, has been implicated in cancers and neurological disorders. However, its role in morphine tolerance remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      A mouse model of morphine tolerance was established via repeated subcutaneous morphine administration. The m\n                      <jats:sup>6<\/jats:sup>\n                      A methylation levels and related enzymes expression in the spinal cord were assessed. Functional validation was conducted via adeno\u2010associated virus (AAV)\u2010mediated ALKBH5 overexpression in the spinal dorsal horn. Next\u2010generation sequencing and GO\/KEGG pathway analysis were performed to identify potential downstream target genes, followed by validation via pharmacological inhibition of SGK1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Morphine\u2010tolerant mice exhibited significantly elevated spinal m\n                      <jats:sup>6<\/jats:sup>\n                      A methylation, mainly because of reduced ALKBH5 expression in superficial dorsal horn neurons. ALKBH5 overexpression attenuated the development of morphine tolerance and partly restored opioid analgesic efficacy, reducing spinal m\n                      <jats:sup>6<\/jats:sup>\n                      A methylation levels and SGK1 expression. Transcriptomic analysis and subsequent validation identified SGK1\u2010associated immune signalling pathways as a pivotal mediator of morphine tolerance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      Decreased expression of ALKBH5 contributes to elevated spinal m\n                      <jats:sup>6<\/jats:sup>\n                      A methylation and SGK1 expression, promoting morphine tolerance. Targeted overexpression of ALKBH5 mitigates morphine tolerance, most likely through modulation of SGK1\u2010associated immune signalling pathways. These findings suggest that the ALKBH5\u2010m\n                      <jats:sup>6<\/jats:sup>\n                      A\u2010SGK1 axis may participate in the epigenetic modulation of morphine tolerance and provides a promising molecular target for mitigating morphine tolerance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70365","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T22:40:46Z","timestamp":1770763246000},"page":"2739-2760","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Down\u2010regulation of M\n                    <sup>6<\/sup>\n                    A demethylase ALKBH5 facilitates morphine tolerance via SGK1 in mice"],"prefix":"10.1111","volume":"183","author":[{"given":"Yufei","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Xiangya Hospital, Hunan Province Clinical Research Center for Anesthesia and Perioperative Medicine Central South University  Changsha China"},{"name":"Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain\u2010Like Intelligence, Clinical Research Center for Anesthesiology and Perioperative Medicine, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine Tongji University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Xiangya Hospital, Hunan Province Clinical Research Center for Anesthesia and Perioperative Medicine Central South University  Changsha China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manyu","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Xiangya Hospital, Hunan Province Clinical Research Center for Anesthesia 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