{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T12:00:03Z","timestamp":1781870403803,"version":"3.54.5"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32172930"],"award-info":[{"award-number":["32172930"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Neuropathic pain (NP), resulting from nerve damage, is difficult to manage and often requires long\u2010term treatment. However, prolonged use of pain medications can lead to addiction and reduced effectiveness over time. Understanding drug tolerance is essential for developing improved pain management strategies. Dexmedetomidine (DEX) is effective in targeting the <jats:italic>\u03b12<\/jats:italic>\u2010adrenergic receptor, providing relief from pain, especially NP. However, its extended use leads to tolerance and hinders its clinical utility. Herein, we investigated tolerance mechanisms and potential applications of this drug in managing NP. Adult C57BL\/6 mice (male) were distributed into DEX Dosage Groups (<jats:italic>n<\/jats:italic>\u2009=\u200948), DEX Tolerance Model Groups (<jats:italic>n<\/jats:italic>\u2009=\u200932), <jats:italic>SGK1<\/jats:italic> Inhibitor GSK650394 Groups (<jats:italic>n<\/jats:italic>\u2009=\u200948), and <jats:italic>NF<\/jats:italic>\u2010<jats:italic>\u03baB<\/jats:italic> Inhibitor PDTC Groups (<jats:italic>n<\/jats:italic>\u2009=\u200932) to explore dexmedetomidine's effects on NP and tolerance mechanisms. NP was established via selective ligation of the sciatic nerve branch (SNI), followed by administration of DEX. The results revealed a dose\u2010dependent analgesic effect of DEX, with significant increases in pain thresholds observed compared to the sham group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Optimal efficacy was found at a dose of 30\u2009\u03bcg\/kg, indicating its potential as an effective treatment for NP (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). However, continuous administration of DEX over 13\u2009days induced analgesic tolerance, evidenced by an initial increase in pain thresholds followed by a gradual decrease (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Despite an initial efficacy in elevating pain thresholds, the analgesic effect of DEX diminished over time, returning to pre\u2010dose levels after 5\u2009days (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Transcriptome sequencing of spinal cord samples from mice receiving multiple DEX injections revealed differential gene expression patterns, notably upregulation of <jats:italic>SGK1<\/jats:italic>, <jats:italic>NR2A<\/jats:italic>, and <jats:italic>NR2B<\/jats:italic> subunits (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Inhibiting <jats:italic>SGK1<\/jats:italic> mitigated DEX\u2010induced tolerance, suggesting its involvement in tolerance development (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Moreover, <jats:italic>NF<\/jats:italic>\u2010<jats:italic>\u03baB<\/jats:italic> inhibition reversed DEX\u2010induced tolerance and implicated the <jats:italic>SGK1<\/jats:italic>\u2010<jats:italic>NF<\/jats:italic>\u2010<jats:italic>\u03baB<\/jats:italic> pathway in the mediation of analgesic tolerance. To sum up, these findings revealed the molecular mechanism underlying DEX\u2010induced analgesic tolerance in the NP model and offer potential avenues for future therapeutic interventions.<\/jats:p>","DOI":"10.1111\/jcmm.70372","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T11:14:19Z","timestamp":1742296459000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Elucidation of Dexmedetomidine\u2010Induced Analgesic Tolerance Mechanisms in Neuropathic Pain With Modulation of <scp><i>SGK1<\/i><\/scp>, <scp><i>NR2A<\/i><\/scp>, and <scp><i>NR2B<\/i><\/scp> Expression via the Spinal <scp><i>SGK1<\/i><\/scp>\/<scp><i>NF<\/i><\/scp>\u2010<scp><i>\u03baB<\/i><\/scp> Signalling Pathway"],"prefix":"10.1111","volume":"29","author":[{"given":"Wang","family":"Huikang","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cao","family":"Shiya","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Di","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3960-1164","authenticated-orcid":false,"given":"Faisal Ayub","family":"Kiani","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"},{"name":"Department of Clinical Sciences, Faculty of Veterinary Sciences Bahauddin Zakariyah University  Multan Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Hao","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Sha","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xuan","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud M.","family":"Abouelfetouh","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"},{"name":"Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine Benha University, Moshtohor  Benha Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zulfiqar","family":"Ahmed","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"},{"name":"Department of Livestock Production, Faculty of Veterinary &amp; 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