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Circular RNAs (ciRNA) are emerging as key regulators of gene expression. Here, we identified a nervous\u2010system\u2010tissues\u2010specific <jats:italic>ciRNA\u2010Kat6<\/jats:italic> with conservation in humans and mice. We aimed to investigate whether and how spinal dorsal horn <jats:italic>ciRNA\u2010Kat6b<\/jats:italic> participates in neuropathic pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Unilateral sciatic nerve chronic constrictive injury (CCI) surgery was used to prepare the neuropathic pain model. The differentially expressed ciRNAs were obtained by RNA\u2010Sequencing. The identification of nervous\u2010system\u2010tissues specificity of <jats:italic>ciRNA\u2010Kat6b<\/jats:italic> and the measurement of <jats:italic>ciRNA\u2010Kat6b<\/jats:italic> and <jats:italic>microRNA\u201026a<\/jats:italic> (<jats:italic>miRNA\u201026a<\/jats:italic>) expression level were carried out by quantitative RT\u2010PCR. The <jats:italic>ciRNA\u2010Kat6b<\/jats:italic> that targets <jats:italic>miRNA\u201026a<\/jats:italic> and <jats:italic>miRNA\u201026a that<\/jats:italic> targets <jats:italic>Kcnk1<\/jats:italic> were predicted by bioinformatics analysis and verified by in vitro <jats:italic>luciferase reports<\/jats:italic> test and in vivo experiments including Western\u2010blot, immunofluorescence, and RNA\u2013RNA immunoprecipitation. The correlation between neuropathic pain and <jats:italic>ciRNA\u2010Kat6b<\/jats:italic>, <jats:italic>miRNA\u201026a<\/jats:italic>, or <jats:italic>Kcnk1<\/jats:italic> was examined by the hypersensitivity response to heat and mechanical stimulus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Peripheral nerve injury downregulated <jats:italic>ciRNA\u2010Kat6b<\/jats:italic> in the dorsal spinal horn of male mice. Rescuing this downregulation blocked nerve injury\u2010induced increase of <jats:italic>miRNA\u201026a<\/jats:italic>, reversed the <jats:italic>miRNA\u201026a<\/jats:italic>\u2010triggered decrease of potassium channel <jats:italic>Kcnk1<\/jats:italic>, a key neuropathic pain player, in the dorsal horn, and alleviates CCI\u2010induced pain hypersensitivities. On the contrary, mimicking this downregulation increased the <jats:italic>miRNA\u201026a<\/jats:italic> level and decreased <jats:italic>Kcnk1<\/jats:italic> in the spinal cord, resulting in neuropathic pain\u2010like syndrome in na\u00efve mice. Mechanistically, the downregulation of <jats:italic>ciRNA\u2010Kat6b<\/jats:italic> reduced the accounts of <jats:italic>miRNA\u201026a<\/jats:italic> binding to <jats:italic>ciRNA\u2010Kat6b<\/jats:italic>, and elevated the binding accounts of <jats:italic>miRNA\u201026a<\/jats:italic> to the 3\u2032 untranslated region of <jats:italic>Kcnk1<\/jats:italic> mRNA and degeneration of <jats:italic>Kcnk1<\/jats:italic> mRNA, triggering in the reduction of KCNK1 protein in the dorsal horn of neuropathic pain mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The <jats:italic>ciRNA\u2010Kat6b<\/jats:italic>\/<jats:italic>miRNA\u201026a\/Kcnk1<\/jats:italic> pathway in dorsal horn neurons regulates the development and maintenance of neuropathic pain, <jats:italic>ciRNA\u2010Kat6b<\/jats:italic> may be a potential new target for analgesic and treatment strategies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14235","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T09:54:29Z","timestamp":1683280469000},"page":"2955-2971","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Downregulation of <scp>ciRNA\u2010<\/scp><i>Kat6b<\/i> in dorsal spinal horn is required for neuropathic pain by regulating <i>Kcnk1<\/i> in <scp>miRNA<\/scp>\u201026a\u2010dependent manner"],"prefix":"10.1111","volume":"29","author":[{"given":"Ling","family":"Xie","sequence":"first","affiliation":[{"name":"Jiangsu Province Key Laboratory of Anesthesiology Xuzhou Medical University  Xuzhou China"},{"name":"Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology Xuzhou Medical University  Xuzhou China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs  Xuzhou China"},{"name":"Department of 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