title: Epigenetic modification of spinal miR-219 expression regulates chronic inflammation pain by targeting CaMKIIγ.
abstract: Emerging evidence has shown that miRNA-mediated gene expression modulation contributes to chronic pain, but its functional regulatory mechanism remains unknown. Here, we found that complete Freund's adjuvant (CFA)-induced chronic inflammation pain significantly reduced miRNA-219 (miR-219) expression in mice spinal neurons. Furthermore, the expression of spinal CaMKIIγ, an experimentally validated target of miR-219, was increased in CFA mice. Overexpression of spinal miR-219 prevented and reversed thermal hyperalgesia and mechanical allodynia and spinal neuronal sensitization induced by CFA. Concurrently, increased expression of spinal CaMKIIγ was reversed by miR-219 overexpression. Downregulation of spinal miR-219 in naive mice induced pain-responsive behaviors and increased p-NMDAR1 expression, which could be inhibited by knockdown of CaMKIIγ. Bisulfite sequencing showed that CFA induced the hypermethylation of CpG islands in the miR-219 promoter. Treatment with demethylation agent 5'-aza-2'-deoxycytidine markedly attenuated pain behavior and spinal neuronal sensitization, which was accompanied with the increase of spinal miR-219 and decrease of CaMKIIγ expression. Together, we conclude that methylation-mediated epigenetic modification of spinal miR-219 expression regulates chronic inflammatory pain by targeting CaMKIIγ.
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Li-Jiao
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Yan-Qiang
authors.initials: YQ
authors.lastname: Li
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Hao
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Cui
authors.initials: C
authors.lastname: Yin
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Yang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Yubai
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Lu
authors.initials: L
authors.lastname: Hua
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Zhou-Ya
authors.initials: ZY
authors.lastname: Xue
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, XuZhou 221002, China caojl03100@yahoo.com.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D059350:Chronic Pain / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D005620:Freund's Adjuvant / Q000009:adverse effects; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D010147:Pain Measurement; D034741:RNA, Small Interfering / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic
chemical_list: C578248:MIRN219 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D005620:Freund's Adjuvant; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKIIγ; epigenetics; microRNA; pain; spinal cord