title: miR-365 targets β-arrestin 2 to reverse morphine tolerance in rats.
abstract: Morphine tolerance is a challenging clinical problem that limits its clinical application in pain treatment. Non-coding microRNAs (miRNAs) modulate gene expression in a post transcriptional manner, and their dysregulation causes various diseases. However, the significance of miRNAs in morphine tolerance is still poorly understood. In the present study, we hypothesized that microRNA-365 (miR-365) is a key functional small RNA that reverses morphine tolerance through regulation of β-arrestin 2 in rats. Here, microarray analysis and quantitative real-time PCR showed that miR-365 was robustly decreased in the spinal cord after chronic morphine administration. In situ hybridization and immunochemistry double staining showed that miR-365 was expressed in neurons of the spinal cord. We identified β-arrestin 2 as the target gene of miR-365 by bioinformatics analysis and luciferase reporter assay. The data showed that overexpression of miR-365 prevented and reversed established morphine tolerance, and increased expression of miR-365 caused a decrease in expression of β-arrestin 2 protein. miR-365 downregulation is involved in the development and maintenance of morphine tolerance through regulation of β-arrestin 2, and miR-365 upregulation provides a promising and novel approach for treatment of morphine tolerance.
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhong
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Zongbin
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Zhuofeng
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Qulian
authors.initials: Q
authors.lastname: Guo
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Wangyuan
authors.initials: W
authors.lastname: Zou
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002408:Catheters, Indwelling; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000235:genetics*; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D007278:Injections, Spinal; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D009020:Morphine / Q000494:pharmacology*; D010146:Pain / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000071560:beta-Arrestin 2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; C000605257:Arrb2 protein, rat; C000597594:MIRN365 microRNA, rat; D035683:MicroRNAs; D000071560:beta-Arrestin 2; D009020:Morphine