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      Emerging roles of microRNAs in morphine tolerance

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          Abstract

          Morphine is commonly used in clinical management to alleviate moderate-to-severe pain. However, prolonged and repeated use of morphine leads to tolerance. Morphine tolerance is a challenging clinical problem that limits its clinical application in pain treatment. The mechanisms underlying morphine tolerance are still not completely understood. MicroRNAs (miRNAs) are small noncoding RNAs containing 18~22 nucleotides that modulate gene expression in a post-transcriptional manner, and their dysregulation causes various diseases. miRNAs bind to the 3ʹ-UTR (untranslated region) of target gene mRNA, inhibiting or destabilizing translation of the transcripts. Morphine causes differential miRNA upregulation or downregulation. This review will present evidence for the contribution of miRNAs to tolerance of the antinociception effect of opioids.

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          Most cited references 59

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          Crystal structure of the μ-opioid receptor bound to a morphinan antagonist

          Summary Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many of their undesirable side effects (sedation, apnea and dependence) by binding to and activating the G-protein-coupled μ-opioid receptor (μOR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the μOR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most GPCRs published to date, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the μOR crystallizes as a two-fold symmetric dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.
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            Identification and consequences of miRNA-target interactions--beyond repression of gene expression.

            Comparative genomics analyses and high-throughput experimental studies indicate that a microRNA (miRNA) binds to hundreds of sites across the transcriptome. Although the knockout of components of the miRNA biogenesis pathway has profound phenotypic consequences, most predicted miRNA targets undergo small changes at the mRNA and protein levels when the expression of the miRNA is perturbed. Alternatively, miRNAs can establish thresholds in and increase the coherence of the expression of their target genes, as well as reduce the cell-to-cell variability in target gene expression. Here, we review the recent progress in identifying miRNA targets and the emerging paradigms of how miRNAs shape the dynamics of target gene expression.
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              Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.

              Morphine is a powerful pain reliever, but also a potent inducer of tolerance and dependence. The development of opiate tolerance occurs on continued use of the drug such that the amount of drug required to elicit pain relief must be increased to compensate for diminished responsiveness. In many systems, decreased responsiveness to agonists has been correlated with the desensitization of G-protein-coupled receptors. In vitro evidence indicates that this process involves phosphorylation of G-protein-coupled receptors and subsequent binding of regulatory proteins called beta-arrestins. Using a knockout mouse lacking beta-arrestin-2 (beta arr2-/-), we have assessed the contribution of desensitization of the mu-opioid receptor to the development of morphine antinociceptive tolerance and the subsequent onset of physical dependence. Here we show that in mice lacking beta-arrestin-2, desensitization of the mu-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of beta-arrestin-2 does not prevent the chronic morphine-induced up-regulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                10 April 2019
                2019
                : 12
                : 1139-1147
                Affiliations
                [1 ]Department of Anesthesiology, Xiangya Hospital, Central South University , Changsha, Hunan 410008, People’s Republic of China
                Author notes
                Correspondence: Wangyuan ZouDepartment of Anesthesiology, Xiangya Hospital, Central South University , 87 Xiangya Road, Changsha, Hunan410008, People’s Republic of ChinaTel +8 67 318 432 7413Fax +8 67 318 432 7413Email wangyuanzou@ 123456csu.edu.cn
                Article
                187592
                10.2147/JPR.S187592
                6497837
                © 2019 Huang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 2, Tables: 1, References: 78, Pages: 9
                Categories
                Review

                Anesthesiology & Pain management

                camkii/nmdar, β-arrestin 2, mor, morphine tolerance, microrna

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