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      The Regulatory Mechanisms and Therapeutic Potential of MicroRNAs: From Chronic Pain to Morphine Tolerance

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          Abstract

          Chronic pain, including cancer-related pain, is a pain condition often caused by inflammation or dysfunctional nerves. Chronic pain treatment poses a significant health care challenge, where opioids especially morphine are widely used and patients often develop tolerance over time with aggravated pain. microRNA (miRNA) is known to play important roles in regulating gene expressions in the nervous system to affect neuronal network plasticity related to algogenesis and the developing of morphine tolerance. In this article, we reviewed studies conducted in rodent animal models investigating the mechanisms of miRNAs regulation in chronic pain with different phenotypes and morphine tolerance. In addition, the potential of targeting miRNAs for chronic pain and morphine tolerance treatment is also reviewed. Finally, we point out the directions of the future research in chronic pain and morphine tolerance.

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          Most cited references 126

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          Most mammalian mRNAs are conserved targets of microRNAs.

          MicroRNAs (miRNAs) are small endogenous RNAs that pair to sites in mRNAs to direct post-transcriptional repression. Many sites that match the miRNA seed (nucleotides 2-7), particularly those in 3' untranslated regions (3'UTRs), are preferentially conserved. Here, we overhauled our tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3'UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites. The new tool more efficiently incorporates new genomes and more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs. The improved background model enabled preferential conservation of a new site type, the "offset 6mer," to be detected. In total, >45,000 miRNA target sites within human 3'UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved miRNAs, even when considering only more recently emerged targets. Although pairing to the 3' end of miRNAs can compensate for seed mismatches, this class of sites constitutes less than 2% of all preferentially conserved sites detected. The new tool enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (P(CT)) correlating with experimental measurements of repression. Our expanded set of target predictions (including conserved 3'-compensatory sites), are available at the TargetScan website, which displays the P(CT) for each site and each predicted target.
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            Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment.

            This large scale computer-assisted telephone survey was undertaken to explore the prevalence, severity, treatment and impact of chronic pain in 15 European countries and Israel. Screening interviews identified respondents aged 18 years with chronic pain for in-depth interviews. 19% of 46,394 respondents willing to participate (refusal rate 46%) had suffered pain for 6 months, had experienced pain in the last month and several times during the last week. Their pain intensity was 5 on a 10-point Numeric Rating Scale (NRS) (1 = no pain, 10 = worst pain imaginable) during last episode of pain. In-depth interviews with 4839 respondents with chronic pain (about 300 per country) showed: 66% had moderate pain (NRS = 5-7), 34% had severe pain (NRS = 8-10), 46% had constant pain, 54% had intermittent pain. 59% had suffered with pain for two to 15 years, 21% had been diagnosed with depression because of their pain, 61% were less able or unable to work outside the home, 19% had lost their job and 13% had changed jobs because of their pain. 60% visited their doctor about their pain 2-9 times in the last six months. Only 2% were currently treated by a pain management specialist. One-third of the chronic pain sufferers were currently not being treated. Two-thirds used non-medication treatments, e.g,. massage (30%), physical therapy (21%), acupuncture (13%). Almost half were taking non-prescription analgesics; 'over the counter' (OTC) NSAIDs (55%), paracetamol (43%), weak opioids (13%). Two-thirds were taking prescription medicines: NSAIDs (44%), weak opioids (23%), paracetamol (18%), COX-2 inhibitors (1-36%), and strong opioids (5%). Forty percent had inadequate management of their pain. Interesting differences between countries were observed, possibly reflecting differences in cultural background and local traditions in managing chronic pain. Chronic pain of moderate to severe intensity occurs in 19% of adult Europeans, seriously affecting the quality of their social and working lives. Very few were managed by pain specialists and nearly half received inadequate pain management. Although differences were observed between the 16 countries, we have documented that chronic pain is a major health care problem in Europe that needs to be taken more seriously.
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              Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs.

              MicroRNAs (miRNAs) are initially expressed as long transcripts that are processed in the nucleus to yield approximately 65-nucleotide (nt) RNA hairpin intermediates, termed pre-miRNAs, that are exported to the cytoplasm for additional processing to yield mature, approximately 22-nt miRNAs. Here, we demonstrate that human pre-miRNA nuclear export, and miRNA function, are dependent on Exportin-5. Exportin-5 can bind pre-miRNAs specifically in vitro, but only in the presence of the Ran-GTP cofactor. Short hairpin RNAs, artificial pre-miRNA analogs used to express small interfering RNAs, also depend on Exportin-5 for nuclear export. Together, these findings define an additional cellular cofactor required for miRNA biogenesis and function.
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                Author and article information

                Contributors
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                16 March 2018
                2018
                : 11
                Affiliations
                1Department of Anesthesiology, The Affiliated Hospital of Qingdao University , Qingdao, China
                2Department of Anesthesiology, The Affiliated Yantai Yuhuangding Hospital, Qingdao University , Qingdao, China
                Author notes

                Edited by: Guilherme Lucas, University of São Paulo, Brazil

                Reviewed by: Clive R. Bramham, University of Bergen, Norway; Vinod Tiwari, Johns Hopkins University, United States

                *Correspondence: Yongxin Liang liangzi66@ 123456hotmail.com
                Article
                10.3389/fnmol.2018.00080
                5864932
                Copyright © 2018 Dai, Chu, Ma, Yan, Zhang and Liang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 127, Pages: 15, Words: 11977
                Categories
                Neuroscience
                Review

                Neurosciences

                bone cancer pain, microrna, microglia, morphine tolerance, chronic pain

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