title: μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster.
abstract: Since their discovery, miRNAs have emerged as a promising therapeutical approach in the treatment of several diseases, as demonstrated by miR-212 and its relation to addiction. Here we prove that the miR-212/132 cluster can be regulated by morphine, through the activation of mu opioid receptor (Oprm1). The molecular pathways triggered after morphine administration also induce changes in the levels of expression of oprm1. In addition, miR-212/132 cluster is actively repressing the expression of mu opioid receptor by targeting a sequence in the 3' UTR of its mRNA. These findings suggest that this cluster is closely related to opioid signaling, and function as a post-transcriptional regulator, modulating morphine response in a dose dependent manner. The regulation of miR-212/132 cluster expression is mediated by MAP kinase pathway, CaMKII-CaMKIV and PKA, through the phosphorylation of CREB. Moreover, the regulation of both oprm1 and of the cluster promoter is mediated by MeCP2, acting as a transcriptional repressor on methylated DNA after prolonged morphine administration. This mechanism explains the molecular signaling triggered by morphine as well as the regulation of the expression of the mu opioid receptor mediated by morphine and the implication of miR-212/132 in these processes.
authors.affiliation: Institute of Neurosciences of Castilla y Leon (INCyL), C/Pintor Fernando Gallego, 1, 37007, Salamanca, Spain.|Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca-Edificio Virgen de la Vega. Décima Planta, P° de San Vicente 58-182, 37007, Salamanca, Spain.
authors.forename: Adrian
authors.initials: A
authors.lastname: Garcia-Concejo
authors.affiliation: Institute of Neurosciences of Castilla y Leon (INCyL), C/Pintor Fernando Gallego, 1, 37007, Salamanca, Spain.|Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca-Edificio Virgen de la Vega. Décima Planta, P° de San Vicente 58-182, 37007, Salamanca, Spain.
authors.forename: Ada
authors.initials: A
authors.lastname: Jimenez-Gonzalez
authors.affiliation: Institute of Neurosciences of Castilla y Leon (INCyL), C/Pintor Fernando Gallego, 1, 37007, Salamanca, Spain.|Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Salamanca, C/ Alfonso X El Sabio, 0 S-N Campus Miguel De Unamuno, 37007, Salamanca, Spain.|Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca-Edificio Virgen de la Vega. Décima Planta, P° de San Vicente 58-182, 37007, Salamanca, Spain.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Rodríguez
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020935:MAP Kinase Signaling System; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D005810:Multigene Family; D017450:Receptors, Opioid, mu / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D000701:Analgesics, Opioid; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; D017450:Receptors, Opioid, mu; D029961:Zebrafish Proteins; C000592936:mirn132 microRNA, zebrafish; C000609288:mirn212 microRNA, zebrafish; D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases