μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster

• Published in: PloS one Vol. 11; no. 7; p. e0157806
• Main Authors: Garcia-Concejo, Adrian, Jimenez-Gonzalez, Ada, Rodríguez, Raquel E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.07.2016; Public Library of Science (PLoS)
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; Addictions; Alzheimer's disease; Alzheimers disease; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacology; Animals; Biology and life sciences; Biomedical research; Ca2+/calmodulin-dependent protein kinase II; Ca2+/calmodulin-dependent protein kinase IV; Cells, Cultured; Clusters; Cocaine; Cyclic AMP response element-binding protein; Cyclic AMP-Dependent Protein Kinases - metabolism; Deoxyribonucleic acid; DNA; Embryos; Experiments; Gene expression; Gene Expression Regulation, Developmental - drug effects; Gene Knockdown Techniques; Hospitals; Immunohistochemistry; In Situ Hybridization; Kinases; Laboratory animals; MAP kinase; MAP Kinase Signaling System; MeCP2 protein; Medical research; Medical treatment; Medicine and Health Sciences; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - metabolism; MicroRNAs; MicroRNAs - genetics; Morphine; Morphine - administration & dosage; Morphine - pharmacology; Multigene Family; Narcotics; Neurosciences; Opioid receptors (type mu); Phosphorylation; Post-transcription; Protein kinase A; Proteins; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; Research and Analysis Methods; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Signal transduction; Signaling; Time Factors; Zebrafish; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; United States > US; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0157806

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.