Morphine regulates dopaminergic neuron differentiation via miR-133b.
Morphine is one of the analgesics used most to treat chronic pain, although its long-term administration produces tolerance and dependence through neuronal plasticity. The ability of morphine to regulate neuron differentiation in vivo has been reported. However, the detailed mechanisms have not yet been elucidated because of the inability to separate maternal influences from embryonic events. Using zebrafish embryos as the model, we demonstrate that morphine decreases miR-133b expression, hence increasing the expression of its target, Pitx3, a transcription factor that activates tyrosine hydroxylase and dopamine transporter. Using a specific morpholino to knock down the zebrafish μ-opioid receptor (zfMOR) in the embryos and selective mitogen-activated protein kinase inhibitors, we demonstrate that the morphine-induced miR-133b decrease in zebrafish embryos is mediated by zfMOR activation of extracellular signal-regulated kinase 1/2. A parallel morphine-induced down-regulation of miR-133b was observed in the immature but not in mature rat hippocampal neurons. Our results indicate for the first time that zebrafish embryos express a functional μ-opioid receptor and that zebrafish serves as an excellent model to investigate the roles of microRNA in neuronal development affected by long-term morphine exposure.
Sanchez-Simon
Fatima Macho
FM
Department of Biochemistry and Molecular Biology, Institute of Neuroscience, University of Salamanca, Salamanca, Spain.
Zhang
Xiao Xiao
XX
Loh
Horace H
HH
Law
Ping-Yee
PY
Rodriguez
Raquel E
RE
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D015027:Zebrafish
D000701:Analgesics, Opioid; C549446:MIRN133 microRNA, rat; C553925:MIRN133 microRNA, zebrafish; D035683:MicroRNAs; D017450:Receptors, Opioid, mu; D009020:Morphine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004298:Dopamine