Morphine regulates dopaminergic neuron differentiation via miR-133b

Fatima Macho Sanchez-Simon, Xiao Xiao Zhang, Horace H Loh, Ping-Yee Law, Raquel E. Rodriguez

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)935-942
Number of pages8
JournalMolecular Pharmacology
Issue number5
StatePublished - Nov 2010


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