RT Journal Article
SR Electronic
T1 Morphine Regulates Dopaminergic Neuron Differentiation via miR-133b
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 935
OP 942
DO 10.1124/mol.110.066837
VO 78
IS 5
A1 Fatima Macho Sanchez-Simon
A1 Xiao Xiao Zhang
A1 Horace H. Loh
A1 Ping-Yee Law
A1 Raquel E. Rodriguez
YR 2010
UL http://molpharm.aspetjournals.org/content/78/5/935.abstract
AB 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.