Morphine Regulates Dopaminergic Neuron Differentiation via miR-133b

Abstract

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 -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 -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.

Expression of tachykinin receptors (tacr1a and tacr1b) in zebrafish: influence of cocaine and opioid receptors

“…In this study, the knockdown of ZfDOR2 and ZfMOR regulated the expression of tacr1a and tacr1b respectively, indicating that tachykinin and the opioid systems are closely interrelated in zebrafish, as has been described in mammals (Minami et al 1995, Pfeiffer et al 2003, Guan et al 2005, Yu et al 2009). As the set of MOs of opioid receptors was effective, as previously demonstrated by Sanchez-Simon et al (2010), and replicated in our study, we are convinced that the changes on the expression of the TACRs are a consequence of the downregulation of the opioid receptors. As we are studying the changes of gene expression in vivo whole-mount zebrafish embryos, it is difficult to know whether the effects that we observe are specifically produced by opioid receptors as other genes or elements can also regulate both the opioid and the tachykinin system.…”

Do Opioids Activate Latent HIV-1 by Down-Regulating Anti-HIV microRNAs?

“…Increasing evidence suggests that morphine treatment can modulate the expression of various miRNAs (Wu et al 2009;Dave and Khalili 2010;Sanchez-Simon et al 2010). Since morphine down regulates the expression of anti-HIV miRNAs in monocytes in vitro and heroin addicts have lower levels of these miRNAs in PBMCs (Wang et al 2011), and down-regulation of these miRNAs can promote replication of latent HIV-1 in resting CD4+ T cells (Huang et al 2007) and in monocytes (Wang et al 2009) …”

Morphine Regulates Expression ofμ-Opioid Receptor MOR-1A, an Intron-Retention Carboxyl Terminal Splice Variant of theμ-Opioid Receptor (OPRM1) Gene via miR-103/miR-107

“…Mu opioids such as morphine modulate expression of a number of miRNAs (Sanchez-Simon et al, 2010;Zheng et al, 2010;Wu et al, 2008Wu et al, , 2013Dave and Khalili, 2010;He et al, 2010;Wang et al, 2011), and several miRNAs regulate MOR-1 expression (Wu et al, 2008(Wu et al, , 2009He et al, 2010). Dysregulation of miRNAs has been linked to morphine tolerance and addiction Dreyer, 2010;Hwang et al, 2012;Tapocik et al, 2013).…”