μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster
Adrian Garcia-Concejo1,2, Ada Jimenez-Gonzalez1,2, Raquel E Rodríguez1,3,2
1Institute of Neurosciences of Castilla y Leon (INCyL), C/Pintor Fernando Gallego, 1, 37007, Salamanca, Spain.
Abstract:
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.
Insights
Morphine regulates the miR-212/132 cluster, which in turn controls mu opioid receptor (Oprm1) expression. This feedback loop impacts opioid signaling and morphine response.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- MicroRNAs (miRNAs) are implicated in various diseases, with miR-212 showing relevance to addiction.
- Opioid receptors, particularly the mu opioid receptor (Oprm1), are central to opioid signaling and addiction.
Purpose of the Study:
- To investigate the regulatory relationship between the miR-212/132 cluster and morphine, specifically its effect on Oprm1 expression.
- To elucidate the molecular pathways involved in morphine-induced regulation of miR-212/132 and Oprm1.
Main Methods:
- Investigated the effect of morphine on miR-212/132 cluster expression via Oprm1 activation.
- Analyzed the post-transcriptional regulation of Oprm1 mRNA by the miR-212/132 cluster.
- Examined signaling pathways including MAP kinase, CaMKII-CaMKIV, PKA, CREB phosphorylation, and MeCP2 involvement.
Main Results:
- Morphine administration regulates the miR-212/132 cluster through Oprm1 activation.
- The miR-212/132 cluster represses Oprm1 expression by targeting its 3' UTR.
- Morphine-induced signaling pathways, including MeCP2, modulate both Oprm1 and miR-212/132 expression.
Conclusions:
- The miR-212/132 cluster acts as a post-transcriptional regulator of opioid signaling, modulating morphine response.
- A feedback mechanism exists where morphine influences miR-212/132, which then regulates Oprm1 levels.
- These findings provide molecular insights into morphine's effects and the role of miRNAs in opioid addiction.
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