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mu-Opioid receptor agonists differentially regulate the expression of miR-190 and NeuroD

Hui Zheng1, Yan Zeng, Xiaoxiao Zhang

  • 1Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455-0217, USA. zhen0091@umn.edu

Molecular Pharmacology
|October 27, 2009
PubMed

Insights

Fentanyl and morphine, mu-opioid receptor (OPRM1) agonists, differentially regulate microRNAs (miRNAs) via distinct extracellular signal-regulated kinase (ERK) pathways. Fentanyl selectively down-regulates miR-190 through a beta-arrestin2-dependent ERK pathway.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Mu-opioid receptor (OPRM1) agonists like morphine and fentanyl activate extracellular signal-regulated kinase (ERK) via distinct signaling pathways.
  • Morphine utilizes the protein kinase C (PKC) pathway, while fentanyl acts through a beta-arrestin2-dependent mechanism.
  • These divergent pathways lead to differential cellular localization of phosphorylated ERK and distinct transcriptional factor activation.

Purpose of the Study:

  • To investigate the influence of morphine and fentanyl on microRNA (miRNA) expression through their respective OPRM1-mediated signaling pathways.
  • To identify specific miRNAs regulated by these distinct pathways and elucidate the underlying mechanisms.

Main Methods:

  • Primary cultures of rat hippocampal neurons and mouse hippocampi were treated with morphine or fentanyl for 3 days.
  • miRNA expression profiling was performed to identify differentially expressed miRNAs.
  • Specific inhibitors (U0126 for ERK phosphorylation, PKC inhibitor) and knockout models (beta-arrestin2(-/-) mice) were used to dissect the signaling pathways involved.

Main Results:

  • Seven miRNAs were identified as being regulated by either morphine, fentanyl, or both.
  • Fentanyl, but not morphine, significantly down-regulated miR-190 expression.
  • This fentanyl-induced miR-190 down-regulation was dependent on beta-arrestin2-mediated ERK phosphorylation and was not affected by PKC inhibition.
  • Expressional changes in a miR-190 target, neurogenic differentiation 1 (NeuroD), correlated with miR-190 levels.

Conclusions:

  • Agonist-selective ERK phosphorylation pathways downstream of OPRM1 differentially regulate miRNA expression.
  • Fentanyl's down-regulation of miR-190 is mediated by a beta-arrestin2-dependent ERK pathway, distinct from morphine's PKC-dependent pathway.
  • OPRM1 may regulate NeuroD pathways through the control of miR-190 expression, highlighting a novel mechanism of opioid action.

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