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Opioid-Induced Regulation of Cortical Circular-Grin2b_011731 Is Associated with Regulation of circGrin2b Sponge

Aria Gillespie1, Stephanie E Daws1

  • 1Daws Laboratory, Center for Substance Abuse Research, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.

International Journal of Molecular Sciences
|June 13, 2025
PubMed

Insights

Opioid use upregulates circular RNA circGrin2b in the brain, potentially by downregulating Fused in Sarcoma. This circRNA interacts with miR-26b-3p, suggesting a new pathway in opioid addiction.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Opioid use alters brain neurobiology, particularly in regions like the orbitofrontal cortex (OFC), impacting decision-making and emotional regulation.
  • Circular RNA (circRNA) circGrin2b is upregulated in the OFC following chronic heroin self-administration (SA).
  • circGrin2b originates from Grin2b, which encodes the GluN2B subunit of NMDA receptors, but its regulatory mechanisms and downstream effects are unknown.

Purpose of the Study:

  • To investigate the upstream regulatory mechanisms of circGrin2b biogenesis in response to opioids.
  • To explore the downstream consequences of circGrin2b dysregulation, specifically its potential role as a microRNA (miRNA) sponge.
  • To examine the relationship between circGrin2b, its regulatory factors, and miRNA pathways in the context of opioid exposure.

Main Methods:

  • Established an in vitro primary cortical cell culture model to study circGrin2b expression after morphine exposure.
  • Measured mRNA expression of circRNA splicing factors, including Fused in Sarcoma (Fus).
  • Utilized luciferase reporter assays to confirm the interaction between circGrin2b and miR-26b-3p.

Main Results:

  • Morphine exposure led to the downregulation of Fus, a negative regulator of circRNA biogenesis.
  • Downregulation of Fus was associated with increased circGrin2b and decreased miR-26b-3p expression.
  • A significant negative correlation between circGrin2b and miR-26b-3p was observed in the OFC of rats after heroin SA.

Conclusions:

  • Opioid-induced regulation of circGrin2b represents a neuroadaptation in the brain.
  • circGrin2b may function as a miRNA sponge, impacting downstream miRNA signaling pathways.
  • These findings highlight a novel molecular mechanism potentially involved in opioid addiction.
Keywords:
circular RNAmicroRNAmorphineopioidssplicing

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