MicroRNA-mRNA networks are dysregulated in opioid use disorder postmortem brain: Further evidence for opioid-induced neurovascular alterations.

Introduction: To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function.
Methods: Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues.
Results: miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways overlapped strongly. Among the dominant enriched biological processes were tissue development and morphogenesis, and MAPK signaling pathways. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with a potential functional impact on transcriptomic changes. Further, using correlation network analysis, we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified a correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system, and inflammatory pathways.
Discussion: These findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse and shed new light on miRNA network regulators of cellular response to opioid drugs.
Competing Interests: SS received research support from Flow Neuroscience and contributes as a study investigator for clinical trials by Compass pathways, Relmada, Liva Nova, and Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Grimm, Mendez, Stertz, Meyer, Fries, Gandhi, Kanchi, Selvaraj, Teixeira, Kosten, Gunaratne, Coarfa and Walss-Bass.)