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

Abstract

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. 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. miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways were highly overlapping, with tube development and morphogenesis, and pathways related to endothelial cell function and vascular organization, among the dominant enriched biological processes. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with 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. Our refined miRNA-mRNA networks enabled identification of novel pharmaco-chemical interventions for OUD, particularly targeting the TGF beta-p38MAPK signaling pathway. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system and inflammatory pathways. These findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse.

Epigenetic regulation in opioid induced hyperalgesia

“…The discovery of ncRNAs has revolutionized our understanding of regulation of gene expression and opened new avenues for therapeutic intervention ( Kopp & Mendell, 2018 ). Many diseases, including cancer and neurological disorders, have been linked to dysregulation of ncRNA expression or function ( Grimm et al, 2022 , Yao et al, 2019 ). Though research on ncRNAs could be used to develop new diagnostic and therapeutic strategies, this avenue remains mostly unexplored regarding underlying factors that drive OIH.…”

“…Further, a study on postmortem brain and blood tissue from people with OUD revealed miRNA alterations associated with changes in endothelial cell function and tube development. Notably, miR-92a-3p was upregulated and miR-29a downregulated in the brain, both acting via the p38 MAPK signaling pathway ( Grimm et al, 2022 ). p38 MAPK has been highly correlated with various pain states ( Anand et al, 2011 , Crown et al, 2008 , Mai et al, 2020 ), so it is possible that differential expression of p38 MAPK associated miRNAs after prolonged opioid usage could potentiate pain and lead to OIH.…”

MicroRNA-mediated translational pathways are regulated in the orbitofrontal cortex and peripheral blood samples during acute abstinence from heroin self-administration

“…Only one such study has been performed with human samples, and this is likely due to the challenges of collecting blood and postmortem samples in a timely manner. Grimm et al reported the correspondence of frontal cortex brain and blood miRNA levels in postmortem human samples from OUD subjects and observed a large overlap in miRNA expression [65]. Of the miRNA profile measured in the BA9 region, the authors observed differential expression of hsa-miR-10b-5p, hsa-miR-337-3p, has-miR-340-5, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-379-5p, hsa-miR-486-3p, hsa-miR-495-3p, and hsa-miR-758-3p [65], which were all dysregulated in the OFC of heroin-exposed rats in the current study.…”

“…Grimm et al reported the correspondence of frontal cortex brain and blood miRNA levels in postmortem human samples from OUD subjects and observed a large overlap in miRNA expression [65]. Of the miRNA profile measured in the BA9 region, the authors observed differential expression of hsa-miR-10b-5p, hsa-miR-337-3p, has-miR-340-5, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-379-5p, hsa-miR-486-3p, hsa-miR-495-3p, and hsa-miR-758-3p [65], which were all dysregulated in the OFC of heroin-exposed rats in the current study. Investigation into the relationship between drug exposure and regulation of brain miRNAs that can also be detected in the periphery can be accomplished easily with rodent models of self-administration but has yet to be done.…”

Circadian rhythm disruptions associated with opioid use disorder in the synaptic proteomes of the human dorsolateral prefrontal cortex and nucleus accumbens

“…The dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc) are key brain regions involved in cognitive, mood, and reward alterations in OUD [9][10][11]. Recent human postmortem brain studies from us [2,3] and others [4,6,12,13] reported a potential interplay between proinflammatory and synaptic remodeling in DLPFC and NAc in OUD. Moreover, we recently implicated circadian rhythm regulation of neuroinflammatory, neurovascular, and neurotransmission (e.g., dopaminergic, GABAergic, and opioidergic signaling) in DLPFC and NAc of OUD subjects [2,3].…”