MicroRNA-mediated translational pathways are regulated in the orbitofrontal cortex and peripheral blood samples
Mary Tresa Zanda1,2, Leila Saikali1,3, Paige Morris1,2
1Center for Substance Abuse Research, Temple University, Philadelphia, PA, United States.
Abstract:
Opioid misuse in the United States contributes to >70% of annual overdose deaths. To develop additional therapeutics that may prevent opioid misuse, further studies on the neurobiological consequences of opioid exposure are needed. Here we sought to characterize molecular neuroadaptations involving microRNA (miRNA) pathways in the brain and blood of adult male rats that self-administered the opioid heroin. miRNAs are ∼18-24 nucleotide RNAs that regulate protein expression by preventing mRNA translation into proteins. Manipulation of miRNAs and their downstream pathways can critically regulate drug seeking behavior. We performed small-RNA sequencing of miRNAs and proteomics profiling on tissue from the orbitofrontal cortex (OFC), a brain region associated with heroin seeking, following 2 days of forced abstinence from self-administration of 0.03 mg/kg/infusion heroin or sucrose. Heroin self-administration resulted in a robust shift of the OFC miRNA profile, regulating 77 miRNAs, while sucrose self-administration only regulated 9 miRNAs that did not overlap with the heroin-induced profile. Conversely, proteomics revealed dual regulation of seven proteins by both heroin and sucrose in the OFC. Pathway analysis determined that heroin-associated miRNA pathways are predicted to target genes associated with the term "prion disease," a term that was also enriched in the heroin-induced protein expression dataset. Lastly, we confirmed that a subset of heroin-induced miRNA expression changes in the OFC are regulated in peripheral serum and correlate with heroin infusions. These findings demonstrate that peripheral blood samples may have biomarker utility for assessment of drug-induced miRNA pathway alterations that occur in the brain following chronic drug exposure.
Insights
Opioid misuse impacts over 70% of overdose deaths. This study reveals how heroin alters microRNA (miRNA) pathways in the brain and blood, offering potential for new therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Opioid misuse is a critical public health issue in the US, causing a majority of overdose fatalities.
- Understanding the neurobiological effects of opioid exposure is vital for developing effective therapeutics to prevent misuse.
- MicroRNAs (miRNAs) are key regulators of gene expression, influencing various biological processes, including drug-seeking behaviors.
Purpose of the Study:
- To investigate molecular neuroadaptations, specifically microRNA (miRNA) pathway changes, in the brain and blood of rats following heroin self-administration.
- To characterize the impact of heroin on miRNA and protein expression in the orbitofrontal cortex (OFC), a region implicated in drug seeking.
Main Methods:
- Adult male rats self-administered heroin or sucrose.
- Small-RNA sequencing and proteomics profiling were performed on orbitofrontal cortex (OFC) tissue after 2 days of abstinence.
- miRNA and protein expression changes were analyzed and correlated with heroin infusions.
Main Results:
- Heroin self-administration significantly altered the OFC miRNA profile, affecting 77 miRNAs, distinct from sucrose effects.
- Proteomics revealed dual regulation of seven proteins by both heroin and sucrose.
- Pathway analysis indicated that heroin-associated miRNA targets are linked to "prion disease," also enriched in protein expression data.
- A subset of brain miRNA changes was detected in peripheral serum, correlating with heroin intake.
Conclusions:
- Heroin self-administration induces significant, specific miRNA pathway alterations in the OFC.
- Peripheral serum miRNA changes may serve as biomarkers for brain-based alterations following chronic drug exposure.
- These findings highlight the potential of targeting miRNA pathways for novel opioid misuse therapeutics.
