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Oxycodone self-administration induces microRNA and gene expression changes in the rat nucleus accumbens [miRNA-seq]

ABSTRACT: Prescription opioid abuse remains a critical public health concern and is a major risk factor for the development of opioid use disorder (OUD). Thus, there is an urgent need to better understand the neurobiological mechanisms underlying OUD in order to develop therapeutics and address the ongoing opioid epidemic. In this study, we hypothesized that microRNAs regulate gene expression changes following oxycodone self-administration. To test our hypothesis, we utilized a long-access drug self-administration paradigm in rats. Briefly, adult male Sprague-Dawley rats were trained to self-administer oxycodone (0.15mg/kg/infusion) or saline and were sacrificed 24h (withdrawal) following the last self-administration session. Brains were collected and the nucleus accumbens (NAc) was extracted and was processed for small RNA and RNA sequencing. We found that oxycodone self-administration changed the expression of 40 genes and 16 mature microRNAs (miRNAs). Bioinformatic predictions revealed that opioid-regulated genes are predicted targets of differentially regulated miRNAs, suggesting that miRNAs contribute to opioid-mediated transcriptomic changes in the NAc. Furthermore, we validated some of these findings in an independent cohort of male and female rats and across different stages of the addiction cycle. We identified miRNAs that are dynamically regulated during oxycodone withdrawal, as well as others that exhibit sustained regulation across different stages of the addiction cycle. Taken together, our data show that miRNAs may contribute to opioid-regulated gene expression and point to the therapeutic potential of miRNAs for OUD.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE337891 | GEO | 2026/09/30

REPOSITORIES: GEO

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Project description:The number of individuals diagnosed with opioid use disorder (OUD) has risen steeply because of the increased prescribing of opioid drugs like oxycodone for chronic pain relief. OUD is characterized by loss of control of drug taking, continued drug use in the presence of adverse consequences, and repeated relapses to drug taking. Repeated exposure to oxycodone self-administration can lead to addiction in certain rats while others remain unaffected. Understanding the molecular mechanisms between these two groups holds promise for developing strategies to combat addiction. To identify signaling pathways associated with oxycodone addition, this study used male Sprague-Dawley rats to self-administer oxycodone for 20 days according to short-(ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized after 2 hours of self-administration cessation and their dorsal striata were used for RNA sequencing analysis. LgA rats escalated their oxycodone intake and developed into 2 phenotypes, named long-access high (LgA-H, addicted) and long-access lower (LgA-L, non-addicted) rats, based on the level of escalation and drug taken during the self-administration experiment. RNA sequencing revealed many differentially expressed genes in the oxycodone-addicted rats in comparison to other groups. DAVID analysis indicated that some of these genes were involved in potassium transport, ATP binding, and regulation of synaptic processes. Ingenuity pathway analysis (IPA) revealed previous involvement of some genes in OUD and cognitive processes. RNA sequencing and RT-PCR analysis of dorsal striatum samples unveiled a significant upregulation of potassium channel genes Kcnma1, Kcnk9, Kcnq1, Kcnd3, and Kcng3 in LgA-H rats, which was corelated with oxycodone intake. We also identified increased expression for Cldn3, Serping1, and Serpinh1 in ShA rats. Taken together, these observations identified potassium channels as potential targets for the treatment of oxycodone use disorder.

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Oxycodone self-administration induces microRNA and gene expression changes in the rat nucleus accumbens [miRNA-seq]

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