Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Int J Mol Sci. 2022 Jan 27;23(3):1453. doi: 10.3390/ijms23031453.
The number of drug overdose deaths involving opioids continues to rise in the United States. Many patients with opioid use disorder (OUD) that seek treatment still experience relapse. Perseverant opioid seeking behaviors represent a major challenge to treating OUD and additional therapeutic development will require insight into opioid-induced neurobiological adaptations. In this study, we explored the regulation of a novel class of RNAs, circular RNAs (circRNAs), by the addictive opioid heroin in the rat orbitofrontal cortex (OFC), a brain region that mediates behavioral responses to rewarding stimuli. Microarray analysis identified 76 OFC circRNAs significantly regulated in male rats after heroin self-administration. We evaluated the specificity of these findings by measuring heroin-associated circRNA expression in female rats after heroin self-administration and in rats that self-administered sucrose. We identify circGrin2b, circUbe2cp, circAnks1a, circAdcy5 and circSlc24A2 as heroin-responsive circRNAs in the OFC. Linear mRNA levels of heroin-associated circRNAs were unchanged except for and . An integrated bioinformatics analysis of regulated circRNAs identified microRNAs predicted to bind heroin-associated circRNAs and downstream targets of circRNA: microRNA sponging. Thus, heroin regulates the expression of OFC RNA splice variants that circularize and may impact cellular processes that contribute to the neurobiological adaptations that arise from chronic heroin exposure.
在美国，涉及阿片类药物的药物过量死亡人数继续上升。许多患有阿片类药物使用障碍（OUD）并寻求治疗的患者仍会复发。坚持使用阿片类药物的行为对治疗 OUD 构成了重大挑战，需要深入了解阿片类药物引起的神经生物学适应。在这项研究中，我们探索了新型 RNA 即环状 RNA（circRNA）在大鼠眶额皮质（OFC）中的调节作用，该脑区介导对奖赏刺激的行为反应。微阵列分析鉴定了 76 种 OFC circRNA 在雄性大鼠海洛因自我给药后显著调节。我们通过测量雌性大鼠在海洛因自我给药后和大鼠在自我给药蔗糖后与海洛因相关的 circRNA 表达，评估了这些发现的特异性。我们确定 circGrin2b、circUbe2cp、circAnks1a、circAdcy5 和 circSlc24A2 是 OFC 中海洛因反应性 circRNA。除了 和 外，与海洛因相关的 circRNA 的线性 mRNA 水平没有变化。受调控 circRNA 的综合生物信息学分析确定了预测与与海洛因相关的 circRNA 结合的 microRNA 和 circRNA 下游靶标：microRNA 海绵。因此，海洛因调节 OFC RNA 剪接变体的表达，这些剪接变体可能会影响导致慢性海洛因暴露产生的神经生物学适应的细胞过程。
