Opioid use kills tens of thousands of Americans each year, devastates families and entire communities, and cripples the health care system. Exposure to opioids causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug seeking and drug taking that can remain a lifelong struggle. The persistence of these neuroadaptations is mediated in part by epigenetic remodeling of gene expression programs in discrete brain regions. Although the majority of work examining how epigenetic modifications contribute to addiction has focused on psychostimulants such as cocaine, research into opioid-induced changes to the epigenetic landscape is emerging. This review summarizes our knowledge of opioid-induced epigenetic modifications and their consequential changes to gene expression. Current evidence points toward opioids promoting higher levels of permissive histone acetylation and lower levels of repressive histone methylation as well as alterations to DNA methylation patterns and noncoding RNA expression throughout the brain's reward circuitry. Additionally, studies manipulating epigenetic enzymes in specific brain regions are beginning to build causal links between these epigenetic modifications and changes in addiction-related behavior. Moving forward, studies must leverage advanced chromatin analysis and next-generation sequencing approaches combined with bioinformatics pipelines to identify novel gene networks regulated by particular epigenetic modifications. Improved translational relevance also requires increased focus on volitional drug-intake models and standardization of opioid exposure paradigms. Such work will significantly advance our understanding of how opioids cause persistent changes to brain function and will provide a platform on which to develop interventions for treating opioid addiction.

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阿片类药物成瘾的表观遗传机制

阿片类药物的使用每年导致数以万计的美国人死亡，摧毁家庭和整个社区，并使医疗保健系统瘫痪。暴露于阿片类药物会导致参与奖励处理和动机的大脑区域发生长期变化，导致脆弱的个体从事病理性的药物寻求和吸毒，这可能是一生的斗争。这些神经适应的持续存在部分是由离散大脑区域中基因表达程序的表观遗传重塑介导的。尽管研究表观遗传修饰如何导致成瘾的大部分工作都集中在可卡因等精神兴奋剂上，但对阿片类药物引起的表观遗传变化的研究正在兴起。本综述总结了我们对阿片类药物诱导的表观遗传修饰及其对基因表达的相应变化的了解。目前的证据表明，阿片类药物会促进较高水平的组蛋白乙酰化和较低水平的抑制性组蛋白甲基化，以及整个大脑奖励回路中 DNA 甲基化模式和非编码 RNA 表达的改变。此外，在特定大脑区域操纵表观遗传酶的研究开始在这些表观遗传修饰与成瘾相关行为的变化之间建立因果关系。展望未来，研究必须利用先进的染色质分析和下一代测序方法，结合生物信息学管道来识别受特定表观遗传修饰调控的新基因网络。提高转化相关性还需要更加关注自愿药物摄入模型和阿片类药物暴露范式的标准化。这些工作将极大地促进我们对阿片类药物如何导致大脑功能持续变化的理解，并将提供一个平台，在此平台上开发治疗阿片类药物成瘾的干预措施。