Epigenetic Mechanisms of Opioid Addiction

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.