Epigenetic Mechanisms of Opioid Addiction

Abstract Opioid use kills tens of thousands of Americans each year, devastates families and entire communities, and cripples the healthcare 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 like cocaine, research into opioid-induced changes to the epigenetic landscape is beginning to emerge. This review summarizes our knowledge of opioid-induced epigenetic modifications and their consequential changes to gene expression. Current evidence points towards opioids promoting higher levels of permissive histone acetylation and lower levels of repressive histone methylation, as well as alterations to DNA methylation patterns and non-coding 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 next-generation sequencing approaches and chromatin purification techniques combined with bioinformatics analyses to identify novel gene networks regulated by particular epigenetic modifications. Improved translational relevance will also require increased focus on volitional drug-intake models and standardization of exposure paradigms. Such work will significantly advance our understanding of how opioids cause persistent changes to brain function, and provide a platform on which to develop interventions for treating opioid addiction.