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 nextgeneration 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.

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

“…Because of the many shared pathways across brain regions in OUD, we comprehensively mapped the extent of transcriptional overlap between the DLPFC and NAc. Such analyses may provide critical insight into the functional alterations across DLPFC-NAc circuits (3,11,(66)(67)(68)(69). To investigate overlap of alterations between regions, we used Rank-Rank Hypergeometric Overlap (RRHO) analysis (70,71).…”

“…Further investigation into these overlapping transcripts revealed pathways enriched for factors that control the formation and degradation of the extracellular matrix (ECM) and pro-inflammatory cytokine-mediated signaling. These pathways implicate neuroinflammation as a driver of ECM remodeling and synaptic reorganization, processes which are critical for opioid-induced neuroplasticity (11).…”

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

“…Immediate effects of opioids result in decreased levels of consciousness, sedation (Collett 1998 ; Thompson 2000 ; Indelicato and Portenoy 2002 ), drowsiness, and sleep disturbances (Moore and Dimsdale 2002 ; Bourne and Mills 2004 ; Qureshi and Lee-Chiong 2004 ). While acute opioid exposure can impair cognition in healthy subjects (Lawlor 2002 ; Ersek et al 2004 ), enduring cognitive and psychomotor deficits occur with chronic opioid use (Sjogren et al 2000 ; Dublin et al 2015 ; Roberts et al 2018 ; Wollman et al 2019 ; Serafini et al 2020 ), including altered pain perception (opioid-induced hyperalgesia), dysregulated reward/saliency processing, hyperkatifeia, and epigenetic changes, which can persist years following abstinence (Ersche et al 2006 ; Browne et al 2020 ). The behavioral changes seen with long-term opioid use are accompanied by lasting structural and epigenetic (e.g., altered DNA methylation and expression of non-coding RNAs) alterations in brain regions implicated in mood, reward, and motivation (Upadhyay et al 2010 ; Dublin et al 2015 ; Volkow and Morales 2015 ; Koob and Volkow 2016 ; Serafini et al 2020 ).…”

Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter

“…Following the initial exposure, the addictive substance continues to have a persistent effect, and this suggests a form of cellular memory. There is strong evidence that epigenetic processes, including DNA methylation, play a key role in maintaining the long-term effects of the additive substance [16,17]. Studies particularly in model organisms have shown that drugs of abuse trigger intracellular signaling cascades that alter gene transcription, repeated exposure to the drug then results in remodeling of the epigenome that persists over time, and these epigenetic processes maintain the long-term changes in steadystate gene expression that underlie addiction [16,[18][19][20].…”