Epigenetic Mechanisms of Opioid Addiction

doi:10.1016/j.biopsych.2019.06.027

Biological Psychiatry

Volume 87, Issue 1, 1 January 2020, Pages 22-33

https://doi.org/10.1016/j.biopsych.2019.06.027 Get rights and content

Abstract

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.

Section snippets

Histone Modifications

Gene expression depends on the ability of transcriptional machinery to access DNA, which is tightly packed into chromatin. To condense genetic material, DNA strands are wound around protein octamer spools known as histones. Histones are formed from combinations of 4 proteins: H2A, H2B, H3, and H4 32, 33. The N-terminal tails of these proteins undergo extensive covalent modifications that either loosen or tighten the histone’s grip on DNA. Such epigenetic modifications are the most studied in

Role of Epigenetic and Transcriptional Regulators in Response to Opioids

Most of the evidence for a relationship between opioid use and epigenetic alterations discussed above is correlational. However, studies directly manipulating enzymes responsible for epigenetic modifications are beginning to build causal relationships between specific forms of epigenetic regulation and opioid-induced behavioral abnormalities. Numerous enzymes contribute to establishing the epigenetic landscape at a given locus and can serve one of three functions: writers, which place marks;

Transcriptional Consequences of Long-term Opioid Exposure

Exposure to drugs of abuse or to drug-associated stimuli elicits multiple waves of transcription. The rapid and transient induction of several immediate early genes (IEGs) sets the stage for persistent changes to the expression of effector genes critical for long-term plasticity. These waves of gene expression regulate, and are regulated by, epigenetic modifications.

Conclusions and Future Directions

Our understanding of how opioids induce persistent neuroplastic changes within the brain’s reward circuitry is growing. Several epigenetic changes have been identified and linked to changes in gene expression programs that interact with the physiology of neurons, including higher levels of permissive histone acetylation and lower levels of repressive histone methylation. Manipulations of epigenetic editors suggests that these modifications potentiate behavioral responses to opioids. Complex

Acknowledgments and Disclosures

This work was supported by the Natural Sciences and Engineering Research Council of Canada (postdoctoral fellowship to CJB), Boehringer Ingelheim Fonds (doctoral fellowship to AG), and National Institutes of Health (Grant Nos. P01DA047233 and R37DA007359 [to EJN]).

We thank Jill Gregory for assistance with figure preparation.

The authors report no biomedical financial interests or potential conflicts of interest.

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ReviewEpigenetic Mechanisms of Opioid Addiction

Abstract

Section snippets

Histone Modifications

Role of Epigenetic and Transcriptional Regulators in Response to Opioids

Transcriptional Consequences of Long-term Opioid Exposure

Conclusions and Future Directions

Acknowledgments and Disclosures

J Pain

Eur J Pharmacol

Brain Res Brain Res Rev

Life Sci

Biol Psychiatry

Pharmacol Biochem Behav

Eur J Pharmacol

Biochem Pharmacol

Neuropharmacology

Cell

Curr Opin Neurobiol

Eur J Pharmacol

Biol Psychiatry

Brain Res

Brain Res

Pain

Toxicol Lett

Toxicol Lett

Neuropharmacology

Neurosci Lett

Neurosci Lett

Neurosci Lett

Cell Rep

Cell

Trends Neurosci

J Biol Chem

Behav Brain Res

Neuron

Neurochem Int

Brain Res Mol Brain Res

Pharmacol Biochem Behav

Centers for Disease Control and Prevention: Provisional counts of drug overdose death (as of August 6, 2017)

The Impact of the Opioid Crisis on the Healthcare System: A Study of Privately Billed Services

Key substance use and mental health indicators in the United States: Results from the 2017 National Survey on Drug Use and Health. Rockville, MD

Non-medical use of prescription opioids is associated with heroin initiation among US veterans: A prospective cohort study

Addiction

Neurocircuitry of addiction

Neuropsychopharmacology

Neural mechanisms of addiction: The role of reward-related learning and memory

Annu Rev Neurosci

Opioids excite dopamine neurons by hyperpolarization of local interneurons

J Neurosci

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Proc Natl Acad Sci U S A

The effects of opioid peptides on dopamine release in the nucleus accumbens: An in vivo microdialysis study

J Neurochem

The neurobiology of opiate reinforcement

Crit Rev Neurobiol

Regional, developmental, and cell cycle-dependent differences in mu, delta, and kappa-opioid receptor expression among cultured mouse astrocytes

Glia

Endogenous opioid systems and the growth of oligodendrocyte progenitors: Paradoxical increases in oligodendrogenesis as an indirect mechanism of opioid action

Glia

Endogenous opioid system in developing normal and jimpy oligodendrocytes: mu and kappa opioid receptors mediate differential mitogenic and growth responses

Glia

Acute morphine exposure increases the brain distribution of [18F]DPA-714, a PET biomarker of glial activation in nonhuman primates

Int J Neuropsychopharmacol

Transcriptional and epigenetic mechanisms of addiction

Nat Rev Neurosci

Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals

Nat Genet

Brain function and chromatin plasticity

Nature

Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories—indications for novel treatments of addiction

Eur J Neurosci

It is a complex issue: Emerging connections between epigenetic regulators in drug addiction

Eur J Neurosci

Review
Epigenetic Mechanisms of Opioid Addiction