Epigenetic Modulation of Opioid Receptors by Drugs of Abuse

Abstract

Chronic exposure to drugs of abuse produces profound changes in gene expression and neural activity associated with drug-seeking and taking behavior. Dysregulation of opioid receptor gene expression is commonly observed across a variety of abused substances including opioids, cocaine, and alcohol. Early studies in cultured cells showed that the spatial and temporal gene expression of opioid receptors are regulated by epigenetic mechanisms including DNA and histone modifications and non-coding RNAs. Accumulating evidence indicate that drugs of abuse can modulate opioid receptor gene expression by targeting various epigenetic regulatory networks. Based on current cellular and animal models of substance use disorder and clinical evidence, this review summarizes how chronic drug exposure alters the gene expression of mu, delta, kappa, and nociceptin receptors via DNA and histone modifications. The influence of drugs of abuse on epigenetic modulators, such as non-coding RNAs and transcription factors, is also presented. Finally, the therapeutic potential of manipulating epigenetic processes as an avenue to treat substance use disorder is discussed.

Keywords: DNA methylation; drugs of abuse; epigenetics; gene expression; histone modifications; noncoding RNAs; opioid receptors.

Figure 1

Schematic mechanisms of epigenetic mechanisms. (A) DNA methylation typically occurs at CpG dinucleotides (5mC), in which cytosines are methylated by DNA methyltransferases (DNMTs). The added methyl group(s) can be converted to hydroxymethyl (5hmC) by TET family proteins. Both 5mC and 5hmC are abundant in the brain. (B) Histone modifications mark the transcriptionally active or silenced chromatin states. Methylation and acetylation are two major studied histone modifications in drugs of abuse. The silenced chromatin is enriched with histone H3 lysine 9 (H3K9me) and 27 (H3K27me) methylations, whereas the active chromatin is covered by hyperacetylated histones and tri-methylated histone H3 lysine 4 (H3K4me3). (C) The long noncoding RNAs (lncRNAs) are likely involved in recruiting histone modifying enzymes that add or remove histone marks that control the local chromatin status, thereby, affecting transcription, either positively or negatively. (D) microRNAs (miRNAs) down-regulate mRNA levels either by mediating the degradation of mRNA or blocking translation. Circular RNAs (circRNAs) are a new class of ncRNA that may antagonize the function of miRNA by sponging and may also have gene regulation potency.

Figure 2

The regulatory DNA elements and corresponding TFs within the promoters of mouse Oprm (A), Oprd (B), Oprk (C), and human OPRL (D) genes. (A–C) Thick blue lines highlight validated promoters [6,154]. (D) Predicted regulatory elements and TF-binding sites at the human OPRL gene. Black arrows indicate reported transcription initiation sites from the promoters. (A–D) +1 shows the initiation codon of the open reading frame. Purple boxes are exons. Numbers above each map indicate the relative ends of validated promoter regions, regulatory sequences, or TF-binding sites, with respect to the +1 codon. Abbreviations: AP1, activator protein 1; AP2, activator protein 2; CREB, cyclic adenosine monophosphate (cAMP) response element binding protein; NF-κB, nuclear factor κB; Ets, E-twenty six; Ik, Ikaros; NRSE, neurorestrictive silencer element; Oct-1, octamer-1; PARP1, poly(ADP-ribose) polymerase 1; PCBP, poly C binding protein; PU.1, PU box binding; Sox, Sry-like high-mobility group box gene; Sp1, specificity protein 1; Sp3, specificity protein 3; STAT, signal transducers and activators of transcription; USF, upstream stimulatory factor; c-Myc, cellular Myelocytomatosis; EGR, early growth response protein; ETF, electron transfer flavoprotein; CP1, CCAAT transcription factor.

Figure 3

A hypothetical model of epigenetic suppression of Oprm1 by drugs of abuse. (A) Potential cross-regulation between DNA methylation and histone modifications on Oprm1. The drugs of abuse enhance MeCP2 and other methyl-CpG-binding domain (MBD) proteins, which recognize DNA methylation and mark the promoter of Oprm1. This results in the recruitment of HDAC1, which removes the acetyl groups from the locus. The process suppresses the promoter from transcriptional activities; thus, Oprm1 expression level is dampened. (B) ncRNA mediated suppression of Oprm1. Morphine treatment enhances the levels of MRAK159688 (lncRNA), miR-23b, miR-339 and Let-7 family miRNAs [152,165]. All these ncRNAs can recruit transcriptional co-repressors to suppress the transcription of Oprm1. Alternatively, they can limit Oprm1 mRNA translation by directly binding to its 3′UTR or sequestering the mRNA at the processing body (P-body).