Differentially expressed gene networks, biomarkers, long noncoding RNAs, and shared responses with cocaine identified in the midbrains of human opioid abusers

Manal H Saad,Carl J Schmidt,Francesca Luca,Michael H Guerra,Alaina M Jaster,Michael J Bannon,Candace L Savonen,Roger Pique-Regi,Adnan Alazizi,Philip D Olson,Matthew Rumschlag

doi:10.1038/s41598-018-38209-8

Abstract

Opioid abuse is now the most common cause of accidental death in the US. Although opioids and most other drugs of abuse acutely increase signaling mediated by midbrain dopamine (DA)-synthesizing neurons, little is known about long-lasting changes in DA cells that may contribute to continued opioid abuse, craving, and relapse. A better understanding of the molecular and cellular bases of opioid abuse could lead to advancements in therapeutics. This study comprises, to our knowledge, the first unbiased examination of genome-wide changes in midbrain gene expression associated with human opioid abuse. Our analyses identified differentially expressed genes and distinct gene networks associated with opioid abuse, specific genes with predictive capability for subject assignment to the opioid abuse cohort, and genes most similarly affected in chronic opioid and cocaine abusers. We also identified differentially expressed long noncoding RNAs capable of regulating known drug-responsive protein-coding genes. Opioid-regulated genes identified in this study warrant further investigation as potential biomarkers and/or therapeutic targets for human substance abuse.

Highlights

Drug-related deaths, the majority of which involve opioid use, exceed all other causes of accidental death in the U.S The past several decades have been characterized by parallel increases in prescription opioid sales, opioid treatment admissions, and prescription opioid overdose deaths, followed by a resurgence in heroin abuse and deaths and, most recently, a steep rise in opioid deaths involving fentanyl or fentanyl analogs[1,2]
The current investigation represents, to our knowledge, the first unbiased examination of genome-wide changes in midbrain gene expression associated with human opioid abuse
To ascertain changes in gene expression associated with opioid abuse, we performed high-throughput RNA-sequencing on postmortem ventral midbrain specimens from chronic opioid users (N = 30) and drug-free control subjects (N = 20), as described in the Methods

Summary

Introduction

Drug-related deaths, the majority of which involve opioid use, exceed all other causes of accidental death in the U.S The past several decades have been characterized by parallel increases in prescription opioid sales, opioid treatment admissions, and prescription opioid overdose deaths, followed by a resurgence in heroin abuse and deaths and, most recently, a steep rise in opioid deaths involving fentanyl or fentanyl analogs[1,2]. Neuroadaptations such as drug dependence, craving, and relapse are thought to arise from persistent changes in gene expression[5,6] While such changes have been identified in human forebrain targets of DA signaling Analyses revealed differentially expressed genes and gene networks associated with opioid abuse, including those genes more predictive of subject assignment to the correct (drug-free or opioid-abusing) cohort, and those most affected by opioid and cocaine use. Based on these data, further study seems warranted to determine the potential of these genes as biomarkers and/or therapeutic targets for substance abuse

Methods

Results

Conclusion