microRNA expression levels in the nucleus accumbens correlate with morphine‐taking but not morphine‐seeking behaviour in male rats

Abstract

A powerful motivation to seek opioids remains after drug cessation and intensifies during extended periods of abstinence. Unfortunately, biomarkers associated with continued drug seeking have not been described. Moreover, previous studies have focused on the effects of early abstinence with little exploration into the long-term drug-induced mechanisms that occur after extended abstinence. Here we demonstrated that 30 days (D) of forced abstinence results in a time-dependent increase in morphine seeking in a rat model of morphine selfadministration (SA). We measured expression of known drug-responsive microRNAs (miRNAs) in the nucleus accumbens, an area critical for rewardrelated plasticity, during early or late abstinence in animals that underwent either a cue-induced relapse test or no relapse test. miRNAs are small noncoding RNAs that represent suitable biomarker candidates due to their longlasting nature. mir-32-5p levels during early abstinence negatively correlated with active lever pressing in both cue-exposed and cue-naïve animals. mir-1298-5p positively correlated with drug SA history after a relapse test during late abstinence. When animals underwent acute abstinence with no relapse test, mir-1298-5p correlated with drug infusions and active lever pressing during SA. In late abstinence with no relapse test, mir-137-3p negatively correlated with drug infusions. Regulation of mir-32-5p target genes and significant correlation of target gene mRNA with mir-32-5p was observed after abstinence. These results indicate that lasting regulation of miRNA expression is associated with drug intake following morphine SA. In addition, we conclude

The nuclear factor E2-related factor 2 participates in morphine-induced autophagy

“…Chronic morphine exposure could induce drug addiction and affect brain functions [21][22][23][24]. As we all know, withdrawal is a part of morphine addiction, this uncomfortable syndrome occurs after morphine discontinued and it was also the major reason of relapse.…”

MicroRNA-mediated translational pathways are regulated in the orbitofrontal cortex and peripheral blood samples during acute abstinence from heroin self-administration

“…The regions of the OFC dissected were the ventral OFC and lateral OFC subregions. For extraction of total RNA from OFC tissue, the miRVANA PARIS RNA extraction kit (Life Technologies, Carlsbad, CA) was used, as we have previously reported [ 7 , 24 , 34 ]. Exosomal RNA was extracted from blood serum using the SeraMir Exosome RNA Amplification Kit (System Biosciences, Palo Alto, CA), according to the manufacturer’s instructions.…”

“…Because of this, miRNA-mediated inhibition of protein translation is an essential regulatory mechanism for modulation of gene expression and the proteome [ 11 ]. Exposure to all classes of drugs can induce long-lasting alterations to brain miRNA expression profiles and regulation of miRNA function can modulate drug seeking behavior [ 7 , 12 – 24 ]. Manipulation of individual miRNA expression or functional capabilities has been reported to regulate seeking for the opioids morphine and heroin, as well as psychostimulants and alcohol [ 14 , 17 , 20 , 21 , 23 , 24 ].…”

“…Thus, identifying miRNAs and their associated downstream protein pathways that are regulated in the brain as a result of chronic opioid exposure represents a novel strategy for determining previously understudied mechanisms that may have therapeutic relevance for the reduction of opioid seeking in OUD. Brain-region specific and drug dose-dependent regulation of miRNAs occurs [ 7 ], which necessitates the need to uncover the miRNA profile that results following a wide range of drug exposure protocols. In the present study, we have begun addressing these critical issues by performing small RNA sequencing of miRNAs and protein profiling on the OFC of rats that self-administered heroin at a dose of 0.03 mg/kg/infusion and underwent forced abstinence for 2 days (early abstinence).…”

Molecular and Epigenetic Aspects of Opioid Receptors in Drug Addiction and Pain Management in Sport

“…MiRNAs participate in the molecular pathways that modulate the behavioral phenotypes and the cellular neuroadaptations induced by opioid exposure. A recent study conducted in a rat model of morphine self-administration identified several drug-responsive microRNAs in the NAcc and revealed that their lasting expression profiles correlate with morphine-taking but not morphine-seeking behavior in males, since the miRNA profile undergoes regulation from early to late abstinence [144]. Therefore, miRNA signature may represent a marker of past drug abuse.…”