Neuroplasticity, axonal guidance and micro‐RNA genes are associated with morphine self‐administration behavior

Abstract

Neuroadaptations in the ventral striatum (VS) and ventral midbrain (VMB) following chronic opioid administration are thought to contribute to the pathogenesis and persistence of opiate addiction. In order to identify candidate genes involved in these neuroadaptations we utilized a behavior genetics strategy designed to associate contingent intravenous drug self-administration with specific patterns of gene expression in inbred mice differentially predisposed to the rewarding effects of morphine. In a yoked-control paradigm, C57BL/6J mice showed clear morphine-reinforced behavior whereas DBA/2J mice did not. Moreover, the yoked-control paradigm revealed the powerful consequences of self-administration versus passive administration at the level of gene expression. Morphine self-administration in the C57BL/6J mice uniquely up- or down-regulated 237 genes in the VS and 131 genes in the VMB. Interestingly, only a handful of the C57BL/6J self-administration genes (<3%) exhibited a similar expression pattern in the DBA/2J mice. Hence, specific sets of genes could be confidently assigned to regional effects of morphine in a contingent- and genotype-dependent manner. Bioinformatics analysis revealed that neuroplasticity, axonal guidance and microRNAs (miRNAs) were among the key themes associated with drug self-administration. Noteworthy were the primary miRNA genes H19 and microRNA containing gene (Mirg), processed respectively to mature miRNAs miR-675 and miR-154, since they are prime candidates to mediate network-like changes in responses to chronic drug administration. These miRNAs have postulated roles in dopaminergic neuron differentiation and mu-opioid receptor regulation. The strategic approach designed to focus on reinforcement-associated genes provides new insight into the role of neuroplasticity pathways and miRNAs in drug addiction.

Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

“…Optogenetic experiments further define the role of these neuronal subtypes, with D1, but not D2, MSNs mediating tolerance and reward [81,82]. Transcriptional and proteomic profiles outline morphine-induced changes in phosphorylation cascades, energy status, and cell morphology [83,84]. It is unclear if the cellular adaptations observed in the striatum are restricted to opioid receptor-expressing cells or are a result of pass-forward allostasis (Box 2).…”

Morphine Regulates Expression ofμ-Opioid Receptor MOR-1A, an Intron-Retention Carboxyl Terminal Splice Variant of theμ-Opioid Receptor (OPRM1) Gene via miR-103/miR-107

“…Mu opioids such as morphine modulate expression of a number of miRNAs (Sanchez-Simon et al, 2010;Zheng et al, 2010;Wu et al, 2008Wu et al, , 2013Dave and Khalili, 2010;He et al, 2010;Wang et al, 2011), and several miRNAs regulate MOR-1 expression (Wu et al, 2008(Wu et al, , 2009He et al, 2010). Dysregulation of miRNAs has been linked to morphine tolerance and addiction Dreyer, 2010;Hwang et al, 2012;Tapocik et al, 2013). Yet there has been a lack of information regarding miRNA Fig.…”

Novel biomarkers to assess in utero effects of maternal opioid use: First steps toward understanding short‐ and long‐term neurodevelopmental sequelae

“…Opioid dose is a poor predictor 13 ; some factors that have been associated with NAS severity include: cooccurring exposure to benzodiazepines, 14,15 anti-depressants, 16,17 marijuana use or heavy smoking, 18,19 as well as genetic factors. 24,25 MiRNAs are highly regulated by exposure to drugs of abuse [26][27][28][29][30][31] and emerging evidence also suggests that they play an important role in the etiology of addiction. Further, decisions to initiate pharmacotherapy rely partly on subjective observer-rated scoring.…”

“…20,21 None of these factors are sufficient to reliably predict NAS severity, and the mechanisms by which they impact NAS are not well understood. [27][28][29][31][32][33] Specifically, opioid consumption drastically alters the miRNA landscape in the brain. Biomarkers indicative of individual fetal brain responses to opioid exposure would be invaluable to augment observer-rated assessments that guide pharmacotherapy decision-making and contribute to personalized risk assessments for mothers antenatally.…”

“…Further, decisions to initiate pharmacotherapy rely partly on subjective observer-rated scoring. [28][29][30][31][34][35][36][37][38] Additionally many miRNAs regulate the expression of molecules involved in opioid signaling, 30,34,36,38 which may have important implications for fetuses chronically exposed to opioids over the course of pregnancy. Unraveling the mechanisms underlying opioid-related neurodevelopmental disruptions in humans will require noninvasive methods.…”