Project description:<p>The proposed study examined the prevalence of various genetic polymorphisms thought to be involved in opioid abuse among current heroin users. In addition to providing blood samples for genetics analysis, participants completed a number of questionnaires that allowed us to learn detailed information about their current and history of opioid drug use. </p>
Project description:Analyse of gene expression modification after chronic analgesic treatment. The hypothesis tested in the present study was that oxycodone and morphine induced gene expression modification. Results provide important information to understand the analgesic effects of oxycodone as compared to morphine in a neuropathic pain model Total RNA obtained from DRG of neuropathic or control animals after oxycodone or morphine treatment
Project description:In addition to their intrinsic rewarding properties. opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a unique population of PBn-projecting pyramidal neurons restricted to the DPn that express μ-opioid receptors (μORs). Disrupting μOR signaling in these neurons switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify DPn neurons as key substrates for the abuse liability of opioids.
Project description:Prescription opioids such as oxycodone have been widely used in the United States and have contributed to the ongoing opioid epidemic. While many individuals limit use to prescribed contexts, a subset transitions to misuse and, in some cases, to illicit opioid use. Identifying behavioral and biological factors that predict this vulnerability is critical for improving prevention and intervention strategies. Here, we investigated whether individual differences in behavioral flexibility and gut microbiome composition are associated with future oxycodone intake using a translationally relevant model of oral oxycodone self-administration in male and female Long-Evans rats. We established a model in which distinct intake phenotypes emerged, characterized by animals with high versus low oxycodone consumption. Behavioral flexibility, assessed using a contingency degradation task, was associated with oxycodone intake, identifying it as a potential behavioral biomarker of vulnerability. In parallel, oral oxycodone exposure altered gut microbiome composition, and microbiome features were associated with both behavioral flexibility and drug-taking behavior. These findings support a framework in which individual differences in opioid intake arise from the interaction of pre-existing behavioral traits and biological states, including gut microbiome composition which provides a foundation for identifying predictive biomarkers and developing individualized strategies to mitigate risk for opioid misuse.
Project description:Sensitivity to the subjective reinforcing properties of opioids has a genetic component and can predict addiction liability of opioid compounds. We previously identified Zhx2 as a candidate gene underlying increased brain concentration of the oxycodone (OXY) metabolite oxymorphone (OMOR) in BALB/cJ (J) versus BALB/cByJ (By) females that could increase OXY state-dependent reward. A large structural intronic variant is associated with a robust reduction of Zhx2 expression in J mice, which we hypothesized enhances OMOR levels and OXY addiction-like behaviors. We tested this hypothesis by modeling the loss-of-function variant through knocking out the Zhx2 coding exon (E3KO). Integrative transcriptomic and proteomic analysis of E3KO mice identified astrocyte function, cell adhesion, extracellular matrix properties, and endothelial cell functions as pathways influencing brain OXY metabolite concentration and behavior. These results support Zhx2 as a quantitative trait gene underlying brain OMOR concentration that is associated with changes in OXY behavior and implicate potential quantitative trait mechanisms that together inform our overall understanding of Zhx2 in brain function.