Developing a Gene-Based Approach for Lasting Protection from Opioid Use Disorder

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PROJECT SUMMARY Opioid use disorders pose a substantial public health burden, with consistently high rates of morbidity and mortality. Though many interventions exist, all modalities suffer some degree of treatment nonadherence and response failure, which suggests a need for more effective solutions. When bound to Gi-coupled Mu opioid receptors (MuORs) in ventral tegmental area (VTA) GABAergic neurons, opioids cause disinhibition of VTA dopaminergic neurons, which then increases dopamine release in the nucleus accumbens (NAc), a key driver of reward signaling in the brain. Various methods of modulating VTA activity have been found to modify opioid-seeking behavior, but little work has been done to take this information in a therapeutic direction. Inspired by recent work using inhibitory DREADDs to attenuate heroin seeking behavior, this project seeks to utilize the MuOR itself as a means to inhibit reward signaling in a way that has clear translational value. The MuOR mutation D114(2.50)N is one of the best characterized variants of this receptor, and is known to exhibit a significant reduction in binding affinity and potency for various opioid ligands compared to the wild-type receptor. This mutant, which will be referred to as LAMuOR (Low Affinity Mu Opioid Receptor), may be exploited to create a genetically encoded tool that, when expressed in the VTA, inhibits the response of the reward pathway to exogenously administered opioids, while remaining unresponsive to endogenous ligands. Thus, the goal of this project is to test the hypothesis that LAMuOR suppresses opioid taking by responding preferentially to opioids of abuse – such as during fentanyl self-administration – while remaining unresponsive during physiological reward signaling. If successful, LAMuOR may ultimately prove to be a novel translational strategy by which a single treatment could confer life-long protection from opioid use disorders.