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

项目摘要 类阿片使用障碍造成了巨大的公共卫生负担，发病率一直很高 and mortality.虽然存在许多干预措施，但所有方式都存在一定程度的治疗不依从性 以及应对失败，这表明需要更有效的解决方案。当与Gi偶联的Mu阿片类药物结合时 腹侧被盖区（VTA）GABA能神经元中的MuOR受体，阿片类药物引起VTA的去抑制 多巴胺能神经元，然后增加多巴胺释放在丘脑核（NAc），一个关键的驱动程序 大脑中的奖励信号。已经发现调节VTA活性的各种方法可以改变VTA活性。 阿片类药物寻求行为，但很少有工作已经做了治疗方向采取这一信息。 受最近使用抑制性DREADD来减弱海洛因寻求行为的工作的启发，该项目旨在 利用MuOR本身作为一种手段，以具有明确翻译价值的方式抑制奖励信号传导。 MuOR突变D114（2.50）N是该受体的最佳表征变体之一， 已知其对各种阿片样物质配体的结合亲和力和效力与 野生型受体这种突变体，将被称为LAMuOR（低亲和力Mu阿片样受体）， 可以被用来创造一种基因编码的工具，当在VTA中表达时， 奖励途径，外源性给予阿片类药物，而保持无反应的内源性 配体。因此，本项目的目标是检验LAMuOR通过以下方式抑制阿片类药物服用的假设： 优先对滥用阿片类药物作出反应-例如在芬太尼自我给药期间-同时 在生理奖励信号中反应迟钝如果成功，《LAMuOR》最终可能会被证明是一部小说 翻译策略，通过这种策略，单次治疗可以终身保护阿片类药物使用障碍。

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.