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

项目总结 阿片类药物使用障碍构成了重大的公共卫生负担，发病率一直很高。 和死亡率。尽管存在许多干预措施，但所有治疗方式都会出现不同程度的治疗不依从。 和响应失败，这表明需要更有效的解决方案。当与Gi偶联的Mu阿片结合时 腹侧被盖区(VTA)GABA能神经元的受体(MUOR)，阿片类药物可解除对VTA的抑制 多巴胺能神经元，然后增加伏核(NAC)中的多巴胺释放，这是一个关键的驱动因素 大脑中的奖励信号。各种调节VTA活性的方法已经被发现可以改变 阿片类药物寻找行为，但几乎没有做什么工作来将这些信息转化为治疗方向。 受最近使用抑制性DREADD来减少海洛因寻找行为的工作的启发，该项目试图 利用MuOR本身作为一种手段，以一种具有明显翻译价值的方式来抑制奖励信号。 MuOR突变D114(2.50)N是该受体最具特征的变体之一， 已知的各种阿片配体的结合亲和力和效力与 野生型受体。这个突变体将被称为LAMuOR(低亲和力Mu阿片受体)， 可以被利用来创造一种遗传编码的工具，当在VTA中表达时，抑制 外源性给药阿片类药物的奖赏途径，同时对内源性保持无反应 配基。因此，这个项目的目标是检验LAMuor通过以下方式抑制阿片类药物服用的假设 优先应对滥用阿片类药物--例如在芬太尼自我给药期间--同时保持 在生理奖赏信号过程中没有反应。如果成功，《拉穆尔》最终可能会被证明是一部小说 翻译战略，通过单一治疗可以提供终身保护，免受阿片类药物使用障碍的影响。

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.