Interrogating the cholinergic basis of opioid use disorder

摘要：阿片类药物使用障碍的胆碱能基础探究 阿片类药物在治疗疼痛方面提供了无与伦比的临床疗效，并在以下方面提供了显著的治疗潜力： 治疗焦虑抑郁和精神病然而，阿片类药物也有同样有害的副作用 会导致阿片类药物使用障碍阿片受体的三种主要亚型已被确定，它们是 每一种都在许多细胞中表达。由于传统药物影响给定体积中的所有细胞，因此 难以绘制药物介导行为的细胞类型特异性贡献。为了解决这个问题，我们开发了 DART （药物受到束缚的严重限制），其工作原理是通过基因编程一个细胞子集， 并将特定药物浓缩到比其他任何地方高1000倍的水平，从而将药物作用限制在 所选择的细胞子集。在这里，我们建议开发、表征和分发一个全面的工具集 专注于阿片类神经药理学作为广泛采用这些试剂的路线图，我们建议 行为实验的动机是最近的双盲安慰剂对照试验，其中胆碱能药物 在阿片类药物使用障碍的治疗中表现出有效性。我们将检验μ OR在 胆碱能中间神经元介导阿片类药物的有害（成瘾）作用，独立于有益（镇痛）作用 方面的影响.拟议的技术将提供前所未有的机会，建立因果行为的作用 阿片类神经药物由确定的细胞类型介导。因为这些技术都植根于 治疗相关的神经药物，提供临床相关性，而无需牺牲 机械的严格

ABSTRACT: Interrogating the cholinergic basis of opioid use disorder Opioids offer unmatched clinical efficacy in the treatment of pain, and offer pronounced therapeutic potential in the treatment of anxiety, depression, and psychosis. Nevertheless opioids come with equally harmful side effects that can lead to opioid use disorder. Three major subtypes of opioid receptors have been identified, which are each expressed in numerous cells. Because traditional drugs impact all cells in a given volume, it has been difficult to map cell type-specific contributions of drug-mediated behavior. To address this gap, we developed DART (drugs acutely restricted by tethering), which works by genetically programming a subset of cells to capture and concentrate a specific drug to levels ~1000 times higher than anywhere else, thus restricting drug action to the chosen subset of cells. Here, we propose to develop, characterize, and distribute a comprehensive toolset focused on opioid neuropharmacology. As a roadmap for the widespread adoption of these reagents, we propose behavioral experiments motivated by a recent double-blind placebo-controlled trial in which a cholinergic drug demonstrated efficacy in the treatment of opioid use disorder. We will test the hypothesis that μORs on cholinergic interneurons mediate the harmful (addictive) effects of opioids, independent of helpful (analgesic) effects. The proposed technologies will offer the unprecedented opportunity to establish causal behavioral roles of opioid neuropharmaceuticals mediated by defined cell types. Because the technologies are rooted in therapeutically relevant neuropharmaceuticals, clinical relevance is provided without the need to sacrifice mechanistic rigor.