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讨 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 治疗焦虑症、忧郁症和精神病的疗法。然而，阿片类药物也有同样有害的副作用。 这可能会导致阿片类药物使用障碍。已经确定了阿片受体的三种主要亚型，即 每种基因都在许多细胞中表达。因为传统药物影响给定体积的所有细胞，所以它一直是 很难描绘药物介导的行为对细胞类型的特定贡献。为了解决这一差距，我们开发了 飞镖 (药物受到拴系的严重限制)，它的工作原理是通过遗传编程捕获一部分细胞 并将一种特定的药物浓缩到比其他任何地方高出1000倍的水平，从而将药物作用限制在 选定的单元格子集。在这里，我们建议开发、描述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 由最近一项双盲安慰剂对照试验推动的行为实验，在该试验中，一种胆碱能药物 在治疗阿片类药物使用障碍方面表现出了有效性。我们将测试μOR的假设 胆碱能中间神经元介导阿片类药物的有害(成瘾)效应，不依赖于有帮助的(止痛药)。 效果。拟议的技术将提供前所未有的机会来建立因果行为角色 由确定的细胞类型介导的阿片类神经药物。因为这些技术植根于 治疗相关的神经药物，提供临床相关性，而不需要牺牲 机械上的严谨。

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.