Interrogating the cholinergic basis of opioid use disorder

探究阿片类药物使用障碍的胆碱能基础

基本信息

批准号：
10044348
负责人：
Michael R Tadross
金额：
$ 48.3万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044348
关键词：
Absence of pain sensation Acute Address Adjuvant Therapy Adoption Affect Analgesics Animals Axon Behavior Behavioral Buprenorphine Catalogs Cells Cholinergic Agents Clinical Clinical Trials Communities Development Dopamine Dose Foundations Galantamine In Vitro Incidence Infusion procedures Interneurons Knowledge Lead Ligands Literature Locales Maps Mediating Mental Depression Methadone Methods Modeling Mutation Naloxone Neuropharmacology Neurosciences Nucleus Accumbens Opiate Addiction Opioid Opioid Antagonist Opioid Receptor Opioid agonist Oxymorphone Pain management Pharmaceutical Preparations Pharmacology Plant Roots Psychotic Disorders Publishing Reagent Risk Rodent Model Role Science Signal Transduction Specificity Substance Use Disorder System Technology Testing Therapeutic Time Validation Work anxiety treatment brain volume cell type chemical genetics cholinergic clinical efficacy clinically relevant cognitive enhancement dependence relapse design double-blind placebo controlled trial drug action experimental study in vivo insight mu opioid receptors novel opioid use opioid use disorder overexpression receptor risk minimization side effect theories tool

项目摘要

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.

摘要：探讨阿片类药物使用障碍的胆碱能基础阿片类药物在治疗疼痛方面具有无与伦比的临床疗效，并在以下方面具有显着的治疗潜力：然而，阿片类药物治疗焦虑、抑郁和精神病也有同样有害的副作用。已鉴定出可导致阿片类药物使用障碍的三种主要亚型：由于传统药物会影响给定体积内的所有细胞，因此它们都在许多细胞中表达。很难绘制药物介导行为的细胞类型特异性贡献为了解决这一差距，我们开发了。镖（受到束缚严重限制的药物），其工作原理是对细胞子集进行基因编程以捕获并将特定药物浓缩至比其他任何地方高约 1000 倍的水平，从而将药物作用限制在在这里，我们建议开发、表征和分发一个全面的工具集。我们建议重点关注阿片类药物神经药理学作为广泛采用这些试剂的路线图。受最近一项双盲安慰剂对照试验启发的行为实验，其中胆碱能药物我们将检验 μORs 对阿片类药物使用障碍的治疗效果。胆碱能中间神经元介导阿片类药物的有害（成瘾）作用，与有益（镇痛）无关所提出的技术将为建立因果行为角色提供前所未有的机会。因为这些技术植根于特定细胞类型介导的阿片类神经药物。治疗相关的神经药物，无需牺牲即可提供临床相关性机械的严谨性。