Center for chronic pain and drug abuse

摘要总体而言，慢性疼痛和药物滥用中心： 这是P50申请PAR-16-009的重新提交，以启动慢性疼痛和药物治疗中心 虐待我们中心的建议是建立在认识到阿片类药物成瘾和慢性疼痛从事相同的 大脑回路，中脑边缘系统尽管鸦片类药物继续被用于治疗数百万慢性疼痛， 患者，慢性疼痛是持续阿片类药物流行病的主要贡献者，实际上没有科学的 了解控制慢性疼痛和阿片类药物暴露之间相互作用的机制。我们 该中心的组织是为了揭示因果控制这种相互作用的机制，并积极寻找 关键的分子，电路和生物标志物，并最终，新的非成瘾性治疗方案的慢性 痛苦我们的首要假设是慢性疼痛状态为阿片类药物启动了边缘系统回路 滥用，而且，相关的适应性取决于慢性疼痛和阿片类药物的持续时间和剂量 exposure.该假设将使用一系列尖端工具进行严格测试，以研究潜在的 从基因到分子，电路和全脑解剖和功能的机制。患者 慢性背痛（CBP）是最大和最具特征的人群，有阿片类药物滥用障碍的风险。 项目1将使用先进的脑成像方法来研究CBP的大脑特性，并在大鼠模型中进行研究。 慢性疼痛（SNI），阿片类药物暴露。人体研究将是1）横断面的，比较大脑解剖结构 和功能之间的组;和2）在受试者内，检查大脑活动和网络特性， 短暂的阿片类药物戒断和再次暴露于安慰剂、阿片类药物或多巴胺。该研究旨在确定：生物标志物 阿片类药物使用障碍（OUD）;与阿片类药物使用障碍相关的大脑扭曲和认知，情感和运动变化 阿片类药物暴露;多巴胺能回路在OUD和阿片类药物镇痛中的作用。并行脑成像 慢性疼痛（SNI）和吗啡暴露（MSA或MCPP）大鼠将建立跨物种 通信和询问电路研究项目2-4。项目2将重点关注涉及的电路 动机和成瘾（mPFC，NAc，VTA）;项目3将侧重于阿片类药物的情景记忆和复发 寻求（背侧海马，dH，与VTA和皮质的相互作用）;项目4将侧重于遗传定义 中脑边缘区的单细胞适应性（VTA及其与阿片样物质的连接） NAc和dH），寻找新的分子靶点来控制慢性疼痛。所有动物研究将使用相同的 慢性疼痛的模型项目2-4使用转基因小鼠;项目2，3使用光-和化疗- 遗传学和电生理学;项目4使用单细胞转录组学。啮齿动物行为核心将 为所有项目生成具有MSA或MCPP的SNI啮齿动物。计算和统计核心将提供数据 处理支持，并能够与整个研究界共享数据。行政核心将 监督该计划的组织和教育任务，包括试点项目要素， 将资助年轻科学家的小型项目，以加速中心的科学发展。 1

Abstract Overall, Center for Chronic Pain and Drug Abuse: This is a resubmission of a P50 application, PAR-16-009, to launch a Center for Chronic Pain and Drug Abuse. Our Center proposal is built on the recognition that opioid addiction and chronic pain engage the same brain circuitry, the mesolimbic system. Although opiates continue to be prescribed to millions of chronic pain patients, and chronic pain is a primary contributor to the ongoing opiate epidemic, there is virtually no scientific knowledge regarding mechanisms that control the interaction between chronic pain and opioid exposure. Our Center is organized to uncover mechanisms that causally control this interaction, and to aggressively search for critical molecules, circuits, and biomarkers, and ultimately, novel non-addictive treatment options for chronic pain. Our overarching hypothesis is that the chronic pain state primes limbic circuitry for opiate abuse, and also, that associated adaptations depend on the duration and dose of both chronic pain and opioid exposure. The hypothesis will be rigorously tested using an array of cutting-edge tools, to study the underlying mechanisms from the scale of genes to molecules, circuits and whole-brain anatomy and function. Patients with chronic back pain (CBP) are the largest and best characterized group of humans at risk for opioid abuse disorder. Project 1 will use advanced brain imaging approaches to study brain properties in CBP, and in a rat model of chronic pain (SNI), for opioid exposure. The human studies will be 1) cross-sectional, comparing brain anatomy and function between groups; and 2) within-subject, examining brain activity and network properties during brief opioid withdrawal and re-exposure to placebo, opioid, or dopamine. The study seeks to identify: biomarkers for opioid use disorder (OUD); brain distortions and cognitive, emotional, and motor changes associated with opioid exposure; and the role of dopaminergic circuitry in OUD and opioid analgesia. Parallel brain imaging in rats with chronic pain (SNI) and with morphine exposure (MSA or MCPP) will establish cross-species correspondences, and interrogate circuitry studied in Projects 2-4. Project 2 will focus on circuits involved in motivation and addiction (mPFC, NAc, VTA); Project 3 will focus on episodic memory and relapse for opiate seeking (dorsal hippocampus, dH, interaction with VTA and cortex); Project 4 will focus on genetically defined single-cell adaptations for the mesolimbic region underlying opioid reinforcement (VTA and its connectivity to NAc and dH), searching for novel molecular targets to control chronic pain. All animal studies will use the same model for chronic pain. Projects 2-4 use genetically modified mice; Projects 2, 3 use opto- and chemo- genetics, and electrophysiology; and Project 4 uses single cell transcriptomics. The rodent behavior core will generate SNI rodents with MSA or MCPP for all projects. The computational and statistics core will provide data processing support, and enable data sharing with the research community at large. The administrative core will oversee the organizational, and educational missions of the program, including the pilot projects element, which will fund small projects from junior scientists to accelerate the Center’s science. 1