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，旨在启动慢性疼痛和药物中心 滥用。我们中心的提案建立在认识到阿片类药物成瘾和慢性疼痛具有相同的关系的基础上 大脑回路，中脑边缘系统。尽管阿片类药物继续用于治疗数以百万计的慢性疼痛 患者，慢性疼痛是阿片类药物流行的主要原因，但实际上没有科学依据 有关控制慢性疼痛和阿片类药物暴露之间相互作用的机制的知识。我们的 该中心的组织目的是发现因果控制这种相互作用的机制，并积极寻找 关键分子、回路和生物标志物，以及最终针对慢性病的新型非成瘾治疗方案 疼痛。我们的首要假设是，慢性疼痛状态会引发阿片类药物的边缘回路 滥用，而且相关的适应取决于慢性疼痛和阿片类药物的持续时间和剂量 曝光。该假设将使用一系列尖端工具进行严格测试，以研究其潜在原理 从基因尺度到分子、回路以及全脑解剖和功能的机制。患者患有 慢性背痛 (CBP) 是面临阿片类药物滥用障碍风险的最大且最典型的人群。 项目 1 将使用先进的脑成像方法来研究 CBP 和大鼠模型中的大脑特性 慢性疼痛（SNI），用于阿片类药物暴露。人类研究将是 1) 横断面，比较大脑解剖结构 以及团体之间的职能； 2）在受试者内部，检查大脑活动和网络特性 短暂的阿片类药物戒断并重新接触安慰剂、阿片类药物或多巴胺。该研究旨在确定： 生物标志物 用于阿片类药物使用障碍 (OUD)；大脑扭曲以及与相关的认知、情绪和运动变化 阿片类药物暴露；以及多巴胺能回路在 OUD 和阿片类镇痛中的作用。并行脑成像 患有慢性疼痛（SNI）和吗啡暴露（MSA 或 MCPP）的大鼠将建立跨物种 通信，并询问项目 2-4 中研究的电路。项目2将重点关注涉及的电路 动机和成瘾（mPFC、NAc、VTA）；项目 3 将重点关注阿片类药物的情景记忆和复发 寻找（背侧海马，dH，与 VTA 和皮质的相互作用）；项目 4 将重点关注基因定义 中脑边缘区域的单细胞适应是阿片类药物强化的基础（VTA及其与 NAc 和 dH），寻找控制慢性疼痛的新分子靶点。所有动物研究都将使用相同的 慢性疼痛模型。项目2-4使用转基因小鼠；项目 2、3 使用光和化学 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，并实现与整个研究界的数据共享。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， 将资助初级科学家的小型项目，以加速该中心的科学研究。 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