Center for chronic pain and drug abuse

摘要总的来说，慢性疼痛和药物滥用中心： 这是P50申请的重新提交，PAR-16-009，以启动慢性疼痛和药物中心 虐待。我们的中心建议建立在认识到阿片成瘾和慢性疼痛是相同的基础上 大脑回路，即中脑边缘系统。尽管阿片类药物仍在为数百万慢性疼痛患者开处方 患者，而慢性疼痛是目前阿片类药物流行的主要原因，实际上没有科学的 关于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 中心被组织起来，以发现因果控制这种相互作用的机制，并积极寻找 关键分子、回路和生物标记物，最终，非成瘾性治疗慢性疾病的新选择 疼痛。我们的主要假设是慢性疼痛状态启动了阿片类药物的边缘回路 滥用，以及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。这一假设将使用一系列尖端工具进行严格测试，以研究潜在的 机制从基因的规模到分子、电路和整个大脑的解剖和功能。患有疾病的患者 慢性背痛(CBP)是人类中最大、最具特征的阿片类药物滥用障碍风险人群。 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 慢性疼痛(SNI)，用于阿片类药物暴露。人体研究将是横断面的，比较大脑解剖学。 和组之间的功能；以及2)在受试者内部，检查在 短暂的阿片类药物戒断和再次接触安慰剂、阿片类药物或多巴胺。这项研究试图确定：生物标记物 用于阿片类药物使用障碍(OUD)；大脑扭曲以及与以下相关的认知、情感和运动变化 阿片类药物暴露；以及多巴胺能回路在OUD和阿片类药物镇痛中的作用。并行脑成像技术在临床中的应用 慢性疼痛(SNI)和吗啡暴露(MSA或MCPP)的大鼠将建立跨物种 通信，以及项目2-4中研究的询问电路。项目2将专注于以下方面的电路 动机和成瘾(mPFC、NAC、VTA)；项目3将侧重于情景记忆和鸦片类药物的复发 Seeking(背侧海马体，dh，与VTA和皮质的相互作用)；项目4将侧重于基因定义 阿片类药物强化下中脑边缘区域的单细胞适应(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方法 慢性疼痛的模型。项目2-4使用转基因小鼠；项目2、3使用光学和化学方法- 遗传学和电生理学；项目4使用单细胞转录。啮齿动物行为核心会 为所有项目生成带有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，并实现与广大研究社区的数据共享。行政核心将 监督该方案的组织和教育任务，包括试点项目部分， 将资助初级科学家的小项目，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