Brain reorganization in chronic back pain and opioid exposure

慢性背痛和阿片类药物暴露的大脑重组

• 批准号: 10198885
• 负责人: Apkar Vania Apkarian
• 金额: $ 59.07万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198885
• 关键词: Absence of pain sensation; Analgesics; Anatomy; Animals; Biological Markers; Brain; Brain imaging; Brain scan; Cells; Characteristics; Clinical; Clinical Management; Clinical Trials; Cognitive; Consumption; Crossover Design; Data; Data Analyses; Dependence; Development; Dose; Double-Blind Method; Drug abuse; Emotional; Enrollment; Ensure; Exposure to; Female; Functional Magnetic Resonance Imaging; Genetic study; Human; Hyperalgesia; In Vitro; Individual; Knowledge; Link; Measures; Modeling; Molecular Genetics; Morphine; Motor; Mus; Naproxen; Non-Steroidal Anti-Inflammatory Agents; Opiate Addiction; Opioid; Opioid Analgesics; Outcome; Pain; Participant; Patients; Pharmaceutical Preparations; Phase; Physiological; Placebos; Population; Positron-Emission Tomography; Procedures; Process; Property; Psychological Dependence; Randomized; Rattus; Reporting; Research; Rest; Risk; Risk Factors; Rodent; Scanning; Self Administration; Series; Services; Signs and Symptoms; Sinemet; Study Subject; System; Testing; Time; Translating; United States National Institutes of Health; Validation; Viral; Visit; Vulnerable Populations; Withdrawal; addiction; behavioral response; blind; cell type; chronic back pain; chronic pain; chronic pain management; chronic painful condition; clinical application; conditioned place preference; craving; drug craving; drug withdrawal; experimental group; fluorodeoxyglucose positron emission tomography; human data; human subject; imaging study; in vivo; nerve injury; neural correlate; novel; opioid abuse; opioid epidemic; opioid exposure; opioid therapy; opioid use; opioid use disorder; opioid withdrawal; psychologic; sex; spared nerve; virtual

Abstract: Project 1, Adaptations of the brain in chronic pain with opioid exposure The current opioid epidemic is intimately linked with the clinical management of chronic pain. 15-20% of the US population suffers from the condition, and a sizable proportion of such patients are managed with opioids. Chronic back pain (CBP) is the most common chronic pain condition in the US. Research in the Apkarian lab has shown that brain addiction circuitry (mesocorticolimbic system), critical in opioid use disorder (OUD), is also causally linked to the development of chronic pain. Thus, an overarching hypothesis of this Project, and of our Center, is that opioid abuse liability and the development of chronic pain are interacting brain processes, and critical to explaining clinical outcomes of abuse liability and the loss/moderation of analgesic efficacy. Yet, there is virtually no human or rodent brain imaging evidence on the topic, and physiologic knowledge regarding the interaction between chronic pain, opioid analgesia and abuse liability is minimal. In this project, we will study brain reorganization and behavioral responses in chronic pain with opioid exposure, both in CBP and in a rat model of chronic pain (SNI). Aim 1a will study four groups: i) individuals with CBP managed with opioids and no signs of misuse (n=80); ii) patients with CBP and mild to moderate OUD (mOUD, n=80); iii) patients with CBP managed without opioids (n=25); and iv) healthy controls (n=25). We will track daily analgesic drug consumption and pain and craving reports over 1-2 weeks. In a single scan session, we collect brain anatomical and functional data (resting state fMRI, T1, DTI, ASL) to elucidate the neural correlates of pain, analgesia, and abuse liability. In Aim 1b, all participants from aim 1a will be assessed for motor, cognitive and emotional abilities (NIH Toolbox). Aim 1 results should distinguish between opioid resilient and vulnerable groups, and unravel the impact of opioid exposure on abilities and related brain maladaptations. In Aim 2a, 50% of the patients from groups i and ii (n=40/group) will be enrolled into a placebo-controlled drug withdrawal and re- exposure study. Opioid drug dispensing is delayed to provoke craving and/or increased pain, and participants are scanned during psychological withdrawal and after re-exposure. Re-exposure will involve their opioid drug, placebo, or sinemet and naproxen (DA+NSAID, a potential novel treatment), in a double-blind, randomized, cross-over design. Aim 2b will assess changes in motor, cognitive and emotional abilities at different phases of opioid withdrawal and re-exposure. Aim 2 data will differentiate circuitry for analgesia/hyperalgesia and OUD, test the effects of DA+NSAID on the brain, and the dependence of abilities on opioid states. Aim 3 will track brain activity and functional connectivity reorganization (rsfMRI and FDG PET), in SNI vs. sham rats, +/- morphine exposure. In some rats, brain imaging will be combined with viral chemogenetic manipulations to unravel circuit- and cell- type specific reorganization (for VTA, NAc, and dH). Aim 3 data will provide cross- species correspondences, linking human and rodent circuit adaptations, and establish in-vivo translational validity for the mouse in-vitro studies in Projects 2-4.

摘要：项目1，大脑在慢性疼痛中与阿片类药物暴露的适应 当前的阿片类药物流行与慢性疼痛的临床管理密切相关。 15-20％ 美国人口遭受了这种疾病的痛苦，大量此类患者由阿片类药物进行管理。 慢性背痛（CBP）是美国最常见的慢性疼痛状况。 Apkarian Lab的研究 表明大脑成瘾电路（中皮质降临系统）在阿片类药物使用障碍（OUD）中也很重要 因果关系与慢性疼痛的发展有关。因此，这个项目和我们的总体假设 中心是阿片类药物滥用责任和慢性疼痛的发展正在与大脑过程相互作用，并且 对于解释虐待责任的临床结果和止痛功效的损失/适度至关重要。但是，那里 几乎没有关于该主题的人类或啮齿动物的脑成像证据，也没有有关该主题的生理知识 慢性疼痛，阿片类镇痛和滥用责任之间的相互作用很小。在这个项目中，我们将学习 在CBP和大鼠中，慢性疼痛的脑重组和行为反应以及阿片类药物暴露 慢性疼痛模型（SNI）。 AIM 1A将研究四个小组：i）患有阿片类药物的CBP的人 没有滥用的迹象（n = 80）; ii）CBP和轻度至中度OUD的患者（MOUD，n = 80）； iii）患者 无阿片类药物管理的CBP（n = 25）;和iv）健康对照（n = 25）。我们将跟踪每日镇痛药 消费，疼痛和渴望报告在1-2周内。在一次扫描中，我们收集大脑解剖学 和功能数据（静止状态fMRI，T1，DTI，ASL），以阐明疼痛，镇痛和 虐待责任。在AIM 1B中，AIM 1A的所有参与者都将用于运动，认知和情感 能力（NIH工具箱）。 AIM 1结果应区分阿片类药物弹性和脆弱的群体，以及 揭示阿片类药物暴露对能力和相关脑部疾病的影响。在AIM 2A中，有50％ I和II组的患者（n = 40/组）将被招募到安慰剂控制的药物戒断中 暴露研究。阿片类药物分配被推迟以引起渴望和/或增加疼痛，参与者 在心理戒断期间和重新暴露后进行扫描。重新暴露将涉及其阿片类药物， 安慰剂或sinemet和萘普生（DA+NSAID，一种潜在的新型治疗方法），双盲，随机，随机， 跨界设计。 AIM 2B将在不同阶段的运动，认知和情感能力的变化评估 阿片类药物提取和重新暴露。 AIM 2数据将使镇痛/痛觉过敏和OUD的电路区分开 测试DA+NSAID对大脑的影响以及能力对阿片类药物的依赖性。 AIM 3将跟踪 大脑活动和功能连通性重组（RSFMRI和FDG PET），SNI与假大鼠，+/- 吗啡暴露。在某些大鼠中，大脑成像将与病毒化学发生操作结合 解开电路和细胞类型特异性重组（用于VTA，NAC和DH）。 AIM 3数据将提供交叉 - 物种对应关系，连接人类和啮齿动物电路适应并建立体内翻译 小鼠在项目2-4中的体外研究的有效性。