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，大脑对阿片类药物暴露引起的慢性疼痛的适应 当前阿片类药物的流行与慢性疼痛的临床治疗密切相关。 15-20%的 美国人口患有这种疾病，其中相当一部分患者接受阿片类药物治疗。 慢性背痛 (CBP) 是美国最常见的慢性疼痛状况。 Apkarian 实验室的研究 研究表明，在阿片类药物使用障碍 (OUD) 中至关重要的脑成瘾回路（中皮质边缘系统）也与 与慢性疼痛的发生有因果关系。因此，这个项目以及我们的总体假设 中心，阿片类药物滥用倾向和慢性疼痛的发展是相互作用的大脑过程，并且 对于解释滥用倾向的临床结果和镇痛功效的丧失/减弱至关重要。然而，有 实际上没有关于该主题的人类或啮齿动物脑成像证据，以及有关该主题的生理知识 慢性疼痛、阿片类镇痛和滥用倾向之间的相互作用很小。在这个项目中，我们将研究 CBP 和大鼠中阿片类药物暴露引起的慢性疼痛的大脑重组和行为反应 慢性疼痛模型（SNI）。目标 1a 将研究四个群体：i) 使用阿片类药物治疗的 CBP 个体和 无滥用迹象（n=80）； ii) 患有 CBP 和轻度至中度 OUD 的患者（mOUD，n=80）； iii) 患者 CBP 在不使用阿片类药物的情况下进行治疗 (n=25)； iv) 健康对照 (n=25)。我们会追踪每天的镇痛药物 1-2 周内的消耗、疼痛和渴望报告。在一次扫描过程中，我们收集大脑解剖结构 和功能数据（静息态 fMRI、T1、DTI、ASL），以阐明疼痛、镇痛和疼痛的神经相关性 滥用责任。在目标 1b 中，目标 1a 的所有参与者都将接受运动、认知和情感方面的评估 能力（NIH 工具箱）。目标 1 结果应区分阿片类药物耐受群体和弱势群体，以及 揭示阿片类药物暴露对能力和相关大脑适应不良的影响。在目标 2a 中，50% 第 i 组和第 ii 组的患者（n=40/组）将被纳入安慰剂对照药物戒断和重新治疗 暴露研究。阿片类药物的配发延迟会引起渴望和/或增加疼痛，并且参与者 在心理戒断期间和重新暴露后进行扫描。再次接触将涉及他们的阿片类药物， 安慰剂，或辛奈美和萘普生（DA+NSAID，一种潜在的新型治疗方法），在双盲、随机、 交叉设计。目标 2b 将评估不同阶段运动、认知和情感能力的变化 阿片类药物戒断和重新暴露。目标 2 数据将区分镇痛/痛觉过敏和 OUD 的电路， 测试DA+NSAID对大脑的影响，以及能力对阿片状态的依赖性。目标 3 将追踪 SNI 与假大鼠的大脑活动和功能连接重组（rsfMRI 和 FDG PET），+/- 吗啡暴露。在一些大鼠中，脑成像将与病毒化学遗传学操作相结合，以 解开电路和细胞类型特定的重组（针对 VTA、NAc 和 dH）。目标 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 项目 2-4 中小鼠体外研究的有效性。