Brain reorganization in chronic back pain and opioid exposure

翻译后摘要：项目1，适应大脑在慢性疼痛与阿片类药物暴露 目前阿片类药物的流行与慢性疼痛的临床管理密切相关。15-20%的 美国人口患有这种疾病，相当大比例的此类患者使用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症状。阿普卡利亚实验室的研究 表明在阿片类药物使用障碍（OUD）中至关重要的大脑成瘾回路（中皮质边缘系统）也 与慢性疼痛的发展有因果关系。因此，这个项目的总体假设，以及我们的 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， 对于解释滥用倾向和镇痛疗效丧失/减轻的临床结果至关重要。然而， 几乎没有人类或啮齿动物的大脑成像证据的主题，和生理知识， 慢性疼痛、阿片类镇痛和滥用倾向之间的相互作用是最小的。在这个项目中，我们将研究 慢性疼痛与阿片类药物暴露的脑重组和行为反应，在CBP和大鼠中 慢性疼痛模型（SNI）。目标1a将研究四组：i）使用阿片类药物管理的CBP患者， 无误用迹象（n=80）; ii）CBP和轻度至中度OUD（mOUD，n=80）患者; iii） CBP管理没有阿片类药物（n=25）;和iv）健康对照（n=25）。我们会追踪每天的止痛药 消费和疼痛和渴望报告超过1-2周。在一次扫描中，我们收集了大脑解剖学数据， 和功能数据（静息状态fMRI，T1，DTI，ASL），以阐明疼痛，镇痛， 滥用责任在目标1b中，目标1a中的所有参与者都将接受运动、认知和情绪评估。 能力（NIH）。目标1的结果应区分阿片类药物弹性和弱势群体， 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， 来自组I和组II的患者（n=40/组）将被纳入安慰剂对照的药物停药和再给药。 暴露研究。阿片类药物分发延迟，以引起渴望和/或增加疼痛， 在心理戒断期和再次接触后进行扫描。再次接触将涉及他们的阿片类药物， 安慰剂，或辛尼美和萘普生（DA+NSAID，一种潜在的新型治疗），在一项双盲，随机， 交叉设计目标2b将评估运动、认知和情绪能力在不同阶段的变化。 阿片类药物戒断和再暴露。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将跟踪 SNI与假手术大鼠的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， 解开电路和细胞类型特异性重组（VTA，NAc和dH）。Aim 3数据将提供交叉- 物种对应，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。

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.