Brain reorganization in chronic back pain and opioid exposure

摘要：项目1，阿片类药物暴露的慢性疼痛中大脑的适应 目前的阿片类药物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，其中相当大一部分患者是用阿片类药物治疗的。 慢性背痛(CBP)是美国最常见的慢性疼痛症状。阿普卡里亚实验室的研究已经 研究表明，在阿片类药物使用障碍(OUD)中起关键作用的大脑成瘾回路(中皮质边缘系统)也是 与慢性疼痛的发展有因果关系。因此，这个项目和我们的 中心是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止痛药疗效的丧失/缓和至关重要。然而，在那里 几乎没有关于这个话题的人类或啮齿动物大脑成像证据，也没有关于 慢性疼痛、阿片类止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 慢性疼痛和阿片类药物暴露后的脑重组和行为反应 慢性疼痛模型(SNI)。目标1a将研究四组人：i)接受阿片类药物治疗的CBP患者和 无误用迹象(n=80)；ii)CBP和轻中度BUD患者(n=80)；iii)患者 非阿片类药物治疗的CBP组(n=25)；以及健康对照组(n=25)。我们将跟踪每天的止痛药 消费、疼痛和渴求在1-2周内报告。在一次扫描会议中，我们收集了大脑解剖数据 和功能数据(静息状态fMRI、T1、DTI、ASL)，以阐明疼痛、止痛和 滥用责任。在目标1b中，来自目标1a的所有参与者将接受运动、认知和情绪方面的评估 能力(NIH工具箱)。目标1结果应区分阿片类药物复原者和弱势群体，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%的 来自I组和II组(n=40/组)的患者将登记参加安慰剂控制的药物停药和重新治疗。 暴露研究。阿片类药物分配被推迟，以刺激渴望和/或增加疼痛，参与者 在心理戒断期间和再次暴露后进行扫描。再次暴露将涉及他们的阿片类药物， 安慰剂，或Sinemet和Naproxen(DA+NSAID，一种潜在的新疗法)，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 阿片类药物的戒断和重新暴露。目的2数据将区分用于止痛/痛觉过敏和OUD的电路， 测试DA+NSAID对大脑的影响，以及对阿片类药物状态的能力依赖。Aim 3将跟踪 SNI与Sham大鼠的脑活动和功能连接重组(rsfMRI和FDG PET)，+/- 接触吗啡。在一些大鼠中，脑成像将与病毒化学遗传操作相结合，以 解开电路和单元类型的特定重组(用于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的回路适应，并建立体内翻译 项目2-4中的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.