Neurobiological Consequences of Long-Term Opioid Therapy in the Brain and Spinal Cord

长期阿片类药物治疗对大脑和脊髓的神经生物学后果

• 批准号: 10706466
• 负责人: Katherine Theresa Martucci
• 金额: $ 66.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706466
• 关键词: Absence of pain sensation; Address; Advocate; Affect; Affective; Analgesics; Attenuated; Behavior; Behavioral; Blood; Brain; Brain region; Central Nervous System; Cervical spinal cord structure; Clinical; Clinical Trials; Cognition; Cognitive; Data; Dependence; Dose; Drug Addiction; Female; Functional Magnetic Resonance Imaging; Funding; Future; Goals; Human; Hyperalgesia; Impairment; Knowledge; Measures; Medial; Motivation; National Institute of Drug Abuse; Neurobiology; Nucleus Accumbens; Opiate Addiction; Opioid; Pain management; Patients; Prefrontal Cortex; Probability; Psychology; Publishing; Reporting; Research; Resolution; Rest; Rewards; Risk; Sampling; Sensory; Spinal; Spinal Cord; Spinal cord posterior horn; Stimulus; Strategic Planning; System; Testing; Vertebral column; Work; addiction; brain based; clinical pain; combat; cost; design; dorsal horn; fibromyalgia patients; financial incentive; heat stimulus; improved; innovation; neglect; neural circuit; neuroimaging; novel; opioid epidemic; opioid mortality; opioid therapy; opioid use; opioid use disorder; opioid user; overdose risk; patients who use opioids; response; reward anticipation; reward circuitry; side effect

Project Summary/Abstract Opioids are potent analgesics, and despite considerable side effects and risks for overdose and addiction, many patients continue long-term opioid therapy. Based on prior NIDA-funded research (DA040154), we have published initial data from brain functional MRI (fMRI) studies that demonstrate significantly altered brain response to reward in patients on long-term opioid therapy. Our preliminary data from innovative high- resolution fMRI of the cervical spinal cord revealed disrupted resting-state functional connectivity of the spinal cord dorsal horns in the same patients. Thus, long-term opioid therapy has neurobiological consequences on responses to stimuli and neural circuitry at both brain and spinal cord levels. Due to the opioid epidemic, there is an urgent need to understand neurobiological consequences of opioids, as stated in Goal 1 of the NIDA Strategic Plan, to aid patients and clinicians in opioid cessation strategies, and to inform novel ways to reverse neurobiological consequences of long-term opioid use. Our overall objective in this project is to characterize neurobiological consequences of long-term opioid therapy on brain reward systems and spinal cord circuitry, 2 interacting focal points in the central nervous system. Our central hypothesis is that in long-term opioid therapy patients, opioid use transiently improves responses to stimuli, while disrupting functional connectivity of neural circuits within the brain and spinal cord. To test this hypothesis, we will collect and analyze data from task-based and resting-state fMRI of the brain, and high-resolution fMRI of the spinal cord in long-term opioid users (ie, > 90 days duration, homogeneous sample of female patients with fibromyalgia, as included in our preliminary data). We will evaluate brain and spinal cord fMRI-based activity in opioid patients (N = 40) by using a novel within-subject design to compare activity in active vs non-active opioid states (timed to opioid administration and blood opioid level) to activity in opioid-naïve patients (N = 40) and healthy controls (N = 40). In Aim 1, we will characterize neurobiological consequences of long-term opioid therapy on brain fMRI-based response to reward probability, and on resting-state fMRI-based functional connectivity of a key brain reward circuit. In Aim 2, we will characterize neurobiological consequences of long-term opioid therapy on spinal cord fMRI-based response to noxious heat stimuli, and on resting-state fMRI-based functional connectivity between dorsal horns. To identify neurobiological targets related to clinical endpoints of opioid use/misuse and addiction behavior, exploratory analyses will be integrated across aims to assess relationships between brain and spinal cord fMRI-based endpoints, and cognitive-affective and clinical measures. Together, the proposed project will provide important and rigorous opioid dose-timed evidence of neurobiological consequences of long-term opioid therapy across the central nervous system.

项目概要/摘要 阿片类药物是有效的镇痛药，尽管存在相当大的副作用以及过量和成瘾的风险， 根据 NIDA 资助的先前研究 (DA040154)，许多患者继续长期阿片类药物治疗。 发表的脑功能 MRI (fMRI) 研究的初步数据表明，大脑功能显着 我们的初步数据来自创新的高水平药物治疗患者对奖励的反应。 颈脊髓的分辨率功能磁共振成像显示脊髓静息态功能连接中断 因此，长期阿片类药物治疗会对同一患者的脊髓背角产生神经生物学影响。 由于阿片类药物的流行，大脑和脊髓水平对刺激和神经回路的反应。 正如 NIDA 目标 1 中所述，迫切需要了解阿片类药物的神经生物学后果 战略计划，帮助患者和行人制定阿片类药物戒断策略，并提供新的扭转方法 我们在这个项目中的总体目标是描述长期使用阿片类药物的神经生物学后果。 长期阿片类药物治疗对大脑奖励系统和脊髓回路的神经生物学影响，2 我们的中心假设是长期阿片类药物中的焦点相互作用点。 在治疗患者中，阿片类药物的使用会暂时改善对刺激的反应，同时扰乱功能 为了检验这一假设，我们将收集并研究大脑和脊髓内神经回路的连通性。 分析来自基于任务和静息状态的大脑功能磁共振成像以及脊髓的高分辨率功能磁共振成像的数据 长期阿片类药物使用者（即持续时间 > 90 天，纤维肌痛女性患者的同质样本，如 包括在我们的初步数据中）我们将评估阿片类药物患者的大脑和脊髓功能磁共振成像活动。 (N = 40) 通过使用一种新颖的受试者内设计来比较活性阿片类药物与非活性阿片类药物状态的活性（定时） 阿片类药物给药和血液阿片类药物水平) 未使用阿片类药物的患者 (N = 40) 和健康对照的活动 （N = 40），在目标 1 中，我们将描述长期阿片类药物治疗对大脑的神经生物学后果。 基于功能磁共振成像的奖励概率响应，以及基于静息状态功能磁共振成像的关键功能连接 在目标 2 中，我们将描述长期阿片类药物治疗的神经生物学后果。 基于脊髓 fMRI 的对有害热刺激的反应，以及基于静息态 fMRI 的功能 确定与阿片类药物临床终点相关的神经生物学目标。 使用/误用和成瘾行为，探索性分析将被整合到评估关系的目标中 大脑和脊髓基于功能磁共振成像的终点以及认知情感和临床测量之间的联系。 拟议的项目将为神经生物学提供重要且严格的阿片类药物剂量定时证据 长期阿片类药物治疗对中枢神经系统的影响。