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.

项目总结/摘要 阿片类药物是强效镇痛剂，尽管有相当大的副作用和过量和成瘾的风险， 许多患者继续长期阿片类药物治疗。基于先前NIDA资助的研究（DA 040154），我们 发表的脑功能磁共振成像（fMRI）研究的初步数据表明， 长期阿片类药物治疗患者对奖励的反应。我们的初步数据来自创新高- 颈脊髓的分辨率fMRI显示脊髓的静息状态功能连接中断， 同一患者的脊髓背角。因此，长期阿片类药物治疗对神经生物学的影响， 对大脑和脊髓水平的刺激和神经回路的反应。由于阿片类药物的流行， 正如NIDA目标1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，以帮助患者和临床医生在阿片类药物戒断策略，并告知新的方法来扭转 长期使用阿片类药物的神经生物学后果。我们在这个项目中的总体目标是描述 长期阿片类药物治疗对大脑奖赏系统和脊髓回路的神经生物学后果，2 中枢神经系统中相互作用的焦点。我们的中心假设是，在长期阿片类药物 治疗患者，阿片类药物的使用短暂地改善了对刺激的反应，同时破坏了功能， 大脑和脊髓内神经回路的连接。为了验证这一假设，我们将收集和 分析大脑基于任务和静息状态的功能磁共振成像数据，以及脊髓的高分辨率功能磁共振成像数据， 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， 包括在我们的初步数据中）。我们将评估阿片类药物患者的脑和脊髓基于fMRI的活动 （N = 40）通过使用一种新的受试者内设计比较活性与非活性阿片样物质状态下的活性（定时）， 阿片类药物初治患者（N = 40）和健康对照组中的阿片类药物给药和血液阿片类药物水平）与活性 （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影响。 基于fMRI的对奖励概率的响应，以及基于键的静息状态fMRI的功能连接 大脑奖励回路在目标2中，我们将描述长期阿片类药物治疗的神经生物学后果 脊髓对有害热刺激的基于fMRI的反应，以及静息状态下基于fMRI的功能性 背角之间的连接。确定与阿片类药物临床终点相关的神经生物学靶点 使用/滥用和成瘾行为，探索性分析将整合到目标中，以评估关系 脑和脊髓功能磁共振成像为基础的终点之间，认知情感和临床措施。在一起， 拟议的项目将提供重要且严格的阿片类药物剂量计时神经生物学证据 长期阿片类药物治疗对中枢神经系统的影响