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.

项目摘要/摘要 阿片类药物是潜在的镇痛药，所需的副作用和过量成瘾的风险， 许多患者继续长期阿片类药物治疗。根据先前的NIDA资助研究（DA040154），我们有 发表了来自大脑功能MRI（fMRI）研究的初始数据，这些数据表明大脑显着改变 长期阿片类药物治疗患者的奖励反应。我们来自创新高的初步数据 颈脊髓的分辨率fMRI显示脊柱的静息状态功能连通性中断 同一患者的脐带背角。这是长期阿片类药物疗法对 对大脑和脊髓水平的刺激和神经回路的反应。由于阿片类药物流行 如NIDA的目标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制定阿片类药物戒烟策略，并为逆转方式提供新的方式 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表征 长期阿片类药物治疗对脑奖励系统和脊髓回路的神经生物学后果，2 中枢神经系统中的相互作用焦点。我们的中心假设是长期阿片类药物 治疗患者，阿片类药物的使用会瞬时改善对刺激的反应，同时破坏功能 大脑和脊髓内神经回路的连通性。为了检验这一假设，我们将收集并 分析来自大脑的基于任务和静止状态fMRI的数据，以及脊髓的高分辨率fMRI 长期阿片类药物使用者（即> 90天持续时间，纤维肌痛的女性患者均质样本 包括我们的初步数据）。我们将评估阿片类药物患者的大脑和脊髓fMRI的活性 （n = 40）通过使用新颖的受试者内设计来比较活动与非活动阿片类药物状态的活动（时机 对卵巢药物和血液溶因含量的给药和血液的水平）到没有卵动物的患者（n = 40）和健康对照组的活性 （n = 40）。在AIM 1中，我们将表征长期阿片类药物对大脑的神经生物学后果 基于fMRI对奖励概率的反应以及钥匙的基于fMRI的静止功能连接性 大脑奖励电路。在AIM 2中，我们将表征长期阿片类药物治疗的神经生物学后果 基于脊髓fMRI对有害热刺激的反应，以及基于静止状态fMRI的功能 背角之间的连通性。确定与阿片类药物临床终点有关的神经生物学靶标 使用/失误和成瘾行为，探索性分析将在评估人际关系的目标之间集成 在大脑和脊髓基于fMRI的终点以及认知影响和临床措施之间。一起， 拟议的项目将为神经生物学提供重要而严格的阿片类药物定时证据 整个中枢神经系统长期阿片类药物疗法的后果。