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

项目摘要/摘要 阿片类药物是有效的镇痛剂，尽管有相当大的副作用和过量服药和成瘾的风险， 许多患者继续长期接受阿片类药物治疗。基于之前NIDA资助的研究(DA040154)，我们有 已公布的脑功能磁共振成像(FMRI)研究的初步数据显示，大脑显著改变 长期服用阿片类药物的患者对奖励的反应。我们来自创新高中的初步数据- 颈髓功能磁共振成像显示脊髓静息状态功能连接受损 同一患者的脊髓背角。因此，长期的阿片类药物治疗对 在大脑和脊髓水平上对刺激和神经回路的反应。由于阿片类药物的流行，那里 迫切需要了解阿片类药物的神经生物学后果，如NIDA目标1所述 战略计划，在阿片类药物戒断策略方面帮助患者和临床医生，并提供逆转的新方法 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 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 中枢神经系统中相互作用的焦点。我们的中心假设是长期服用阿片类药物 治疗患者，阿片类药物的使用暂时改善了对刺激的反应，同时扰乱了功能 大脑和脊髓内神经回路的连通性。为了验证这一假设，我们将收集和 分析来自基于任务的和静息状态的脑功能磁共振成像以及高分辨率的脊髓功能磁共振成像的数据 长期使用阿片类药物(例如，持续90天，女性纤维肌痛患者样本，AS 包括在我们的初步数据中)。我们将评估阿片类药物患者基于脑和脊髓功能磁共振成像的活性 (n=40)通过使用新的受试者内设计来比较活跃和非活跃阿片类药物状态下的活动(计时 阿片类药物使用和血液阿片类药物水平)对阿片类药物未成熟患者(N=40)和健康对照的活性的影响 (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fMRI对奖励概率的响应，以及基于静息状态fMRI的键的功能连通性 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。 基于脊髓fMRI对伤害性热刺激的反应和基于静息状态fMRI的功能 背角之间的连通性。确定与阿片类药物临床终点相关的神经生物学指标 使用/误用和成瘾行为，探索性分析将被整合到各种目标中，以评估关系 基于脑和脊髓功能磁共振成像的终点之间的差异，以及认知-情感和临床措施。一起， 拟议的项目将为神经生物学提供重要和严格的阿片类药物剂量时间证据。 长期阿片类药物治疗在整个中枢神经系统的后果。

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.