Opioid Modulation of Retinal Ganglion Cells Providing Photoentrainment of the Circadian Clock

视网膜神经节细胞的阿片类药物调节提供昼夜节律时钟的光诱导

• 批准号: 10200064
• 负责人: Jozsef Vigh
• 金额: $ 36.26万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200064
• 关键词: Acute; Agonist; American; Arthritis; Attenuated; Behavior; Blood-Retinal Barrier; Brain; Calcium Channel; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Cyclic AMP; Darkness; Data; Development; Disease; Drowsiness; Electroencephalography; Electrophysiology (science); Feeling suicidal; Fluorescence; Health; Human; Individual; Ion Channel; Light; Malignant Neoplasms; Mammals; Mediating; Mental Depression; Metabolic Diseases; Methadone; Migraine; Molecular; Morphine; Mus; Neural Pathways; Neurons; Neuropathy; Opiate Addiction; Opioid; Pain management; Pathologic Processes; Pathway interactions; Patients; Pharmacology; Photosensitivity; Potassium; Preparation; Prevalence; Process; Protocols documentation; Pupil light reflex; Reporter; Reporting; Retina; Retinal Ganglion Cells; Risk Factors; Running; Schedule; Severities; Signal Transduction; Signal Transduction Inhibitor; Signal Transduction Pathway; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Sleeplessness; Slice; Structure; Synapses; Telemetry; Testing; Vision; Wild Type Mouse; addiction; base; behavioral study; chronic pain; chronic pain patient; circadian; circadian pacemaker; comorbidity; experimental study; melanopsin; modifiable risk; mu opioid receptors; multi-electrode arrays; neuronal circuitry; neuroregulation; novel; opioid therapy; opioid user; patch clamp; postsynaptic; response; retinal neuron; side effect; sleep pattern; suprachiasmatic nucleus; therapeutic target; tool; voltage clamp

Abstract Chronic pain (CP) is a cardinal feature of a diverse spectrum of diseases including arthritis, migraine, cancer, metabolic disorders, and neuropathies; it afflicts at least 20– 30% of Americans. Opioids remain the pharmacological cornerstone of CP therapy, despite potentially harmful side effects. In addition to the high propensity for developing opioid addiction, insomnia-type sleep problems associated with daytime sleepiness and depression occur in approximately 90% of those receiving long-term opioid treatment to reduce suffering from CP. Importantly, sleep disorder is a serious risk factor for suicidal ideation in CP patients receiving opioid therapy. Therefore, understanding the cellular mechanisms and neuronal circuits contributing to sleep disturbances associated with long-term opioid therapy in those suffering from chronic pain is absolutely critical for determining whether sleep disruption is a modifiable risk factor for suicidal ideation. Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting to the suprachiasmatic nucleus and other sleep-promoting brain centers are the principal conduits responsible for photoentrainment of sleep/wake cycle. We found that ipRGCs express µ-opioid receptors (MORs) and our preliminary data shows that MOR specific agonists strongly attenuate light-evoked firing of ipRGCs. Strong evidence suggests that systemically applied opioids cross the tight blood/retina barrier and reach ipRGCs. The objectives of the current proposal are to analyze how opioids alter light-evoked activity of ipRGCs and to study the behavioral consequences of opioid modulation of ipRGC-mediated photoentrainment of circadian sleep/wake cycles. The results of this project will provide a mechanistic description of a novel neural pathway by which systemically administered opioids alter light-driven behavior, including sleep/wake cycle. Additionally, the data will predict the feasibility of using MOR selective antagonists for focal targeting of MORs expressed by ipRGCs to reduce the severity and inherent comorbidities of sleep disorders in patients receiving long-term opioid therapies.

抽象的 慢性疼痛 (CP) 是多种疾病的主要特征，包括 关节炎、偏头痛、癌症、代谢紊乱和神经病；它困扰着至少20- 30%的美国人。阿片类药物仍然是 CP 治疗的药理学基石， 尽管有潜在的有害副作用。除了高发展倾向之外 阿片类药物成瘾、与白天嗜睡相关的失眠型睡眠问题和 大约 90% 接受长期阿片类药物治疗的人会出现抑郁症 减少 CP 的痛苦。重要的是，睡眠障碍是自杀的严重危险因素 接受阿片类药物治疗的 CP 患者的意念。因此，了解细胞 导致睡眠障碍的机制和神经元回路 对于那些患有慢性疼痛的人来说，长期阿片类药物治疗绝对是有效的 对于确定睡眠中断是否是可改变的风险因素至关重要 自杀意念。 含有黑视蛋白的本质光敏视网膜神经节细胞（ipRGC） 投射到视交叉上核和其他促进睡眠的大脑中心是 负责睡眠/觉醒周期的光诱导的主要导管。我们 发现 ipRGC 表达 µ-阿片受体 (MOR) 以及我们的初步数据 表明 MOR 特异性激动剂强烈减弱 ipRGC 的光诱发放电。 强有力的证据表明，全身应用的阿片类药物会穿过紧密的血液/视网膜 屏障并到达 ipRGC。当前提案的目标是分析如何 阿片类药物改变 ipRGC 的光诱发活动并研究其行为后果 阿片类药物对 ipRGC 介导的昼夜节律睡眠/觉醒光诱导的调节 循环。该项目的结果将为新型神经网络提供机制描述 全身施用阿片类药物改变光驱动行为的途径，包括 睡眠/觉醒周期。此外，数据将预测使用 MOR 选择性的可行性 拮抗剂用于局部靶向 ipRGC 表达的 MOR，以减轻严重程度和 接受长期阿片类药物治疗的患者存在睡眠障碍的固有合并症。