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）是潜水疾病谱系的主要特征 关节炎，偏头痛，癌症，代谢性疾病和神经病；它至少折磨20 – 30％的美国人。阿片类药物仍然是CP治疗的药物基石， 尽管可能有害副作用。除了发展的高希望 卵毒素成瘾，失眠型睡眠问题与白天嗜睡和 抑郁症发生在接受长期阿片类药物治疗的患者中约90％发生 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患者的念头。因此，了解细胞 机理和神经元电路导致与睡眠障碍相关的睡眠障碍 在患有慢性疼痛的人中，长期阿片类药物疗法绝对是 确定睡眠中断是否是可修改的风险因素的至关重要 自杀的想法。 含有黑色素的含有内在光敏的残留神经节细胞（IPRGC） 投射到界面核和其他促进睡眠的大脑中心是 负责睡眠/唤醒周期光注射的主要导管。我们 发现IPRGC表达µ-阿片类药物接收器（MOR）和我们的初步数据 表明，特定于MOR的激动剂强烈衰减IPRGC的诱发发射。 有力的证据表明，系统地使用阿片类药物穿过紧密的血/视网膜 障碍和触及IPRGC。当前建议的对象是分析 opioids改变了IPRGC的轻度诱发活性，并研究行为后果 IPRGC介导的昼夜节律光疗法的阿片类药物调节 周期。该项目的结果将提供新型中性的机械描述 系统管理的阿片类药物改变了轻度驱动的行为，包括 睡眠/唤醒周期。此外，数据将预测使用MOR选择性的可行性 IPRGC表达的MOR的焦点靶向的拮抗剂，以减少严重性和 接受长期阿片类药物疗法的患者睡眠障碍的固有合并症。