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

摘要 慢性疼痛(CP)是多种疾病的基本特征，包括 关节炎、偏头痛、癌症、代谢紊乱和神经病；它至少困扰着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。除了发展的高倾向外， 阿片成瘾，失眠型睡眠问题与白天嗜睡和 在接受长期阿片类药物治疗的患者中，大约90%会出现抑郁 减少脑瘫的痛苦。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慢性阻塞性肺病患者的思维状态。因此，理解细胞 导致睡眠障碍的机制和神经元回路 长期使用阿片类药物治疗对那些遭受慢性疼痛的人来说绝对是 对于确定睡眠中断是否是可修改的风险因素至关重要 自杀念头。 含有黑素的固有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枢是 负责光携带睡眠/觉醒周期的主要管道。我们 发现ipRGC表达微阿片受体(MORs)和我们的初步数据 结果显示，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，系统应用的阿片类药物穿过了紧绷的血液/视网膜 阻隔并到达ipRGCs。当前提案的目标是分析如何 阿片类物质改变ipRGC的光诱发活动并研究其行为后果 阿片类药物对ipRGC介导的昼夜睡眠/觉醒的光包裹的调节作用 循环。该项目的结果将提供一种新的神经的机械描述 系统给予阿片类药物改变光驱动行为的途径，包括 睡眠/唤醒周期。此外，数据将预测使用MOR SELECTIONAL的可行性 IpRGC表达的靶向MORS的拮抗剂可减轻严重程度和 接受长期阿片类药物治疗的患者睡眠障碍的固有共病。

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.