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

摘要 慢性疼痛（CP）是多种疾病的主要特征，包括 关节炎，偏头痛，癌症，代谢紊乱和神经病;它折磨至少20- 30%的美国人阿片类药物仍然是CP治疗的药理学基础， 尽管有潜在的有害副作用。除了高倾向于发展 阿片类药物成瘾，与白天嗜睡相关的失眠型睡眠问题， 抑郁症发生在大约90%的接受长期阿片类药物治疗的人中， 减轻CP的痛苦。重要的是，睡眠障碍是自杀的一个严重风险因素 接受阿片类药物治疗的CP患者的思维能力。因此，了解细胞 机制和神经回路有助于睡眠障碍相关 长期阿片类药物治疗慢性疼痛的患者， 对于确定睡眠中断是否是一个可改变的风险因素至关重要， 自杀意念 含黑视素的内在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的神经元是 负责睡眠/觉醒周期的光夹带的主要管道。我们 发现ipRGCs表达μ-阿片受体（MORs），我们的初步数据显示， 显示莫尔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穿过紧密的血液/视网膜 屏障并到达ipRGC。本提案的目标是分析如何 阿片类药物改变ipRGCs的光诱发活性，并研究其行为后果。 ipRGC介导的昼夜节律睡眠/觉醒的光诱导的阿片调节 自行车.该项目的结果将提供一个新的神经机制的描述 全身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，数据将预测使用莫尔选择性 用于靶向由ipRGC表达的MOR的局灶性拮抗剂，以降低严重性， 接受长期阿片类药物治疗的患者中睡眠障碍的固有合并症。

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.