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

摘要 阿片类药物是止痛治疗的基石，但也会产生众多副作用。 除了有很高的成瘾倾向外，反复服用阿片类药物还会导致渐进性 睡眠障碍，表现为日益严重的失眠和日间困倦/睡眠。阿片类药物- 诱发性睡眠障碍(OISD)是多种物质使用障碍的强烈预测因素， 包括自杀意念在内的精神共病。阿片类止痛药的主要靶点 药物是微阿片受体(MOR)。MORS在睡眠/清醒时被广泛表达 因此，系统传递的阿片类药物可能会干扰多个部位的睡眠 行动。重要的是，还没有就具体的CNS地点达成共识 治疗或滥用阿片类药物会引发OISD，目前的治疗方法也不会 具体解决OISD。 表达黑素的固有光敏性视网膜神经节细胞(IpRGCs)同步 睡眠/醒来时间表对环境中的光/暗循环(“光夹带”)的影响 向人类和大多数哺乳动物的大脑发送光诱发的棘波序列。我们最近的工作 研究表明，ipRGC表达MORS，而MOR选择性激动剂通过这种方式直接抑制 IpRGC的光响应。此外，我们已经证明，在长期、系统地交付时， 吗啡在眼睛内积聚，并作用于ipRGC表达的MORS来改变 睡眠/清醒有规律的节律，同时导致慢性吗啡触发 行为敏感化。 当前提案的目标是分析阿片类药物在人体内沉积的动力学 眼球和ipRGC中MOR信号的特异性直接有助于逐渐 不断恶化的OISD。我们还将测试MORS的拮抗剂是否在工程纳米颗粒中传递 进入眼睛可以减少OISD。这些结果将为一部小说提供一种机械的描述 全身应用阿片类药物改变睡眠/觉醒周期的神经通路。另外， 结果表明，使用玻璃体腔内MOR选择性拮抗剂来减少 长期服用阿片类药物患者睡眠障碍的严重程度和固有并发症 治疗。

Abstract Opiates are the cornerstone of analgesic therapy, but also produce numerous side effects. Besides their high propensity for addiction, repeated opioid administration leads to progressive sleep disorders, expressed as worsening insomnia and daytime sleepiness/sleeping. Opioid- induced sleep disorders (OISDs) are strong predictors of multi-substance use disorders, and psychiatric comorbidities including suicidal ideation. The primary target of opioid analgesic drugs is the µ-opioid receptor (MOR). MORs are widely expressed within the sleep/wake circuitry, therefore systemically delivered opioids might interfere with sleep at multiple sites of action. Importantly, no consensus has been reached on which specific CNS sites therapeutic or abused opioids act upon to trigger OISD, nor do current therapies specifically address OISD. Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) synchronize the sleep/wake schedule to environmental cycles of light/darkness (“photoentrainment”) by sending light-evoked spike trains to the brain in humans and most mammals. Our recent work demonstrated that ipRGCs express MORs by which MOR-selective agonists directly inhibit the light responses of ipRGCs. Furthermore, we have shown that upon chronic, systemic delivery, morphine accumulates in the eye, and acts on MORs expressed by ipRGCs to alter the regular rhythm of sleep/wake while contributing to the chronic morphine-triggered behavioral sensitization. The objectives of the current proposal are to analyze whether kinetics of opioid deposition in the eye along with specifics of MOR signaling in ipRGCs directly contribute to the gradually worsening OISD. We will also test if antagonist of MORs delivered in engineered nanoparticles into the eye can reduce OISDs. The results will provide a mechanistic description of a novel neural pathway by which systemically administered opioids alter sleep/wake cycle. Additionally, the results will show the feasibility of using intravitreal MOR selective antagonists to reduce the severity and inherent comorbidities of sleep disorders in patients receiving long-term opioid therapies.