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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

基本信息

批准号：
10736610
负责人：
Jozsef Vigh
金额：
$ 38.65万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736610
关键词：
ABCB1 gene Address Adenylate Cyclase Affect Agonist Analgesics Artificial nanoparticles Behavior Behavioral Blood Blood - brain barrier anatomy Blood-Retinal Barrier Brain Cells Chronic Competitive Binding Consensus Coupled Coupling Cyclic AMP Darkness Data Deposition Development Devices Diclofenac Dose Drowsiness Drug Delivery Systems Drug Kinetics Electroencephalography Electrophysiology (science)Encapsulated Etiology Eye Feeling suicidal GTP-Binding Proteins Grant Human Image Kinetics Light Mammals Measures Mediating Micelles Molecular Morphine Mus Naloxone Neural Pathways Neurons Opioid Opioid Analgesics Opioid Receptor Pain Threshold Pathway interactions Patients Preparation Process Reporter Retina Retinal Ganglion Cells Schedule Severities Signal Transduction Site Sleep Sleep Deprivation Sleep Disorders Sleep Wake Cycle Sleep disturbances Sleeplessness Substance Use Disorder System Telemetry Testing Therapeutic Training Transfection Up-Regulation Work addiction adeno-associated viral vector antagonist behavioral sensitization biomaterial compatibility chemical binding chronic pain management chronic pain patient circadian pacemaker comorbidity connective tissue-activating peptide copolymer endogenous opioids improved insight inward rectifier potassium channel melanopsin nanoparticle neuroregulation novel opioid abuse opioid therapy patch clamp pharmacologic polysubstance use psychiatric comorbidity response side effect therapeutic target tool trafficking voltage

项目摘要

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.

摘要阿片类药物是镇痛治疗的基石，但也产生许多副作用。除了他们的高成瘾倾向外，重复的阿片类药物给药会导致进行性的睡眠障碍，表现为失眠加重和白天嗜睡/睡眠。阿片类- 诱发性睡眠障碍（OISDs）是多种物质使用障碍的强预测因子，精神共病包括自杀意念。阿片类镇痛药的主要作用靶点阿片受体（莫尔）。MORs在睡眠/觉醒中广泛表达，因此，全身递送的阿片类药物可能会干扰多个部位的睡眠。行动上重要的是，对于哪些特定的中枢神经系统位点尚未达成共识治疗性或滥用的阿片类药物作用于触发OISD，目前的治疗方法也没有特别是关于OISD。表达黑视素的内在光敏视网膜神经节细胞（ipRGC）同步根据光/暗的环境循环（“光诱导”）的睡眠/唤醒时间表，向人类和大多数哺乳动物的大脑发送光诱发的尖峰序列。我们最近的工作证明ipRGC表达MOR，MOR选择性激动剂通过其直接抑制IPRGC的表达。 ipRGC的光响应。此外，我们已经表明，在长期的，全身性的交付，吗啡在眼睛中积聚，并作用于ipRGC表达的MORs，以改变眼睛的功能。规律的睡眠/觉醒节律，同时有助于慢性吗啡触发的行为敏感化本提案的目的是分析阿片样物质沉积的动力学是否在眼沿着ipRGC中的莫尔信号传导的特异性直接促成了 OISD恶化我们还将测试MORs拮抗剂是否在工程纳米颗粒中递送可以减少OISDs。结果将提供一个新的机制描述系统给予阿片类药物改变睡眠/觉醒周期的神经通路。此外，本发明还结果将显示使用玻璃体内莫尔选择性拮抗剂来减少长期接受阿片类药物治疗患者睡眠障碍的严重程度和固有合并症治疗