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.

抽象的阿片类药物是镇痛疗法的基石，但也会产生许多副作用。除了对成瘾的高度承诺外，反复的阿片类药物给药导致了进步睡眠障碍，表达为令人担忧的失眠和白天的嗜睡/睡眠。阿片类药物诱导的睡眠障碍（OISD）是多材料使用障碍的有力预测指标，并且精神病合并症，包括自杀想法。阿片类镇痛药的主要靶标药物是阿片受体（MOR）。 MOR在睡眠/唤醒中广泛表达电路，因此系统地传递的阿片类药物可能会干扰多个地点的睡眠行动。重要的是，尚未就哪些特定CNS站点达成共识治疗或滥用阿片类药物可以触发OISD，也不是当前的疗法专门解决OISD。表达黑色素，本质上光敏的残留神经节细胞（IPRGC）同步光/黑暗的环境周期的睡眠/唤醒时间表（“光疗法”）在人类和大多数哺乳动物的大脑上向大脑发送轻型诱人的尖峰火车。我们最近的工作证明IPRGC表达了Mor选择性激动剂直接抑制的MOR IPRGC的光反应。此外，我们已经证明，经过慢性，全身交付，吗啡在眼睛中积聚，并作用于IPRGC表示改变的MOR 导致慢性吗啡触发的同时，常规的睡眠/唤醒节奏行为敏化。当前建议的对象是分析阿片类药物沉积动力学是否在眼睛以及IPRGC中MOR信号的细节直接有助于较旧 OISD恶化。我们还将测试在工程纳米颗粒中提供的MORS的对手进入眼睛可以减少OISD。结果将提供小说的机械描述神经途径系统地施用阿片类药物会改变睡眠/唤醒周期。此外，结果将表明使用玻璃体内MOR选择性拮抗剂减少的可行性接受长期阿片类药物的患者睡眠障碍的严重程度和固有的合并症疗法。