OTOENDOSCOPE PAIRED AGENT IMAGING OF OPIOID RECEPTOR KINETICS DURING DEPENDENCY AND WITHDRAWAL

依赖和戒断期间阿片受体动力学的耳内镜配对药剂成像

基本信息

批准号：
9529842
负责人：
Jonathan T Elliott
金额：
$ 19.93万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9529842
关键词：
Address Affinity Agonist Anatomy Area Behavior Binding Budgets Caliber Centers for Disease Control and Prevention (U.S.)Chinchilla (genus)Chronic Clinic Clinical Communities Coupled Custom Dependence Development Devices Ear Endoscopes Epidemic Evaluation Exposure to Flow Cytometry Fluorescence Fluorescent Probes Funding Future Ganglia Genetic Geometry Health Care Costs Human Image Imaging Device Imaging technology Impact evaluation Individual Injury Kinetics Knock-out Knowledge Label Labyrinth Ligand Binding Light Lighting Malignant Neoplasms Measurement Measures Methods Military Personnel Modeling Molecular Biology Monitor Mus Naloxone National Institute of Biomedical Imaging and Bioengineering Nature Opiate Addiction Opioid Opioid Antagonist Opioid Peptide Opioid Receptor Opioid agonist Opioid user Optical Tomography Pain management Patients Peptides Pharmaceutical Preparations Phenotype Physicians Physiological Plasma Population Positron-Emission Tomography Predictive Value Prescription opioid overdose Prevention Public Health Recovery Relapse Research Research Personnel Risk Rodent Model Series Services Severities Signal Transduction Societies Source Specialist Specificity Stratification Surface System Techniques Technology Testing Time Tissues United States United States National Institutes of Health Withdrawal Withdrawal Symptom Work addiction chronic pain clinical application cost desensitization design ganglion cell high risk imaging agent imaging capabilities improved in vivo individual variation lens molecular imaging mouse model mu opioid receptors novel opioid abuse opioid exposure opioid therapy opioid use opioid use disorder optical imaging prescription opioid misuse prevent receptor receptor expression receptor internalization relapse prediction relapse risk sensor societal costs spiral ganglion synthetic peptide targeted agent technology development tool

项目摘要

Summary / Abstract Opioid abuse is now a full-fledged epidemic in the United States. The CDC estimates that over 165,000 people have died from prescription opioid overdoses since 1999, and that 3,900 people start nonmedical use of prescription opioids each day. As a result, opioid use disorder (OUD) costs society an estimated $55 billion per year—twice the annual budget of the entire NIH. Most individuals with OUD began taking opioids on the advice of their physician to manage pain from work injury or injury sustained during military service, often without any knowledge of the risks of dependency. It is increasingly clear that the risks of dependency and addiction were greatly underestimated by the scientific community as well, that the most commonly administered opioids have among the highest physical and physiological dependence potentials of any abused class of drugs. However, genetic differences within the naïve population predispose certain individuals to OUD once they are exposed to opioids in a clinical setting or otherwise. These genetic differences result in mu-opioid receptor (MOR) phenotypes that differ in binding, desensitization and internalization behavior—differences which are associated with higher risk of addiction and higher severity in withdrawal symptoms (the biggest predictor of relapse). Paired agent imaging (PAI) is an established method that can quantify receptor-ligand binding potential (BP) in vivo, and could the ability to measure rate of receptor internalization if fluorescent agonist and antagonist pairs are used instead of untargeted/targeted agent pairs. These two parameters—internalization rate and binding potential—are hypothesized to predict risk of OUD in naïve users and risk of relapse in individuals recovering from OUD. We hypothesize that these clinically important differences in opioid receptor expression and behavior can be measured by otoendoscopic paired agent imaging (OPAI) of the inner ear. Therefore, we seek R21 funding under the NIBIB “trailblazer” opportunity to: (1) design and assemble a rigid otoendoscope to perform PAI of opioid binding kinetics in the inner ear, and (2) use otoendoscopic paired agent imaging (OPAI) to quantify receptor behavior during chronic opioid exposure and following naloxone-induced withdrawal using fluorescently-labeled opioid peptide agonist/antagonist pairs. The otoendoscope will consist of commercially available Storz endoscope (<2.5 mm diameter) coupled to a small module that splits the image into three bands (RGB, 700- and 800- fluorescence) and then transmits to a single sCMOS camera. A multi-LED light source of specific illumination and excitation bands is transmitted down the endoscope via the Storz light guide coupler. By the end of the project, we will address three hypotheses: (1) spiral ganglia cells of the inner ear can be imaged using an otoendoscope in order to quantify binding potential and internalization, (2) binding and internalization rate predict chronic opioid exposure and naloxone-induced withdrawal in a chinchilla model of OUD. The potential impact of this research is substantial: the ability to quantify the individual variations in opioid receptor behavior non-invasively could improve the diversion of individuals at-risk for OUD away from opioids, could prevent opioid abuse in patients using opioids for chronic pain management, and could aid in the recovery of OUD by stratifying severity of withdrawal and, by extension, relapse risk to provide individualized, appropriate support.

摘要 /摘要阿片类药物滥用现在是美国的全面流行。疾病预防控制中心估计超过165,000人自1999年以来死于处方阿片类药物过量的处方，3,900人开始非医学使用处方阿片类药物每天。结果，阿片类药物使用障碍（OUD）使社会估计每人550亿美元一年 - 整个NIH的年度预算。大多数患有OUD的人开始接受阿片类药物的建议他们的物理人管理在服兵役期间因劳动伤害或受伤而受伤的疼痛，通常没有任何了解依赖风险。越来越明显的是，依赖和成瘾的风险是最常见的阿片类药物也被科学界大大低估了在任何滥用类药物类别的最高身体和身体依赖潜力中。然而，一旦暴露于某些人在临床环境中或其他情况下的绿o中。这些遗传差异导致了Mu-Apoid受体（MOR）结合，脱敏和内在化行为不同的表型 - 相关的差异戒断症状的成瘾风险更高，严重程度较高（救济的最大预测指标）。配对代理成像（PAI）是一种既定的方法，可以在体内量化受体配体结合势（BP），如果荧光激动剂和拮抗剂对是，可以测量受体内在化速率的能力代替不靶向/靶向代理对。这两个参数 - 内部化率和绑定潜在的 - 假设可以预测幼稚的使用者的OUD风险，并恢复个人的救济风险来自Oud。我们假设这些在阿片受体表达和行为上的临床上重要差异可以通过内耳的耳管镜配对剂成像（OPAI）来测量。因此，我们寻求R21 尼比卜“开拓者”的资金机会：（1）设计和组装僵化的耳管镜来表演内耳中阿片类药物结合动力学的PAI，（2）使用耳管镜配对剂成像（OPAI）进行量化慢性阿片类药物暴露期间的受体行为以及纳洛酮引起的戒断后使用荧光标记的阿片类肽激动剂/拮抗剂对。耳管镜将包括商业上可用的Storz内窥镜（直径<2.5毫米）耦合到一个将图像分为三个频段的小模块（RGB，700-和800-荧光），然后传输到单个SCMOS摄像机。多领灯的来源特定的照明和兴奋带通过Storz Light Guide耦合器向下传播。到项目结束时，我们将解决三个假设：（1）可以成像内耳的螺旋神经节细胞使用耳管镜来量化结合势和内在化，（2）结合和内在化速率预测慢性阿片类药物暴露和纳洛酮引起的OUD龙猫模型中的戒断。这这项研究的潜在影响是很大的：量化阿片类药物接收器中各个变化的能力行为非侵入性可以改善远离阿片类药物的人的个人转移，可以防止使用阿片类药物进行慢性疼痛管理的患者滥用阿片类药物，并可以帮助恢复通过对退出的严重程度进行分层，并通过扩展为中继风险提供个性化的，适当的支持。