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

• 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
• 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

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在美国是一种全面的流行病。疾控中心估计，超过16.5万人 自1999年以来，已有3900人死于处方阿片类药物过量，并开始非医疗用途 每天都有处方阿片类药物。因此，阿片类药物使用障碍(OUD)给社会造成的损失估计为每人550亿美元。 一年--是整个NIH年度预算的两倍。大多数患有OUD的人都按照这个建议开始服用阿片类药物 他们的医生来管理工伤或在服兵役期间受伤的疼痛，通常没有任何 了解依赖的风险。越来越清楚的是，依赖和上瘾的风险是 科学界也大大低估了，最常用的阿片类药物有 在任何滥用类别的药物中，身体和生理依赖潜力最高。然而， 天真人群中的遗传差异使某些个体一旦暴露在 临床或其他方面的阿片类药物。这些遗传差异导致了u-阿片受体(MOR)的产生 在结合、脱敏和内化行为方面不同的表型-相关的差异 有更高的成瘾风险和更严重的戒断症状(复发的最大预测因素)。成对的 试剂成像(PAI)是一种可以在体内定量受体-配体结合潜力(BP)的成熟方法， 如果荧光激动剂和拮抗剂对 用来代替非目标/目标代理对。这两个参数-内化率和结合 潜在的--被假设为预测幼稚使用者的OUD风险和康复个人的复发风险 来自乌德。我们假设这些临床上重要的阿片受体表达和行为差异 可以通过内耳的耳内窥镜配对试剂成像(OPAI)来测量。因此，我们寻求R21 根据NIBIB“开拓者”计划的资助机会：(1)设计和组装硬质耳内窥镜 内耳阿片类药物结合动力学的PAI，以及(2)使用耳内窥镜配对试剂成像(OPAI)定量 受体在慢性阿片类药物暴露和纳洛酮诱导戒断后的行为 荧光标记阿片肽激动剂/拮抗剂对。耳内窥镜将由商业化的 可用的Storz内窥镜(直径2.5 mm)连接到一个将图像分成三个波段的小模块 (RGB、700-和800-荧光)，然后传输到单个scmos相机。一种多发光二极管光源 特定的照明和激发带通过Storz光导耦合器沿内窥镜向下传输。 在项目结束时，我们将解决三个假设：(1)内耳的螺旋神经节细胞可以成像 使用耳内窥镜来量化结合潜力和内化，(2)结合和内化 预测慢性阿片类药物暴露和纳洛酮诱导戒断的比率。这个 这项研究的潜在影响是巨大的：量化阿片受体个体差异的能力 非侵入性行为可以改善OUD高危个体远离阿片类药物的转移，可能 防止使用阿片类药物治疗慢性疼痛的患者滥用阿片类药物，并可帮助恢复 通过对戒断的严重程度进行分层，进而对复发风险进行分层，以提供个性化的、适当的 支持。