A novel clinically-relevant mouse model of chronic overlapping pain conditions for screening analgesics

用于筛选镇痛药的新型临床相关慢性重叠疼痛小鼠模型

• 批准号: 10821681
• 负责人: Andrea G Nackley
• 金额: $ 7.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10821681
• 关键词: Abdomen; Affect; American; Analgesics; Animal Model; Antiinflammatory Effect; Automobile Driving; Back; Behavior; Bilateral; Biological Markers; Catechol O-Methyltransferase; Catecholamines; Chronic; Clinical; Complex; Data; Environmental Risk Factor; Enzymes; Etiology; Event; Exhibits; FDA approved; Female; Fibromyalgia; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Healthcare; High Prevalence; Hyperalgesia; Individual; Inflammation; Inflammatory; Injury; Lead; Mastectomy; Measures; Mechanics; Modeling; Mus; Nerve; Nociceptors; Operative Surgical Procedures; Pain; Parents; Patients; Peripheral; Peripheral Nerves; Persistent pain; Persons; Phase; Plasma; Production; Reporting; Rodent; Rodent Model; Sampling; Site; Stimulus; Stress; Stressful Event; Swimming; Syndrome; Temporomandibular Joint Disorders; Testing; Therapeutic; Time; Variant; Vehicle crash; Vulva; Wild Type Mouse; Work; anxiety-like behavior; behavioral phenotyping; calcium indicator; celecoxib; chronic pain; clinical effect; clinically relevant; cytokine; depressive symptoms; duloxetine; effective therapy; genetic variant; improved; in vivo; in vivo calcium imaging; male; mechanical allodynia; meetings; molecular phenotype; mouse model; multiplex assay; novel; pain behavior; pain model; pain reduction; pharmacologic; pregabalin; psychologic; response; screening

Chronic overlapping pain conditions (COPCs) affect over 100 million people, yet remain ineffectively treated due, in large part, to lack of valid animal models with translational relevance. In response to FOA PAR-18-763, this proposal seeks to develop a new mouse model of COPCs with improved external validity to facilitate discovery of neurotherapeutics with analgesic and anti-inflammatory effects. Our model will incorporate key genetic and environmental factors known to contribute to the etiology of COPCs through enhancing catacholaminergic tone. An estimated 66% of patients with COPCs such as fibromyalgia have functional variants in the gene encoding catechol-O-methyltransferase (COMT; a ubiquitously expressed enzyme that metabolizes catecholamines), that result in low COMT activity. The effect of COMT genotype on pain is modified by stress and injury. For example, individuals with the ‘low activity’ COMT genotype report enhanced pain following stressful events (eg, motor vehicle collision and psychological strain) and injurious surgical procedures (eg, molar extraction and mastectomy). Low COMT, stress, and injury can produce pain by increasing the production of pro-inflammatory cytokines that sensitize nociceptors. Previously, our lab employed a pharmacologic approach to study mechanisms and targets driving COMT-dependent pain, yet this approach does not adequately mimic the complex clinical etiology of COPCs. Thus, the objective of this proposal is to develop and validate a novel mouse model of COPCS in which genetically predisposed COMT+/- mice undergo stressful and injurious events. Our central hypothesis is that COMT+/- mice undergoing transient stressful and injurious events will develop chronic pain at multiple body sites and increased levels of clinically-relevant cytokine biomarkers that will be reduced by existing FDA-approved analgesics. Preliminary data show that COMT+/- mice, which exhibit normal baseline pain behavior, undergoing swim stress and molar extraction surgery develop exaggerated long-lasting pain at multiple body sites (hindpaw, back, and abdomen). Further, COMT+/- mice undergoing swim stress and molar extraction exhibit increased nociceptor activity. The studies proposed herein will extend this work. During the 1.5-year R61 phase, we will establish the magnitude and duration of pain at several body sites, sensitization of primary afferent nociceptors innervating those body sites, and pain-related depressive- and anxiety-like behaviors in our COPC mouse model. Upon meeting the ‘go milestones’: COMT+/- vs WT mice undergoing stress+injury exhibit significant increases (effect size >3) in 1) mechanical pain at multiple body sites and 2) nociceptor activity, we will move to the R33 phase. During the 1.5-year R33 phase, we will evaluate clinically- relevant cytokine biomarkers to determine construct validity and clinically-used analgesics to determine predictive validity of our model. If successful, we will develop a novel mouse model of COPCS with improved validity that will have a significant impact on effective discovery of analgesics with translational relevance.

慢性重叠的疼痛状况（COPC）影响超过1亿人，但仍被无效治疗， 在很大程度上，缺乏具有转化相关性的有效动物模型。为了回应FOA PAR-18-763， 提案旨在开发具有改善外部有效性的新鼠标COPC模型以促进发现 具有镇痛和抗炎作用的神经疗法。我们的模型将包含关键遗传和 已知的环境因素通过增强马cacholamin能张力来促进COPC的病因。 估计有66％的COPC患者（例如纤维肌痛）在编码基因中具有功能变异 Catechol-O-甲基转移酶（COMT；一种代谢儿茶酚胺的普遍表达的酶），该酶 导致COMT活性低。 COMT基因型对疼痛的影响是通过压力和损伤来改变的。例如， 具有“低活动” COMT基因型报告的个体报告会增加压力事件后的疼痛（例如，电动机 车辆碰撞和心理压力）和伤害性手术程序（例如，摩尔提取和 乳房切除术）。低COMT，压力和伤害会通过增加促炎的产生而产生疼痛 感知伤害感受器的细胞因子。以前，我们的实验室采用药物研究 机制和目标驱动COMT依赖性疼痛，但是这种方法并不能充分模仿 COPC的复杂临床病因。这是该提议的目的是开发和验证新颖的 一般易感性COMT +/-小鼠经历压力和受伤事件的COPC的小鼠模型。 我们的中心假设是COMT +/-小鼠经历了短暂的压力和受伤事件 多个身体部位的慢性疼痛和临床上与临床相关的细胞因子生物标志物的水平增加 通过现有FDA批准的镇痛药减少。初步数据显示COMT +/-小鼠，它暴露了正常 基线疼痛行为，经历游泳压力和摩尔萃取手术的持久性 多个身体部位的疼痛（后爪，背部和腹部）。此外，COMT +/-鼠标承受着游泳压力和 摩尔提取提取物增加了伤害感受器的活性。本文提出的研究将扩展这项工作。期间 1。5年的R61阶段，我们将在几个身体部位建立疼痛的幅度和持续时间 支配这些身体部位的主要传入伤害感受器，以及与疼痛相关的抑郁和动画 我们的COPC鼠标模型中的行为。遇到“ Go Milestones”：COMT +/- vs WT MICE正在进行 应力+损伤暴露了显着增加（效应尺寸> 3）1）在多个身体部位的机械疼痛和2） 伤害感受器的活动，我们将转移到R33阶段。在1。5年的R33阶段，我们将在临床上评估 相关的细胞因子生物标志物，以确定构造有效性和临床镇痛药以确定 我们模型的预测有效性。如果成功，我们将开发一个新型的COPC的鼠标模型，并有所改善 有效性将对具有转化相关性的有效发现镇痛药产生重大影响。