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

基本信息

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
项目类别：
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

项目摘要

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.

慢性重叠疼痛 (COPC) 影响着超过 1 亿人，但由于以下原因仍未得到有效治疗：很大程度上是由于缺乏具有转化相关性的有效动物模型，这是对 FOA PAR-18-763 的回应。该提案旨在开发一种新的 COPC 小鼠模型，具有更高的外部有效性，以促进发现我们的模型将结合关键的遗传和抗炎作用的神经治疗药物。已知环境因素通过增强儿茶酚胺能张力而导致 COPC 的病因。据估计，患有慢性阻塞性肺病（例如纤维肌痛）的患者中，有 66% 的基因编码存在功能性变异儿茶酚-O-甲基转移酶（COMT；一种普遍表达的代谢儿茶酚胺的酶）， COMT 基因型对疼痛的影响会因压力和损伤而改变。具有“低活动”COMT 基因型的个体报告称，应激事件（例如，运动车辆碰撞和心理紧张）和伤害性外科手术（例如拔牙和拔牙）乳房切除术）、压力和损伤会通过增加促炎物质的产生而产生疼痛。此前，我们的实验室采用药理学方法进行研究。驱动 COMT 依赖性疼痛的机制和目标，但这种方法并没有充分模仿 COPC 的复杂临床病因学因此，本提案的目的是开发和验证一种新的方法。 COPCS 小鼠模型，其中遗传易感性 COMT+/- 经历压力和伤害事件。我们的中心假设是，经历短暂压力和伤害事件的 COMT+/- 小鼠会发展为身体多个部位的慢性疼痛以及临床相关细胞因子生物标志物水平的增加初步数据显示，COMT+/- 小鼠表现正常。基线疼痛行为、经历游泳压力和拔牙手术后会出现夸张的长期疼痛行为此外，COMT+/- 小鼠在游泳时会出现多个身体部位的疼痛（后爪、背部和腹部）。摩尔拔除表现出伤害感受器活性增加。本文提出的研究将扩展这项工作。在 1.5 年的 R61 阶段，我们将确定多个身体部位的疼痛程度和持续时间、敏化程度支配这些身体部位的初级传入伤害感受器，以及与疼痛相关的抑郁和焦虑样我们的 COPC 小鼠模型中的行为在达到“go 里程碑”时：COMT+/- 与 WT 小鼠进行对比。压力+损伤在 1) 多个身体部位的机械疼痛和 2) 方面表现出显着增加（效应大小 >3）伤害感受器活性，我们将进入 R33 阶段在 1.5 年的 R33 阶段，我们将进行临床评估。相关细胞因子生物标志物以确定构建有效性和临床使用的镇痛药以确定如果成功，我们将开发一种改进的 COPCS 小鼠模型。有效性将对有效发现具有转化相关性的镇痛药产生重大影响。