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

用于筛选镇痛药的慢性重叠疼痛的新型临床相关小鼠模型

基本信息

批准号：
10434449
负责人：
Andrea G Nackley
金额：
$ 35.27万
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/10434449
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 Pharmacology Phase Plasma Production Reporting Rodent Rodent Model Sampling Site Stimulus Stress Stressful Event Swimming Syndrome Temporomandibular Joint Disorders Testing Therapeutic Time Variant Vehicle crash Volition Vulva Wild Type Mouse Woman 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 pregabalin psychologic response screening sham surgery

项目摘要

Chronic overlapping pain conditions (COPCs) affect over 100 million people, predominantly women. Yet, they 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, especially females, 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.

慢性重叠的疼痛条件（COPC）影响了超过1亿人，主要是女性。但是，他们在很大程度上，由于缺乏具有转化相关性的有效动物模型，因此对应有的应有的效力处理。在对FOA PAR-18-763的回应，该提案旨在开发一种新的COPC鼠标模型外部有效性以促进具有镇痛和抗炎作用的神经疗法。我们的模型将结合已知有助于COPC病因的关键遗传和环境因素通过增强降氧化胺能的音调。估计有66％的COPC患者（例如纤维肌痛）在编码Catechol-O-甲基转移酶的基因中具有功能变异（COMT；一个普遍表达的代谢儿茶酚胺的酶，导致COMT活性低。 COMT基因型对压力和伤害改变了疼痛。例如，具有“低活动” COMT基因型报告的个人压力事件（例如，机动车碰撞和心理压力）和受伤的疼痛增加手术程序（例如，摩尔萃取和乳房切除术）。低COMT，压力和伤害会导致疼痛增加感知伤害感受器的促炎性细胞因子的产生。以前是我们的实验室采用药物方法来研究机制和靶向驱动COMT依赖性疼痛的目标，但是方法不能充分模仿COPC的复杂临床病因。那是这个目标建议是开发和验证一种新型的COPC的小鼠模型，其中一般易于易见 COMT +/-小鼠发生压力和受伤的事件。我们的中心假设是COMT +/-小鼠，尤其是女性，经历短暂的压力和受伤事件将在多个身体部位和临床上与临床相关的细胞因子生物标志物的水平升批准的镇痛药。初步数据表明，暴露了正常基线疼痛行为的COMT +/-小鼠，进行游泳压力和摩尔提取手术在多个身体上产生了夸张的长期疼痛站点（后爪，背部和腹部）。此外，COMT +/-小鼠经历了游泳应力和摩尔提取表现出增加的伤害感受器活性。本文提出的研究将扩展这项工作。在1。5年 R61相，我们将在几个身体部位建立疼痛的大小和持续时间，主要的敏感性传入的伤害感受器支配这些身体部位，以及与疼痛有关的抑郁和动画行为我们的COPC鼠标模型。达到“ Go Milestones”时：COMT +/- vs WT小鼠受到压力+伤害在1）在多个身体部位的机械疼痛和2）伤害感受器的机械疼痛中显示出显着增加（效果> 3）活动，我们将移至R33阶段。在1。5年的R33阶段，我们将评估与临床相关的细胞因子生物标志物确定构建体有效性和临床镇痛药以确定预测性我们模型的有效性。如果成功，我们将开发一种具有提高有效性的COPC的新型COPC模型将对具有转化相关性的有效发现镇痛药有重大影响。