权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

慢性重叠性疼痛（COPCs）影响着超过1亿人，但由于，