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

慢性重叠疼痛状况(COPC)影响着1亿多人，其中主要是妇女。然而，他们 仍然没有得到有效的治疗，这在很大程度上是由于缺乏有效的具有翻译相关性的动物模型。在……里面 作为对FOA PAR-18-763的回应，本提案旨在开发一种新的COPC小鼠模型，并对其进行改进 有助于发现具有止痛和抗炎作用的神经疗法的外部有效性。我们的 模型将纳入已知的导致COPC病因学的关键遗传和环境因素 通过增强儿茶酚胺能神经递质。估计66%的COPC患者，如纤维肌痛 在编码儿茶酚-O-甲基转移酶(COMT；一种普遍表达的 代谢儿茶酚胺的酶)，导致COMT活性低。COMT基因分型对遗传易感基因的影响 疼痛会因压力和伤害而改变。例如，具有“低活动度”COMT基因的个体报告 紧张性事件(如机动车碰撞和心理紧张)和伤害后疼痛加剧 外科手术(如磨牙拔除和乳房切除)。低COMT、压力和损伤可通过以下方式产生疼痛 增加致炎细胞因子的产生，使伤害性感受器敏感。此前，我们的实验室 使用药理学方法来研究驱动COMT依赖性疼痛的机制和靶点，但这 该方法不能充分模拟COPC的复杂临床病因。因此，这一行动的目标是 建议开发和验证一种新的COPCS小鼠模型，在该模型中，遗传易感性 COMT+/-小鼠经历应激和伤害事件。我们的中心假设是COMT+/-小鼠， 尤其是女性，在经历短暂的压力和伤害事件后，会在多个阶段发展为慢性疼痛。 身体部位和与临床相关的细胞因子生物标记物水平的增加将被现有的FDA- 批准的止痛药。初步数据显示，COMT+/-小鼠表现出正常的基线疼痛行为， 接受游泳应激和磨牙拔除手术后，多个身体出现夸大的持久疼痛 部位(后爪、背部和腹部)。此外，接受游泳应激和拔除磨牙的COMT+/-小鼠 表现出伤害性感受器活动增加。本文提出的研究将扩展这项工作。在1.5年内 R61阶段，我们将确定疼痛的程度和持续时间在几个身体部位，敏化的初级 支配这些身体部位的传入伤害性感受器，以及与疼痛相关的抑郁和焦虑样行为 我们的COPC小鼠模型。遇到GO里程碑：COMT+/-与遭受应激+损伤的WT小鼠 在1)多个身体部位的机械性疼痛和2)伤害性感受器方面表现出显著增加(效果大小和3) 活动，我们将进入R33阶段。在为期1.5年的R33阶段，我们将评估与临床相关的 确定结构有效性的细胞因子生物标记物和临床使用的止痛药以确定预测性 验证了我们模型的有效性。如果成功，我们将开发一种新的COPCS小鼠模型，并提高有效性 将对有效发现具有翻译相关性的止痛药产生重大影响。

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.