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，但仍然没有得到有效的治疗， 在很大程度上，这是由于缺乏有效的具有翻译相关性的动物模型。为了回应FOA PAR-18-763，这 一项提案旨在开发一种新的COPC小鼠模型，并提高其外部有效性，以促进发现 具有止痛和消炎作用的神经疗法。我们的模型将结合关键的遗传和 已知的环境因素通过增强儿茶酚胺能张力而导致COPC的病因学。 据估计，66%的纤维肌痛等COPC患者的编码基因存在功能变异 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)， 导致COMT活性降低。COMT基因对疼痛的影响会因应激和损伤而改变。例如, 低活动量的COMT基因携带者报告紧张性事件(如运动)后疼痛加剧 车辆碰撞和心理紧张)和破坏性的外科手术(例如，拔除磨牙和 乳房切除)。低COMT、压力和损伤可通过增加促炎因子的产生而产生疼痛 使伤害性感受器敏感的细胞因子。此前，我们的实验室采用了药理学的方法来研究 驱动COMT依赖性疼痛的机制和靶点，然而这种方法并不能充分模拟 COPC的复杂临床病因。因此，这项提议的目标是开发和验证一部小说 COPCS的小鼠模型，在该模型中，遗传易感性的COMT+/-小鼠经历应激和伤害事件。 我们的中心假设是COMT+/-小鼠在经历短暂的应激和伤害事件后会发生 多个身体部位的慢性疼痛和与临床相关的细胞因子生物标志物水平升高 被FDA批准的现有镇痛剂减少。初步数据显示，COMT+/-小鼠表现正常 基线疼痛行为，经历游泳压力和磨牙拔除手术会产生夸大的长期疼痛 身体多处疼痛(后爪、背部和腹部)。此外，COMT+/-小鼠在经历游泳应激和 磨牙拔除表现出伤害性感受器活性增加。本文提出的研究将扩展这项工作。在.期间 在为期1.5年的R61阶段，我们将确定几个身体部位的疼痛程度和持续时间，敏化 支配这些身体部位的初级传入伤害性感受器，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。达到“GO里程碑”：COMT+/-VS WT小鼠 应激+损伤在1)多个身体部位的机械性疼痛和2)显著增加(效应大小和3) 伤害性感受器活动，我们将进入R33阶段。在为期1.5年的R33阶段，我们将进行临床评估- 确定结构效度的相关细胞因子生物标志物和临床使用的止痛药 我们的模型的预测有效性。如果成功，我们将开发一种新的COPCS小鼠模型，并对其进行改进 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, 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.