Development and Validation of a Novel Rat Model of Fibromyalgia

项目摘要 数百万美国人患有纤维肌痛综合征（FMS），并经历严重的残疾和减少 生活质量这种慢性广泛性疼痛综合征伴随着一系列症状，包括慢性 疲劳、非恢复性睡眠、功能性残疾以及认知和情绪障碍。目前使用的动物 FMS的模型在面子、结构和预测有效性方面存在缺陷，这导致了一种翻译， 在动物模型中似乎有希望的新疗法在人体临床试验中失败了。一种策略 为了提高FMS动物模型的面部评价和构建有效性，将测量几个 与人类疾病相关的症状。因此，我们将开发纤维肌痛 模拟模型（FAM），将作为类似于临床使用的诊断指标。我们假设 该指数将改善对动物FMS模型的面部和预测有效性的评价，并将提供一个 定义方法来比较它们。次要终点是比较已建立的利血平 FMS模型和一种创新模型：Dahl盐敏感（SS）大鼠。我们的初步研究表明， 大鼠是自发性异常性疼痛的模型，因为它们在没有外部刺激的情况下表现出机械压力敏感性。 仓促干预。伴随着机械阈值的降低，这些大鼠也不能登上一个 对疼痛刺激的弥漫性伤害性抑制控制反应。该菌株表现出其他表型 与FMS一致，如焦虑、全身和神经炎症以及应激反应功能障碍 建构效度（Construct Validity）这些大鼠也证明了加巴喷丁的预测有效性，但不是吲哚美辛 或地塞米松提供>30%的痛觉过敏改善。我们假设FAM指数将允许 我们确定SS菌株作为FMS模型的适用性。R61阶段将包括三个实验。 (1)六个行为终点将测试同一个体雌性利血平处理的Sprague中的FMS性状。 道利大鼠;疲劳、肌肉压痛、睡眠中断、广泛疼痛、焦虑和 萧条然后将在严格的多变量框架内使用回归模型分析结果 定义可观察临床表型之间的关系，以开发FAM指数。这些数据也将用于 以最大限度地提高测量的内部有效性。(2)我们将证明FAM指数的外部有效性 使用另外两个品系，雌性SS和Brown Norway（BN）大鼠。(3)我们将在以下男性中重复研究： 三种菌株五个统计里程碑将决定是否继续进行进一步的实验。在 在R33阶段，我们将从外部验证SS模型和FAM指数，并通过以下方式检验其预测有效性： 三组实验：（1）在其他大鼠品系中外部验证FAM指数;（2）建立SS （3）观察吲哚美辛、普瑞巴林和度洛沙坦对多发性骨髓瘤的治疗作用 症状域。该建议建立了一个评价面子效度、构念效度和预测效度的指标， 是一种新型的柔性制造系统。该模型对于药物筛选和药理学测试是非常理想的。

PROJECT SUMMARY Millions of Americans suffer from Fibromyalgia syndrome (FMS) and experience severe disability and diminished quality of life. This chronic widespread pain syndrome is accompanied by a range of symptoms including chronic fatigue, non-restorative sleep, functional disability, and cognitive and mood disturbances. Currently used animal models of FMS suffer from deficits in face, construct, and predictive validities, which has resulted in a translation gap; new therapies that appear to be promising in animal models have failed in human clinical trials. One strategy to improve the evaluation of face and construct validities of FMS animal models would be to measure several symptoms that correlate with the human disease in the same animal. We will therefore develop a Fibromyalgia Analog Model (FAM) that will serve as a diagnostic index similar to those used clinically. We hypothesize that this index will improve the evaluation of face and predictive validities of animal FMS models, and will provide a defined method to compare them. A secondary endpoint is a comparison between the established reserpine model of FMS and an innovative model: the Dahl salt-sensitive (SS) rat. Our preliminary studies show that SS rats are a model of spontaneous allodynia, as they exhibit mechanical pressure sensitivity without an external precipitating intervention. Accompanying the decrease in mechanical thresholds, these rats also fail to mount a diffuse noxious inhibitory control response to painful stimuli. This strain demonstrates additional phenotypes consistent with FMS such as anxiety, systemic and neural inflammation and dysfunction in stress response systems (construct validity). These rats also demonstrate predictive validity as gabapentin, but not indomethacin or dexamethasone provides >30% improvement in hyperalgesia. We hypothesize that the FAM index will allow us to determine the suitability of the SS strain as an FMS model. The R61 phase will comprise three experiments. (1) Six behavioral endpoints will test for FMS traits in the same individual female reserpine treated Sprague Dawley rat; behavioral aspects of fatigue, muscle tenderness, disrupted sleep, widespread pain, anxiety, and depression. The results will then be analyzed using regression modelling within a rigorous multivariate framework to define relationships in observable clinical phenotypes to develop the FAM index. The data will also be used to maximize the internal validity of the measurements. (2) We will certify the external validity of the FAM index using two additional strains, female SS and Brown Norway (BN) rats. (3) We will repeat the studies in males of all three strains. Five statistical milestones will determine whether to move forward with further experiments. In the R33 phase, we will externally validate the SS model and FAM index and examine its predictive validity via three sets of experiments: (1) externally validate the FAM index in additional rat strains; (2) establish the SS model in another institute; (3) test the therapeutic effect of indomethacin, pregabalin and duloxetine on multiple symptom domains. This proposal establishes an index to evaluate face, construct and predictive validities as well as a novel model of FMS. This model will be highly desirable for drug screening and pharmacologic testing.