Development and Validation of a Novel Rat Model of Fibromyalgia

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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.