The primary symptom and most debilitating aspect of fibromyalgia syndrome is chronic generalized pain. The pathogenic mechanisms of fibromyalgia pain are very poorly understood and currently available analgesic therapies have proven to be only partially, and unpredictably, effective. Progress in this area has been seriously hindered by the lack of an adequate experimental model of chronic generalized pain. We have recently determined that interruption of vagal-afferent activity from the abdomen in the rat can result in a state of chronic generalized hyperalgesia. Following subdiaphragmatic vagotomy, the nociceptive threshold to mechanical stimulation decreased and bradykinin-induced mechanical hyperalgesia was enhanced. Similar to fibromyalgia, this vagotomy-induced hyperalgesia exhibits marked sex-dependence, with the enhancement of bradykinin-induced hyperalgesia significantly greater in females. The vagotomy-induced generalized hyperalgesia depends on activity of the adrenal medulla, a characteristic also relevant to fibromyalgia syndrome in which chronic stress-induced activation of the sympathoadrenal and hypothalamic-pituitary-adrenal axes may contribute. Therefore, another important dimension of our model is the demonstration of generalized hyperalgesia induced by chronic intermittent stress. The purpose of this application is to further characterize the vagotomy-based model of generalized hyperalgesia, and to use this model to elucidate mechanisms underlying chronic generalized pain. We propose to first perform a detailed analysis of the characteristics of vagotomy-induced hyperalgesia. Second, we will examine the effect of physiological factors important in fibromyalgia, including the sympathoadrenal axis, gastrointestinal influences on vagal afferent activity, and capsaicin-sensitive mechanisms. Third, we will examine the effect of extrinsic factors shown to modulate fibromyalgia pain, including chronic stress and a variety of clinically employed pharmacological and non-pharmacological therapies. The proposed studies should provide important new insights into the pathophysiology of generalized pain conditions, including that associated with fibromyalgia. In this regard, this work can achieve important progress toward a goal that until now has been frustrated by the absence of workable animal models.
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