Urocortin & Musculoskeletal Hyperalgesia

描述（由申请人提供）：在疼痛性肌肉骨骼疾病（如纤维肌痛）和各种疼痛性腹部疾病（如肠易激综合征和间质性膀胱炎）之间存在高度的合并症。这些情况会因压力而恶化，并且，像压力一样，胃肠道疾病与促肾上腺皮质激素释放因子（CRF）和尿皮质素的增加有关。许多尿皮质素的作用与纤维肌痛症的症状特别吻合。首先，文献表明尿皮质素减轻腹部痛觉，我们的初步数据表明尿皮质素同时诱导肌肉骨骼痛觉过敏。其次，尿皮质素抑制循环糖皮质激素，这与纤维肌痛患者的昼夜节律减弱和皮质醇对压力的反应减弱相一致。第三，啮齿类动物对尿皮质素合成的调节存在性别差异，这与雌性纤维肌痛的发病率高于雄性是一致的。最后，我们的初步数据表明，尿皮质素的耐受性不会发展到痛觉过敏的作用，因此，尿皮质素释放的反复激增可能会持续引起痛觉过敏，这与纤维肌痛的慢性性质一致。由于尿皮质素重现了纤维肌痛的许多特征，并且在腹部疾病中升高，我们假设尿皮质素活性的增加会产生肌肉骨骼机械痛觉过敏。为了验证这一点，我们将确定小鼠尿皮质素II是否在性别敏感性、持续时间和药理学敏感性方面模拟人类慢性疼痛状况。我们将1)描述尿皮质素引起痛觉过敏的受体群体，2)评估尿皮质素引起的痛觉过敏对抗痛觉化合物的敏感性，以及3)研究小鼠是否对尿皮质素产生耐受性或是否具有长期的痛觉过敏活性。我们的研究将为痛觉过敏的新的生化机制提供重要信息，并将在以下方面进行转化：如果尿皮质素产生广泛的机械性痛觉过敏，类似于纤维肌痛的症状；1)这将证明在患者中进行研究是合理的，2)这些数据将定义压力、慢性广泛的肌肉骨骼疼痛和腹部疼痛疾病之间可能的因果关系，3)这些研究将提供一个模型来测试缓解人类广泛的肌肉骨骼疼痛的临床干预措施。我们的研究将提供尿皮质素在慢性肌肉骨骼疼痛中的作用的重要机制信息，并可能提供尿皮质素在纤维肌痛症相关疼痛中的作用。我们的研究结果将对疼痛领域的转化研究有三个广泛的好处：首先，如果尿皮质素II概括了纤维肌痛的症状，这将支持尿皮质素有助于纤维肌痛症状的可能性，并将证明该疾病患者的研究是合理的；其次，这些数据将加深我们对疼痛性腹部疾病和慢性肌肉骨骼疼痛之间关系的理解；第三，尿皮质素II在小鼠中的作用将提供一个模型，可用于测试潜在的治疗方法和临床干预措施，以缓解人类普遍存在的肌肉骨骼疼痛。

DESCRIPTION (provided by applicant): There is a high degree of co-morbidity between painful musculoskeletal disorders, such as fibromyalgia, and various painful abdominal disorders, such as irritable bowel syndrome and interstitial cystitis. These conditions are exacerbated by stress, and, like stress, gastrointestinal disorders are associated with increases in corticotropin-releasing factor (CRF) and urocortins. Many of urocortins' effects match symptoms of fibromyalgia syndrome in particular. First, the literature indicates that urocortins attenuate abdominal nociception and our preliminary data suggest that urocortins simultaneously induce musculoskeletal hyperalgesia. Second, urocortins inhibit circulating glucocorticoids, consistent with a diminished diurnal rhythm and attenuated cortisol response to stress in patients with fibromyalgia. Third, there are sex differences in the regulation of urocortin's synthesis in rodents, consistent with the higher incidence of fibromyalgia in females than males. Finally, our preliminary data suggest that tolerance does not develop to the hyperalgesic effect of urocortins, thus, repeated surges in their release may persistently induce hyperalgesia, consistent with the chronic nature of fibromyalgia. Because urocortins recapitulate many characteristics of fibromyalgia and are elevated in abdominal disorders, we hypothesize that increased activity of urocortins produces musculoskeletal mechanical hyperalgesia. To test this, we will determine whether urocortin II in mice models chronically painful conditions in humans in terms of gender sensitivity, duration, and pharmacologic sensitivity. We will 1) characterize the receptor population responsible for the hyperalgesic effects of urocortins, 2) assess the sensitivity of urocortin-induced hyperalgesia to antinociceptive compounds, and 3) investigate whether mice develop tolerance to urocortins or are capable of long-term hyperalgesic activity. Our studies will provide important information about a new biochemical mechanism of hyperalgesia, and they will be translational in the following ways: if urocortins produce widespread mechanical hyperalgesia, similar to symptoms of fibromyalgia: 1) this will justify studies in patients, 2), these data will define a possible causal relationship between stress, chronic widespread musculoskeletal pain, and painful abdominal disorders, and 3) these studies will provide a model to test clinical interventions that relieve widespread musculoskeletal pain in humans. PUBLIC HEALTH RELEVANCE Our studies will provide important mechanistic information about the role of urocortins in chronic musculoskeletal pain and potentially the role of urocortins in the pain associated with fibromyalgia. Our results will have three broad benefits to translational research in the area of pain: first, if urocortin II recapitulates the symptoms of fibromyalgia, this will support the possibility that urocortins contribute to symptoms of fibromyalgia and will justify studies in patients with this disorder; second, these data will deepen our understanding of the relationship between painful abdominal disorders and chronic musculoskeletal pain; and third, the effects of urocortin II in mice will provide a model that can be used to test potential therapies and clinical interventions that relieve widespread musculoskeletal pain in humans.