Urocortin & Musculoskeletal Hyperalgesia

描述(由申请人提供)：痛性肌肉骨骼疾病(如纤维肌痛)和各种腹痛疾病(如肠易激综合征和间质性膀胱炎)的发病率很高。这些情况会因压力而加剧，与压力一样，胃肠道疾病也与促肾上腺皮质激素释放因子(CRF)和尿皮质激素的增加有关。Urocortins的许多作用尤其与纤维肌痛综合征的症状相匹配。首先，文献表明，尿皮质素可减轻腹部伤害性感觉，我们的初步数据表明，尿皮质素同时引起肌肉骨骼痛觉过敏。其次，尿皮质激素抑制循环中的糖皮质激素，与纤维肌痛患者的昼夜节律减弱和皮质醇应激反应减弱一致。第三，啮齿动物尿皮质素合成的调节存在性别差异，这与雌性比雄性更高的纤维肌痛发生率相一致。最后，我们的初步数据表明，耐受性不会发展为urocortins的痛敏效应，因此，它们释放的反复激增可能会持续诱导痛敏，这与纤维肌痛的慢性性质一致。由于尿皮质素概括了纤维肌痛的许多特征，并在腹部疾病中升高，我们假设尿皮质素活性增加会导致肌肉骨骼机械性痛敏。为了测试这一点，我们将确定在小鼠身上的Urocortin II是否在性别敏感性、持续时间和药物敏感性方面模拟了人类的慢性疼痛情况。我们将1)确定导致urocortins痛敏效应的受体群体，2)评估urocortin诱导的痛敏反应对抗伤害感受性化合物的敏感性，3)调查小鼠是否对urocortins产生耐受性或能够产生长期的痛觉过敏活动。我们的研究将提供有关痛敏的一种新的生化机制的重要信息，它们将在以下方面发挥作用：如果urocortins产生广泛的机械痛敏，类似于纤维肌痛的症状：1)这将证明在患者中进行研究的合理性；2)这些数据将确定应激、慢性广泛性肌肉骨骼疼痛和痛性腹部疾病之间可能的因果关系，以及3)这些研究将提供一个模型，以测试缓解人类广泛肌肉骨骼疼痛的临床干预措施。公共卫生相关性我们的研究将提供有关urocortins在慢性肌肉骨骼疼痛中的作用以及可能在与纤维肌痛相关的疼痛中的作用的重要机制信息。我们的结果将对疼痛领域的翻译研究有三大好处：首先，如果urocortin II概括了纤维肌痛的症状，这将支持urocortin促进纤维肌痛症状的可能性，并将证明对这种疾病患者的研究是合理的；其次，这些数据将加深我们对痛性腹部疾病和慢性肌肉骨骼疼痛之间关系的理解；第三，urocortin II在小鼠身上的作用将提供一个可以用于测试缓解人类广泛存在的肌肉骨骼疼痛的潜在治疗和临床干预措施的模型。

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.