Urocortin & Musculoskeletal Hyperalgesia

尿皮质素

基本信息

批准号：
8139097
负责人：
ALICE A LARSON
金额：
$ 32.29万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-28 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8139097
关键词：
Abdomen Abdominal Pain Affect Affinity Animals Area Attenuated Behavioral Biochemical Biological Assay Brain CRF receptor type 1 CRF receptor type 2 Cardiovascular system Characteristics Chronic Chronic Disease Chronic stress Circadian Rhythms Clinical Comorbidity Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Data Diagnosis Disease Dose Endometrium Female Fibromyalgia Future Gastrointestinal Diseases Gastrointestinal tract structure Gender Glucocorticoids Health Hormones Human Hydrocortisone Hyperalgesia Incidence Individual Interstitial Cystitis Intervention Investigation Irritable Bowel Syndrome Link Liquid substance Literature Location Measures Mechanics Minor Modality Modeling Morphine Mus Musculoskeletal Musculoskeletal Diseases Musculoskeletal Pain Nature Nociception Opioid Pain Pathology Pathway interactions Patients Pattern Perception Play Population Proteins Regulation Rodent Role Route Sampling Sequence Homology Sex Characteristics Skeletal Muscle Skin Spinal Cord Stress Symptoms Testing Time Translational Research Waxes acute stress endometriosis gastrointestinal grasp male mouse model prevent receptor response urocortin urocortin II

项目摘要

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.

描述（由申请人提供）：疼痛性肌肉骨骼疾病（例如纤维肌痛）和各种疼痛性腹部疾病（例如肠易激综合征和间质性膀胱炎）之间存在高度共病。这些病症会因压力而加剧，并且与压力一样，胃肠道疾病也与促肾上腺皮质激素释放因子（CRF）和尿皮质素的增加有关。尿皮质素的许多作用尤其与纤维肌痛综合征的症状相符。首先，文献表明尿皮质素可减弱腹部伤害感受，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一致。第三，啮齿类动物尿皮质素合成的调节存在性别差异，这与女性纤维肌痛的发病率高于男性一致。最后，我们的初步数据表明，尿皮质素的痛觉过敏作用不会产生耐受性，因此，尿皮质素释放的反复激增可能会持续诱发痛觉过敏，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，并且在腹部疾病中升高，因此我们假设尿皮质素活性增加会产生肌肉骨骼机械痛觉过敏。为了测试这一点，我们将确定小鼠模型中的尿皮质素 II 是否可以在性别敏感性、持续时间和药理敏感性方面模拟人类的慢性疼痛状况。我们将1）表征负责尿皮质素痛觉过敏作用的受体群体，2）评估尿皮质素诱导的痛觉过敏对镇痛化合物的敏感性，以及3）研究小鼠是否对尿皮质素产生耐受性或能够产生长期的痛觉过敏活性。我们的研究将提供关于痛觉过敏的新生化机制的重要信息，并且它们将以以下方式转化：如果尿皮质素产生广泛的机械痛觉过敏，类似于纤维肌痛的症状：1）这将证明在患者中进行研究的合理性，2），这些数据将确定压力、慢性广泛性肌肉骨骼疼痛和腹部疼痛性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可缓解广泛性疼痛的临床干预措施人类的肌肉骨骼疼痛。公共健康相关性我们的研究将提供有关尿皮质素在慢性肌肉骨骼疼痛中的作用以及尿皮质素在纤维肌痛相关疼痛中的潜在作用的重要机制信息。我们的结果将为疼痛领域的转化研究带来三个广泛的好处：首先，如果尿皮质素 II 重现了纤维肌痛的症状，这将支持尿皮质素导致纤维肌痛症状的可能性，并证明在这种疾病患者中进行研究是合理的；其次，这些数据将加深我们对腹部疼痛疾病与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，可用于测试缓解人类广泛的肌肉骨骼疼痛的潜在疗法和临床干预措施。