Urocortin & Musculoskeletal Hyperalgesia

尿皮质素

基本信息

批准号：
7939609
负责人：
ALICE A LARSON
金额：
$ 33.64万
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/7939609
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 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 public health relevance 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）：疼痛的肌肉骨骼疾病（例如纤维肌痛）和各种疼痛的腹部疾病（例如肠易激综合征和间质膀胱炎）之间存在高度的合并症。这些疾病会因压力加剧，并且像压力一样，胃肠道疾病与促肾上腺蛋白释放因子（CRF）和泌尿果素的增加有关。尿道素的许多作用尤其是纤维肌痛综合征的症状。首先，文献表明尿道质蛋白减弱腹部伤害感受，而我们的初步数据表明尿道质素同时诱导肌肉骨骼肌肉骨膜肌症。其次，泌尿皮质素抑制循环的糖皮质激素，与昼夜节律降低并减弱纤维肌痛患者的皮质醇反应。第三，在啮齿动物中泌尿科素合成的调节中存在性别差异，与男性相比，女性纤维肌痛的发生率更高。最后，我们的初步数据表明，耐受性不会发展到尿道质素的高温作用，因此，其释放中反复的涌现可能会持续诱发痛苦，这与纤维肌痛的慢性性质一致。由于尿道质素概括了纤维肌痛的许多特征并在腹部疾病中升高，因此我们假设尿道质素的活性增加会产生肌肉骨骼机械性痛觉过敏。为了测试这一点，我们将确定小鼠中的尿科质素II在性别敏感性，持续时间和药理学敏感性方面是否慢性地疼痛。我们将1）表征负责泌尿皮质素的高温作用的受体群体，2）评估泌尿皮质素诱导的痛觉过敏的敏感性，以及3）研究小鼠是否发展对泌尿肌素的耐受性还是能够具有长期的高度高敏感性。 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研究将为测试临床干预措施提供模型，以减轻人类的广泛肌肉骨骼疼痛。公共卫生相关性我们的研究将提供有关泌尿皮质素在慢性肌肉骨骼疼痛中的作用的重要机制信息，并可能导致泌尿皮质素在与纤维肌痛相关的疼痛中的作用。我们的结果将对疼痛领域的转化研究有三个广泛的好处：首先，如果泌尿科素II概括了纤维肌痛的症状，这将支持尿道蛋白蛋白素有助于纤维肌痛的症状，并证明对这种疾病患者的研究的可能性；其次，这些数据将加深我们对疼痛腹部疾病与慢性肌肉骨骼疼痛之间关系的理解。第三，小鼠尿素素II的作用将提供一个模型，可用于测试潜在的疗法和临床干预措施，以缓解人类的广泛肌肉骨骼疼痛。