Urocortin & Musculoskeletal Hyperalgesia

尿皮质素

• 批准号: 7989277
• 负责人: ALICE A LARSON
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989277
• 关键词: Adipose tissue; American; Area; Biological Assay; Blood specimen; Brain; Brown Fat; Carbohydrates; Clinical; Collaborations; Data; Diet; Endocrine; Exposure to; Eye; Fatty acid glycerol esters; Fibromyalgia; Flexor; Glucose; Goals; Hormones; Human; Hyperalgesia; Image; Image Analysis; Individual; Intervention; Limb structure; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Metabolic; Metabolism; Modeling; Monitor; Mus; Muscle; Musculoskeletal; Musculoskeletal Pain; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nerve; Nociception; Pain; Palpation; Pathway interactions; Patients; Physiological; Positron-Emission Tomography; Proteins; Recruitment Activity; Regulation; Research; Rest; Sampling; Scientist; Skin; Stress; Study Subject; Supraclavicular; Sympathetic Ganglia; Symptoms; Testing; Therapeutic; Thermogenesis; Time; TimeLine; Tissues; base; fluorodeoxyglucose positron emission tomography; interest; novel; parent grant; psychologic; public health relevance; relating to nervous system; response; statistics; transmission process; uptake; urocortin

DESCRIPTION (provided by applicant): The proposed new studies extend those in mice with fibromyalgia-type musculoskeletal hyperalgesia ("Urocortin & Musculoskeletal Hyperalgesia"; 12/01/08-11/30/13; Larson, P.I.) to studies in humans. The new collaboration between Drs. Larson and Pardo brings together a basic scientist (Larson), who has a long- standing interest in the mechanism of pain transmission with a focus on that seen in patients with fibromyalgia, and a clinical neuroscientist (Pardo), who has expertise in PET imaging. The original proposal was to determine the effect of specific stress hormones on musculoskeletal pain models in mice. The new studies focus on the unique distribution of such pain in patients with fibromyalgia (near the trunk and proximally rather than distally and on the extremities) based on the tendency for cold stress to enhance the symptoms of fibromyalgia. Brown adipose tissue is located near the trunk and proximal extremities-- i.e., in supraclavicular areas and atop sympathetic ganglia in the trunk. Stress activates brown adipose tissue via sympathetic nerves with collaterals to surrounding skin and muscle. We hypothesize that this enhanced sympathetic tone causes sympathetically maintained pain in the skin and muscle surrounding brown adipose tissue. The BIRT research goal is to test this hypothesis by determining whether the pain of fibromyalgia, measured by palpation, nociceptive flexor reflexometry, and established rating scales, correlates with the volume (MRI) or glucose metabolic activity (tissue uptake of fluordeoxyglucose PET) of brown adipose tissue in fibromyalgia patients compared to controls. In these individuals, we will assess whether pain is temporarily relieved by dietary manipulations inhibiting brown adipose activity, or whether the pain is worsened by exposure to cold increasing brown adipose tissue activity. As in the parent grant, samples will be taken to monitor the concentrations of stress hormones (CRF and urocortins I, II and III) in fibromyalgia patients compared to healthy controls, as suggested by the reviewers of the original RO1 proposal. These studies will be the first to test the hypothesis of sympathetically mediated metabolism in brown adipose tissue and the collateral effects upon the pain in related muscles and skin in fibromyalgia syndrome. They can provide a novel inroad toward developing novel assessment and therapeutic strategies. PUBLIC HEALTH RELEVANCE: According to NIAMS statistics, 1 in 73 (1.35%) or approximately 3.7 million Americans suffer from fibromyalgia syndrome. Stress enhances the symptoms of fibromyalgia, but the mechanism by which this occurs is unknown. We hypothesize that stress enhances sympathetic tone to brown adipose tissue as well as to collaterals that innervate the surrounding skin and muscle in areas that overlap with the distribution of fibromyalgia pain. If the amount or activity of brown adipose tissue (determined using FDG PET and MRI) differs in patients with fibromyalgia from that in controls, this will, for the first time, identify the regulation of brown adipose tissue as a potential contributor to fibromyalgia symptoms. Identification of pathways that cause pain in these patients will allow us to test potential therapies and clinical interventions that relieve the symptoms of fibromyalgia.

描述(申请人提供)：拟议的新研究扩展了纤维肌痛型肌肉骨骼痛小鼠的研究(“urocortin&肌肉骨骼痛敏”；12/01/08-11/30/13；Larson，P.I.)在人类身上的研究。Larson博士和Pardo博士之间的新合作汇集了一位基础科学家(Larson)和一位临床神经学家(Pardo)，前者长期对疼痛传递机制感兴趣，重点关注纤维肌痛患者的疼痛传递机制，后者在PET成像方面拥有专业知识。最初的建议是确定特定应激激素对小鼠肌肉骨骼疼痛模型的影响。新的研究集中在纤维肌痛患者中这种疼痛的独特分布(靠近躯干和近端，而不是远端和四肢)，这是基于冷应激增强纤维肌痛症状的趋势。棕色脂肪组织位于躯干和近端肢体附近--即锁骨上区域和躯干交感神经节顶部。压力通过与周围皮肤和肌肉有侧支的交感神经激活棕色脂肪组织。我们推测，这种增强的交感神经张力会导致棕色脂肪组织周围的皮肤和肌肉产生交感神经维持的疼痛。BIRT的研究目标是通过确定纤维肌痛患者的棕色脂肪组织的体积(MRI)或葡萄糖代谢活动(组织对氟脱氧葡萄糖的摄取)是否与对照组相比，确定通过触诊、伤害性屈肌反射测量和确定的分级标准来衡量纤维肌痛的疼痛是否与这一假说相关。在这些人中，我们将评估抑制棕色脂肪活动的饮食操作是否会暂时缓解疼痛，或者暴露在寒冷中会增加棕色脂肪组织的活动是否会加剧疼痛。与父母拨款一样，按照最初RO1提案的审查者的建议，将采集样本以监测纤维肌痛患者与健康对照组相比的应激激素(CRF和urocortins I、II和III)的浓度。这些研究将首次验证在棕色脂肪组织中交感神经调节代谢的假说，以及纤维肌痛综合征对相关肌肉和皮肤疼痛的附带影响。它们可以为开发新的评估和治疗策略提供新的途径。 公共卫生相关性：根据NIAMS的统计数据，每73名美国人中就有1人(1.35%)或大约370万人患有纤维肌痛综合征。压力会增强纤维肌痛的症状，但其发生机制尚不清楚。我们假设，应激增强了棕色脂肪组织的交感神经张力，以及与纤维肌痛疼痛分布重叠的区域中神经周围皮肤和肌肉的侧支。如果纤维肌痛患者棕色脂肪组织的数量或活性(使用FDGPET和MRI测定)与对照组不同，这将首次确定棕色脂肪组织的调节是导致纤维肌痛症状的潜在因素。识别导致这些患者疼痛的途径将使我们能够测试缓解纤维肌痛症状的潜在疗法和临床干预措施。