Urocortin & Musculoskeletal Hyperalgesia

描述（由申请人提供）：所提出的新研究扩展了在患有纤维肌痛型肌肉骨骼痛觉过敏的小鼠中的研究（"Urocortin & Musculoskeletal Hyperalgesia"; 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），他对疼痛传递机制有着长期的兴趣，重点是纤维肌痛患者，以及一位临床神经科学家（Pardo），他拥有PET成像的专业知识。最初的建议是确定特定的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四肢近端附近，即，在锁骨上区和躯干交感神经节上。压力通过交感神经激活棕色脂肪组织，交感神经与周围的皮肤和肌肉有联系。我们推测，这种增强的交感神经张力导致皮肤和肌肉周围棕色脂肪组织的交感神经维持疼痛。BIRT的研究目标是通过确定纤维肌痛的疼痛（通过触诊、伤害性屈肌反射测量法和已建立的评定量表测量）与纤维肌痛患者棕色脂肪组织的体积（MRI）或葡萄糖代谢活性（氟脱氧葡萄糖PET的组织摄取）是否相关（与对照组相比）来验证这一假设。在这些个体中，我们将评估是否通过抑制棕色脂肪活性的饮食操作暂时缓解疼痛，或者是否通过暴露于增加棕色脂肪组织活性的寒冷而加重疼痛。正如原始RO 1提案的评审员所建议的那样，与健康对照组相比，在母基金中，将采集样本以监测纤维肌痛患者的应激激素（CRF和尿皮质素I，II和III）浓度。这些研究将首次检验棕色脂肪组织中交感神经介导的代谢以及纤维肌痛综合征中相关肌肉和皮肤疼痛的附带影响的假设。它们可以为开发新的评估和治疗策略提供新的进展。 公共卫生相关性：根据NIAMS统计，73人中有1人（1.35%）或约370万美国人患有纤维肌痛综合征。压力会增强纤维肌痛的症状，但其发生的机制尚不清楚。我们假设，压力增强了交感神经张力，棕色脂肪组织，以及周围的皮肤和肌肉的区域，与纤维肌痛疼痛的分布重叠的侧枝神经。如果纤维肌痛患者棕色脂肪组织的数量或活性（使用FDG PET和MRI确定）与对照组不同，这将首次确定棕色脂肪组织的调节是纤维肌痛症状的潜在贡献者。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。

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.