Role of Subdiaphragmatic Vagus in Fibromyalgia Syndrome

膈下迷走神经在纤维肌痛综合征中的作用

• 批准号: 6755267
• 负责人: JON DAVID LEVINE
• 金额: $ 25.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-07 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6755267
• 关键词: adrenal medulla; adrenalectomy; analgesia; behavior test; capsaicin; catecholamine inhibitor; chronic pain; diet therapy; disease /disorder model; epinephrine; exercise; fibromyalgia; gastrointestinal function; gender difference; hyperalgesia; laboratory rat; model design /development; neuroendocrine system; nociceptin; nonhuman therapy evaluation; pathologic process; restraint; serotonin inhibitor; stress; sympathectomy; vagotomy; vagus nerve

DESCRIPTION: The primary symptom and most debilitating aspect of fibromyalgia syndrome is chronic generalized pain. The pathogenic mechanisms of fibromyalgia pain are very poorly understood and currently available analgesic therapies have proven to be only partially, and unpredictably, effective. Progress in this area has been seriously hindered by the lack of an adequate experimental model of chronic generalized pain. We have recently determined that interruption of vagal-afferent activity from the abdomen in the rat can result in a state of chronic generalized hyperalgesia. Following subdiaphragmatic vagotomy, the nociceptive threshold to mechanical stimulation decreased and bradykinin-induced mechanical hyperalgesia was enhanced. Similar to fibromyalgia, this vagotomy-induced hyperalgesia exhibits marked sex-dependence, with the enhancement of bradykinin-induced hyperalgesia significantly greater in females. The vagotomy-induced generalized hyperalgesia depends on activity of the adrenal medulla, a characteristic also relevant to fibromyalgia syndrome in which chronic stress-induced activation of the sympathoadrenal and hypothalamic-pituitary-adrenal axes may contribute. Therefore, another important dimension of our model is the demonstration of generalized hyperalgesia induced by chronic intermittent stress. The purpose of this application is to further characterize the vagotomy-based model of generalized hyperalgesia, and to use this model to elucidate mechanisms underlying chronic generalized pain. We propose to first perform a detailed analysis of the characteristics of vagotomy-induced hyperalgesia. Second, we will examine the effect of physiological factors important in fibromyalgia, including the sympathoadrenal axis, gastrointestinal influences on vagal afferent activity, and capsaicin-sensitive mechanisms. Third, we will examine the effect of extrinsic factors shown to modulate fibromyalgia pain, including chronic stress and a variety of clinically employed pharmacological and non-pharmacological therapies. The proposed studies should provide important new insights into the pathophysiology of generalized pain conditions, including that associated with fibromyalgia. In this regard, this work can achieve important progress toward a goal that until now has been frustrated by the absence of workable animal models.

描述：纤维肌痛综合征的主要症状和大多数使人衰弱的方面是慢性广泛性疼痛。纤维肌痛疼痛的致病机制知之甚少，目前可用的镇痛疗法已被证明仅部分有效，有效。由于缺乏足够的慢性广泛性疼痛实验模型，这一领域的进展受到了严重的阻碍。我们最近确定，大鼠腹部的迷走神经活性中断可能导致慢性广泛性痛觉过敏。次肌迷走术后，机械刺激的伤害感受阈值减少，而铁毒素诱导的机械性痛觉过敏也得到了增强。与纤维肌痛相似，这种迷走道造成的痛觉过敏表现出明显的性别依赖性，而女性的心动激素诱导的痛觉症的增强明显更大。迷走神经术引起的广义性痛觉过敏取决于肾上腺髓质的活性，肾上腺髓质的活性也与纤维肌痛综合征有关，其中慢性应激诱导的交感神经肾上腺和下丘脑 - 腹膜 - 肾上腺辅助轴的激活可能会产生贡献。因此，我们模型的另一个重要方面是慢性间歇性应力引起的广义性痛觉过敏的证明。 该应用的目的是进一步表征基于迷走神经术的广义性痛觉过敏模型，并使用该模型来阐明慢性广泛性疼痛的基础机制。我们建议首先对迷走神经术诱导的痛觉过敏的特征进行详细分析。其次，我们将研究生理因素在纤维肌痛中重要的影响，包括交感神经轴，胃肠道对迷走神经传入活性的影响和辣椒素敏感机制。第三，我们将检查显示调节纤维肌痛疼痛的外部因素的影响，包括慢性应激以及多种临床使用的药理和非药理学疗法。拟议的研究应提供有关广义疼痛疾病（包括与纤维肌痛有关的）病理生理学的重要新见解。在这方面，这项工作可以取得重要的进步，直到现在，这一目标一直因缺乏可行的动物模型而感到沮丧。