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: 7016346
• 负责人: JON DAVID LEVINE
• 金额: $ 22.78万
• 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/7016346
• 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最令人衰弱的方面是慢性全身疼痛。人们对纤维肌痛的发病机制知之甚少，目前可用的镇痛疗法已被证明仅部分有效，而且效果不可预测。由于缺乏足够的慢性全身疼痛实验模型，该领域的进展受到严重阻碍。我们最近确定，大鼠腹部迷走神经传入活动的中断可能导致慢性全身性痛觉过敏状态。膈下迷走神经切断术后，机械刺激的伤害性阈值降低，缓激肽诱导的机械痛觉过敏增强。与纤维肌痛类似，这种迷走神经切断引起的痛觉过敏表现出明显的性别依赖性，缓激肽引起的痛觉过敏在女性中的增强明显更大。迷走神经切断术引起的全身性痛觉过敏取决于肾上腺髓质的活动，这一特征也与纤​​维肌痛综合征有关，其中慢性应激诱发的交感肾上腺轴和下丘脑-垂体-肾上腺轴的激活可能有所贡献。因此，我们模型的另一个重要方面是证明慢性间歇性应激引起的全身痛觉过敏。 本申请的目的是进一步表征基于迷走神经切断术的全身性痛觉过敏模型，并使用该模型来阐明慢性全身性疼痛的机制。我们建议首先对迷走神经切断术引起的痛觉过敏的特征进行详细分析。其次，我们将检查对纤维肌痛重要的生理因素的影响，包括交感肾上腺轴、胃肠道对迷走神经传入活动的影响以及辣椒素敏感机制。第三，我们将研究调节纤维肌痛的外在因素的作用，包括慢性应激和各种临床采用的药物和非药物疗法。拟议的研究应该为全身疼痛的病理生理学提供重要的新见解，包括与纤维肌痛相关的疼痛。在这方面，这项工作可以在实现迄今为止因缺乏可行的动物模型而受挫的目标方面取得重要进展。