Mechanisms of Central and Peripheral Hyperalgesia

描述（由申请人提供）：肠易激综合征（IBS）是一种常见的胃肠道疾病，其特征为慢性腹痛和肠功能改变（腹泻和/或便秘）。据估计，IBS影响了美国20%的人口。虽然IBS的病理生理学是未知的，内脏高敏感性（即，响应肠扩张的疼痛阈值降低）是存在于大多数IBS患者中的疾病的临床标志。然而，导致慢性内脏高敏感性的机制目前尚不清楚。 我们的实验室已经获得的证据表明，IBS患者也表现出对实验性热痛刺激的躯体超敏反应。这些新的发现不同于以前的研究，表明IBS相关的超敏反应仅限于肠道。相比之下，我们的数据表明，IBS的特点是更广泛的改变中枢疼痛处理。根据我们的初步数据，我们提出了新的，机械的假设，IBS患者有一个普遍的，但分级的躯体伤害性刺激超敏反应。我们预计，这种躯体超敏反应是由躯体组织的，与结肠共享内脏体融合的下皮节表现出最大的超敏反应。此外，我们建议，超敏反应将更深，紧张刺激比表面，简短的刺激。重要的是，迄今为止，还没有研究人员试图系统地描述IBS患者对多种躯体疼痛刺激的感知和生理反应。因此，我们提出以下具体目标。 具体目标1：测试IBS患者与对照组之间在不同水平提供脊髓输入的空间区域中的躯体超敏反应差异。为了实现这一目标，我们将评估对四种经过充分验证的实验性躯体疼痛刺激（热痛、压痛、冷加压痛、缺血性疼痛）的感知反应，这些疼痛刺激跨越三个身体部位（前臂、腹部、腿部）。 具体目标二：测试IBS患者与对照组之间的差异，作为疼痛刺激特征的函数（深部与浅表，空间区域刺激）。具体目标3：为了表征IBS患者和对照组之间对实验性疼痛刺激的生理反应的差异，并检查生理反应对疼痛感知的贡献。为了实现这一目标，我们将评估心血管和神经内分泌反应的热，机械，冷加压，和缺血性疼痛刺激。具体目标4：通过确定对实验性疼痛刺激的反应是否可预测IBS患者功能性肠病严重程度指数评分的变异性，确定IBS患者躯体疼痛反应的临床相关性。

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain and altered bowel function (diarrhea and/or constipation). IBS is estimated to effect 20% of the United States population. Although the pathophysiology of IBS is unknown, visceral hypersensitivity (i.e., decreased pain thresholds in response to gut distension) is a clinical marker of the disorder present in the majority of patients with IBS. The mechanisms that lead to chronic visceral hypersensitivity, however, are currently unknown. Our laboratory has acquired evidence that patients with IBS also display somatic hypersensitivity in response to experimental thermal pain stimuli. These new findings differ from previous investigations that indicated IBS-associated hypersensitivity is limited to the gut. In contrast, our data suggest that IBS is characterized by more widespread alterations in central pain processing. Based on our preliminary data, we propose the novel, mechanistic hypothesis that IBS patients have a generalized but graded hypersensitivity to somatic nociceptive stimuli. We anticipate that this somatic hypersensitivity is somatotopically organized such that the lower dermatomes that share viscerosomatic convergence with the colon demonstrate the greatest hypersensitivity. Moreover, we propose that the hypersensitivity will be greater for deep, tonic stimuli than for superficial, brief stimuli. Importantly, no investigator to date has attempted to systematically characterize perceptual and physiological responses to multiple somatic pain stimuli among patients with IBS. Therefore, we propose the following specific aims. Specific Aim 1: To test for differences in somatic hypersensitivity between patients with IBS compared to controls across spatial areas that provide spinal input at differing levels. In order to accomplish this aim, we will assess perceptual responses to four well-validated experimental somatic pain stimuli (thermal pain, pressure pain, cold pressor pain, ischemic pain) across three body sites (forearm, abdomen, leg). Specific Aim 2: To test for differences between patients with IBS compared to controls as a function of the characteristics of the pain stimuli (deep vs. superficial, spatial area stimulated). Specific Aim 3: To characterize differences in physiological responses to experimental pain stimuli between IBS patients and controls and to examine contributions of physiological responses to pain perception. In order to accomplish this aim, we will assess cardiovascular and neuroendocrine responses to thermal, mechanical, cold pressor, and ischemic pain stimuli. Specific Aim 4: To establish the clinical relevance of somatic pain responses among IBS patients by determining whether responses to experimental pain stimuli predict variability in IBS patients' scores on the Functional Bowel Disorder Severity Index.