Neurochemical Mechanisms of Visceral Pain

内脏疼痛的神经化学机制

• 批准号: 6899202
• 负责人: RICHARD J Traub
• 金额: $ 35.27万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899202
• 关键词: NMDA receptors; behavior test; cell population study; colon; dorsal horn; electrophysiology; estrogens; female; gastrointestinal sign /symptom; hormone regulation /control mechanism; hormone therapy; hyperalgesia; immunocytochemistry; inflammation; irritable bowel syndrome; laboratory rat; neural information processing; neurochemistry; neurons; neuropharmacology; pain; pain threshold; protein structure function; spinal cord; visceral afferent nerve

DESCRIPTION (provided by applicant): Irritable Bowel Syndrome (IBS) is characterized by abdominal pain in the absence of pathology. Epidemiological studies further show IBS is reported most often in menstruating women compared to post-menopausal women or men suggesting gonadal hormones could be a contributing factor. It was recently hypothesized that the pain of IBS could result from sensitization of visceral afferent fibers or hyperexcitability of dorsal horn neurons. Recent data suggests a role for spinal NMDA receptors in processing noxious and innocuous visceral stimuli and NMDA receptors in the brain are modulated by estrogen. The long-term goal of this application is to examine the effects of estrogen on spinal NMDA receptor-mediated processing of noxious and innocuous colorectal stimuli. We hypothesize that estrogen increases activity at spinal NMDA receptors in the absence and presence of colonic inflammation leading to colorectal allodynia and hyperalgesia. This modulation may result from alterations in NMDA receptor subunit composition or second messenger mediated phosphorylation. Using our model of colorectal distention (CRD), we will test these hypotheses by examining the effects of estrogen replacement in ovariectomized rats on visceral sensory processing in the spinal cord in the absence and presence of colonic inflammation, in the following specific aims: 1) Determine the effects of estrogen on responses to transient innocuous, noxious and inflammatory colorectal stimuli. Behavioral, immunocytochemical and electrophysiological studies will test the hypothesis that estrogen facilitates responses to CRD in the absence and presence of colonic inflammation. 2) Characterize the effects of estrogen on subpopulations of visceroceptive projection neurons using retrograde tract tracing and immunocytochemical localization of Fos expression. This will test the hypothesis that estrogen alters the percentage and segmental distribution of supraspinal projection neurons that respond to CRD in the absence and presence of colonic inflammation. 3) Determine if NMDA receptor-mediated modulation of viscerosensory processing is affected by ovariectomy and estrogen replacement. This will test the hypothesis that the modulation of responses to CRD by estrogen is due to altering activity at NMDA receptors. 4) Determine the mechanism(s) through which estrogen modulates CRD-evoked NMDA receptor activity in the absence and presence of colonic inflammation. This will test the hypothesis that estrogen alters NMDA receptor subunit composition and/or modulates second messenger-mediated phosphorylation of tile NMDA receptor.

描述（由申请人提供）：肠易激综合征（IBS）的特征是在没有病理的情况下进行腹痛。流行病学研究进一步表明，与绝经后男性或男性相比，最常见的IBS经常是在月经妇女中，表明性腺激素可能是一个促成因素。最近可以假设，IBS的疼痛可能是由于内脏传入纤维的敏化或背角神经元过度刺激性的。最近的数据表明，脊柱NMDA受体在脑中的有害和无害的内脏刺激和NMDA受体中的作用是通过雌激素调节的。该应用的长期目标是检查雌激素对有害和无害的结直肠刺激的脊髓NMDA受体介导的加工的影响。我们假设在不存在和存在结肠炎症的情况下，雌激素会增加脊柱NMDA受体的活性，从而导致结直肠内痛和痛觉过敏。该调节可能是由于NMDA受体亚基组成或第二质体介导的磷酸化的改变而引起的。使用我们的结直肠扩张模型（CRD），我们将通过检查卵巢切除大鼠中雌激素替代的影响在缺乏结肠炎症的情况下，在脊髓中的内脏感觉处理中测试这些假设，在以下特定目的中：1）确定雌激素对临时刺激的反应的影响。行为，免疫细胞化学和电生理学研究将检验以下假设，该假设促进了在不存在和存在结肠炎症的情况下对CRD的反应。 2）表征雌激素对使用FOS表达的逆行痕迹和免疫细胞化学定位的雌激素对内脏投射神经元亚群的影响。这将检验以下假设，即雌激素会改变在不存在和存在结肠炎症的情况下对CRD反应的上脊髓投射神经元的百分比和节段性分布。 3）确定NMDA受体介导的内脏处理调节是否受卵巢切除术和雌激素置换的影响。这将检验以下假设：雌激素对CRD的反应的调节是由于NMDA受体的活性改变所致。 4）确定雌激素在不存在和存在结肠炎症的情况下调节CRD诱发的NMDA受体活性的机制。这将检验以下假设：雌激素会改变NMDA受体亚基组成和/或调节瓷砖NMDA受体的第二信使介导的磷酸化。