Mechanisms of Chronic Visceral Hyperalgesia

慢性内脏痛觉过敏的机制

• 批准号: 6639680
• 负责人: ELIE D AL-CHAER
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-05 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639680
• 关键词: behavior test; cell population study; chronic pain; electrophysiology; glutamate receptor; hyperalgesia; image processing; immunocytochemistry; irritable bowel syndrome; laboratory rat; neural information processing; neurons; neuropeptide receptor; neurophysiology; neuroregulation; newborn animals; receptor sensitivity; single cell analysis; somatic reflex; spinal cord; statistics /biometry; substance P; thalamus

DESCRIPTION: Visceral hyperalgesia is a hallmark of the irritable bowel syndrome (IBS), an extremely common disorder, affecting up to 15 percent of the US population with a major socioeconomic impact. Our understanding of the hyperalgesia in functional pain syndromes such as lBS lags behind our knowledge of the mechanisms of other types of visceral pain that are mechanically-induced or caused by inflammatory reactions mainly because of the lack of a valid animal model. Recently, it was shown that functional abdominal pain can be modeled in animals. Colon irritation (CI) in neonatal but not adult rats, can cause a long lasting visceral hyperalgesia that persists long after the initial injury has resolved. In this study, the central hypothesis is that persistent colonic hyperalgesia, residual to neonatal colon irritation, is associated with central neural sensitization maintained by an interactive exchange of information between the spinal cord and thalamus. HYPOTHESIS 1: There exists a postnatal window of time when minimal colon irritation can induce permanent changes in the nervous system that leads to chronic visceral hyperalgesia. SPECIFIC AIM] will define this window of time in postnatal development using noxious mechanical distension or chemical irritation of the colon to cause chronic visceral hyperalgesia. HYPOTHESIS 2: The persistent visceral hyperalgesia residual to neonatal CI is maintained by central plastic changes in neuronal sensitivity. SPECIFIC AIM 2 will demonstrate with immunocytochemistry and electrophysiology, that the chronic visceral hyperalgesia is associated with neuronal sensitization in the spinal cord and the thalamus. HYPOTHESIS 3: The sensitization is maintained in part by neuronal mechanisms involving glutamatergic and peptidergic processes. SPECIFIC AIM 3 will determine if blockade of glutamate or neurokinin receptors by specific antagonists will reduce the central sensitization. HYPOTHESIS 4: The central sensitization is maintained by an intact dorsal column (DC) participating in a feed-forward dynamic exchange of information between the dorsal horn of the spinal cord and the thalamus. SPECIFIC AIM 4 will demonstrate, using electrophysiology and behavior studies, that the sensitization is mediated by an intact DC-thalamus communication that maintains thalamic sensitization and amplifies spinal neuronal sensitivity via descending pathways. The long-term objective of the proposed study is to define the neurophysiological correlates of chronic visceral hyperalgesia and hence to identify novel therapeutic targets for the relief of pain in patients with functional bowel disorders.

内脏痛觉过敏是肠易激综合征的一个标志 综合征（IBS），一种非常常见的疾病，影响高达15%的 对美国社会经济产生重大影响的人口。我们理解 功能性疼痛综合征如LBS中的痛觉过敏落后于我们的知识 其他类型的内脏疼痛的机制是机械引起的 或由炎症反应引起，主要是因为缺乏有效的 动物模型最近，研究表明，功能性腹痛可以 以动物为模型。新生大鼠而非成年大鼠的结肠刺激（CI）可 引起持续时间长的内脏痛觉过敏， 伤病已经解决。在这项研究中，中心假设是， 结肠痛觉过敏，新生儿结肠刺激的残留，与 中枢神经敏感性通过以下交互式交换来维持： 脊髓和丘脑之间的信息。假设1：存在一个 出生后的时间窗口，当最小的结肠刺激可以诱导永久性的 导致慢性内脏痛觉过敏的神经系统变化。 具体目标]将定义这个时间窗口，在产后发展使用 结肠的有害机械扩张或化学刺激， 慢性内脏痛觉过敏假设2：持续的内脏 新生儿脑梗死后残余的痛觉过敏通过中枢可塑性改变维持 神经元敏感性。SPECIFIC AIM 2将展示 免疫细胞化学和电生理，慢性内脏 痛觉过敏与脊髓中的神经元敏化有关， 丘脑假设3：敏化部分由神经元维持。 涉及谷氨酸能和肽能过程的机制。具体目标3 将决定是否通过特异性的谷氨酸或神经激肽受体阻断 拮抗剂将降低中枢致敏作用。假设4：中央 致敏是由一个完整的背柱（DC）参与维持， 前馈动态信息交换之间的背角的 脊髓和丘脑具体目标4将证明，使用 电生理学和行为学研究表明，致敏作用是由 一个完整的DC-丘脑通信，维持丘脑敏化， 通过下行通路增强脊髓神经元的敏感性。长期 这项研究的目的是确定神经生理学相关因素， 慢性内脏痛觉过敏，从而确定新的治疗 用于缓解功能性肠病患者疼痛的靶点。