Mechanisms of Chronic Visceral Hyperalgesia

慢性内脏痛觉过敏的机制

• 批准号: 6540315
• 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/6540315
• 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.

描述：内脏痛觉过敏是肠易激的一个特征。 综合征(IBS)是一种非常常见的疾病，影响多达15%的 对社会经济有重大影响的美国人口。我们对这一现象的理解 腰腿痛等功能性疼痛综合征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什么？ 或引起炎症反应的主要原因是缺乏有效的 动物模型。最近，有研究表明，功能性腹痛可以 以动物为模型。新生大鼠的结肠刺激(CI)，而不是成年大鼠，可以 导致持久的内脏痛觉过敏，在最初的 伤势已痊愈。在这项研究中，中心假设是持续的 结肠痛觉过敏，残留于新生儿结肠刺激，与 中枢神经敏感化通过交互交换 脊髓和丘脑之间的信息。假设1：存在一个 出生后轻度结肠刺激可导致永久性结肠刺激的时间窗口 导致慢性内脏痛觉过敏的神经系统变化。 特定目标]将定义出生后发育的这段时间窗口，使用 有害的机械扩张或化学刺激引起的结肠 慢性内脏痛觉过敏。假设2：持续内脏 中枢可塑性改变维持新生儿CI的残余痛觉过敏 在神经元敏感度方面。特定的AIM 2将演示 免疫细胞化学和电生理学，慢性内脏 痛觉过敏与脊髓神经元敏感化和 丘脑。假设3：敏感化部分由神经元维持 涉及谷氨酸和肽能过程的机制。特定目标3 将确定谷氨酸或神经激肽受体的阻断是否通过特定的 拮抗剂会降低中枢敏感度。假设4：中央 敏化是由完整的背柱(DC)参与 前馈动态信息交换之间的背角 脊髓和丘脑。特定的AIM 4将演示，使用 电生理学和行为学研究表明，敏化是由 完整的DC-丘脑通讯，维持丘脑的敏感化和 通过下行通路增强脊髓神经元的敏感性。长期的 拟议研究的目的是定义神经生理学的相关因素。 慢性内脏痛觉过敏的治疗，从而确定新的治疗方法 功能性肠病患者缓解疼痛的靶点。