Mechanisms of Chronic Visceral Hyperalgesia

描述：内脏痛觉过敏是肠易激的一个标志 综合症 (IBS)，一种极其常见的疾病，影响高达 15% 的人 对社会经济产生重大影响的美国人口。我们的理解 功能性疼痛综合征（如 LBS）中的痛觉过敏落后于我们的认识 机械引起的其他类型内脏疼痛的机制 或主要是由于缺乏有效的治疗方法而引起的炎症反应 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）可以 引起长期持续的内脏痛觉过敏，这种过敏在最初的痛觉过敏后仍持续很长时间 伤势已经解决。在这项研究中，中心假设是持续存在 结肠痛觉过敏，残留于新生儿结肠刺激，与 通过交互交换维持中枢神经敏化 脊髓和丘脑之间的信息。假设 1：存在 产后时间窗口，此时最小的结肠刺激就可以引起永久性的 神经系统的变化导致慢性内脏痛觉过敏。 具体目标]将使用以下方法定义产后发育的这个时间窗口 结肠的有害机械扩张或化学刺激导致 慢性内脏痛觉过敏。假设2：持续性内脏 新生儿 CI 残留的痛觉过敏通过中枢塑性变化维持 在神经元敏感性中。具体目标 2 将演示 免疫细胞化学和电生理学表明，慢性内脏 痛觉过敏与脊髓神经元敏化有关 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 将确定特定的谷氨酸或神经激肽受体是否被阻断 拮抗剂会降低中枢敏化。假设4：中央 敏化由完整的背柱（DC）维持，参与 背角之间的前馈动态信息交换 脊髓和丘脑。具体目标 4 将演示，使用 电生理学和行为研究表明，敏化是由 完整的 DC-丘脑通讯，维持丘脑敏化和 通过下行通路增强脊髓神经元的敏感性。长期来看 拟议研究的目的是定义神经生理学相关因素 慢性内脏痛觉过敏的研究，从而确定新的治疗方法 缓解功能性肠道疾病患者疼痛的目标。

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.