PROSTAGLANDINS AND SENSITIZATIONS OF SENSORY NEURONS

已知促炎剂如洋地黄素（PG） 使感觉神经元对伤害性刺激敏感，导致 一种被称为痛觉过敏的高度敏感性。 目前， 我们对前列腺素调节的细胞机制知之甚少， 感觉神经元的敏感性和兴奋性以及PGs的作用 调节神经源性炎症的强度或持续时间 反应 本提案中概述的研究旨在 阐明这些生理机制和PG诱导的改变， 感觉传导级联，其在感觉细胞中产生致敏作用， 背根神经节的神经元。 这项研究利用大鼠背侧神经元的分离， 在细胞培养中生长的根神经节。 该模型准备允许 研究引起PG诱导的细胞机制 在缺乏潜在调节因子的情况下致敏， 其他细胞类型。 因此，促炎剂的直接作用 来调节神经元兴奋性。 PG的作用 和兴奋性化学试剂，如缓激肽和辣椒素， 通过利用全细胞记录电生理学， 穿孔囊泡膜片钳记录技术。缓激肽和 辣椒素用于探测神经元敏化的水平， 阐明PC调制是否发生在第二信使水平 介导的级联反应或直接作用于神经元膜。 初步研究 将建立对电生理学的基本理解 神经元对缓激肽和辣椒素反应的特性。 这 细胞反应形成了检测神经元状态的基本探针 致敏 后续研究将进一步表征 产生PG诱导致敏作用所需的基本参数，例如 如PG浓度、PG类型和PG作用的时间过程。 最后，我们将确定PG激活第二信使的作用- 介导的转导级联在生理机制调节 感觉神经元反应的兴奋性或敏感性。 这些研究应该提供一个基本的了解细胞 调节感觉神经元兴奋性的机制及其作用 在启动和维持神经原性 炎症 这也将有助于我们理解 神经元活动的慢性或长期改变，例如在长期- 术语增强和易化。 最终，如果我们能分离出 离子电导），并建立产生 这种增强的兴奋性，将有可能设计药物， 选择性地阻断这种传导或改变的通路， 与慢性炎症相关的疼痛和高度敏感性 类风湿性关节炎的症状有哪些

Pro-inflammatory agents such as the prostaglandins (PG) are known to sensitize sensory neurons to noxious stimulation, resulting in a condition of heightened sensitivity known as hyperalgesia. At present, we know very little about the cellular mechanisms whereby PGs modulate the sensitivity and excitability of sensory neurons and the role PGs play in regulating the intensity or duration of the neurogenic inflammatory response. The studies outlined in this proposal are designed to elucidate those physiological mechanisms and PG-induced alterations in sensory transduction cascades that produce sensitization in sensory neurons of the dorsal root ganglion. The proposed studies utilize isolated sensory neurons of the rat dorsal root ganglion grown in cell culture. This model preparation permits investigation of the cellular mechanisms giving rise to PG-induced sensitization in the absence of potential modulating factors released by other cell types. Thus, the direct actions of pro-inflammatory agents to regulate neuronal excitability can be determined. The actions of PGs and excitatory chemical agents, such as bradykinin and capsaicin, are recorded electrophysiologically through utilization of whole-cell and perforated-vesicle patch-clamp recording techniques. Bradykinin and capsaicin are used to probe the levels of neuronal sensitization and thus elucidate whether PC modulation occurs at the level of second messenger mediated cascades or directly at the neuronal membrane. Initial studies will establish a fundamental understanding of the electrophysiological properties of the neuronal responses to bradykinin and capsaicin. This cellular response forms the basic probe to examine the state of neuronal sensitization. Subsequent studies, will further characterize the essential parameters required to produce PG-induced sensitization, such as PG concentration, type of PG, and the time course of PG action. Finally, we will establish the role of PG activation of second messenger- mediated transduction cascades in the physiological mechanisms regulating excitability or sensitivity of the response in sensory neurons. These studies should provide a basic understanding of the cellular mechanisms regulating sensory neuron excitability and the roles these processes play in the initiation and maintenance of neurogenic inflammation. This should also contribute to our understanding of chronic or long-term modifications of neuronal activity such as in long- term potentiation and facilitation. Ultimately, if we can isolate the ionic conductance)s) and establish the regulatory mechanisms producing this enhanced excitability, it will be possible to design drugs that selectively block this conductance or the altered pathway and thus, curb the pain and heightened sensitivity associated with chronic inflammatory conditions, such as rheumatoid arthritis.