Extracellular mechanism regulating synaptic function and pain plasticity

摘要： 多达20%的人口将遭受慢性疼痛持续超过6 个月慢性疼痛及其潜在的病理生理学，可导致抑郁症， 其他使人衰弱的神经影响，虽然有有效的治疗方法， 急性疼痛慢性疼痛对大多数目前的治疗有抵抗力， 开发针对这些疼痛背后的分子事件的新疗法 states.神经性和持续性术后疼痛的发生，至少部分是由于长时间的 脊髓背角兴奋性突触传递功能的持续变化 角导致增强的疼痛信号传导（痛觉过敏）和无害的刺激诱发 疼痛（异常性疼痛）。这些突触事件具有神经元可塑性的许多特征， 已经在更高的CNS区域进行了研究。这些变化中有许多是NMDAR依赖性的 导致突触强度增加。一种机制已经出现， 突触功能的这些变化是通过直接的 与EphB受体酪氨酸激酶的分子相互作用。基于我们发布的 工作，我们将测试EphB-NMDAR相互作用是负责的假设， 通过表达NMDAR将NMDAR引导至突触来发展慢性疼痛状态 野生型或突变型EphB 2受体的体外和小鼠中的研究。为了验证这个假设，我们将 确定介导EphB-NDMAR相互作用的机制， 分子和其他工具来破坏这种相互作用， EphB-NMDAR相互作用将减轻慢性疼痛。为了解决这些问题，我们 将采取三个具体目标：1。确定NMDAR上的域 负责EphB-NMDAR相互作用。2.检验VLK是否 指导EphB 2上Y504的磷酸化。3.确定函数 VLK在疼痛可塑性中意义这些目标将共同创造一个新的 知识，将提供EphB-NMDAR的作用更深入的了解 疼痛中的相互作用，并使理解基本机制的进展 慢性疼痛的背后

Abstract: As much as 20% of the population will suffer from chronic pain lasting for more than 6 months. Chronic pain and its underlying pathophysiology, can result in depression and other debilitating neurological effects and although there are effective treatments for acute pain chronic pain is resistant to most current treatments requiring the development of novel therapeutics that target molecular events underlying these pain states. Neuropathic and persistent post-surgical pain occurs, at least in part, due to long lasting changes in the function of excitatory synaptic transmission in the spinal dorsal horn resulting in enhanced pain signalling (hyperalgesia) and innocuous stimuli evoking pain (allodynia). These synaptic events share many features of neuronal plasticity that has been studied in higher CNS areas. Many of these changes are NMDAR dependent resulting in increased synaptic strength. One mechanism that has emerged underlying these changes in synaptic function is the potentiation of NMDAR function by a direct molecular interaction with the EphB receptor tyrosine kinase. Building on our published work, we will test the hypothesis that an EphB-NMDAR interaction is responsible for the development of a chronic pain state by directing NMDARs to synapses by expressing wild type or mutant EphB2 receptors in vitro and in mice. To test this hypothesis, we will determine the mechanism mediating the EphB-NDMAR interaction, characterize molecules and other tools to disrupt this interaction, and determine whether preventing the EphB-NMDAR interaction will alleviate chronic pain. To address these questions we will undertake three specific aims: 1. Determine the domain on the NMDAR responsible for the EphB-NMDAR interaction. 2. Test the hypothesis that VLK directs phosphorylation of Y504 on EphB2. 3. Determine the functional significance of VLK in pain plasticity. Collectively these aims will create a new knowledge that will provide a deeper understanding of the role of EphB-NMDAR interaction in pain and enable progress toward understanding the basic mechanisms behind chronic pain states.