Extracellular mechanism regulating synaptic function and pain plasticity

摘要： 多达20%的人口将遭受持续6年以上的慢性疼痛 月份。慢性疼痛及其潜在的病理生理学，可导致抑郁和 其他衰弱的神经影响，尽管有有效的治疗方法 急性疼痛慢性疼痛对大多数当前的治疗方法都有抵抗力 针对这些疼痛背后的分子事件的新型治疗药物的开发 各州。神经病理性和持续性术后疼痛的发生，至少部分是由于长期的 脊髓背侧兴奋性突触传递功能的持续性变化 导致疼痛信号增强(痛觉过敏)和无害刺激唤起的喇叭 疼痛(超常疼痛)。这些突触事件具有许多神经元可塑性的特征 已经在中枢神经系统较高的地区进行了研究。其中许多更改都依赖于NMDAR 导致突触强度增加。一种已经出现的潜在机制 这些突触功能的变化是NMDAR功能的直接增强 与EphB受体酪氨酸激酶的分子相互作用。在我们出版的基础上 工作中，我们将测试假设，即EphB-NMDAR相互作用导致 通过表达NMDAR引导突触形成慢性疼痛状态 野生型或突变型EphB2受体在体外和小鼠体内。为了检验这一假设，我们将 确定EphB-NDMAR相互作用的调节机制，表征 分子和其他工具来破坏这种相互作用，并确定是否阻止 EphB-NMDAR的相互作用将缓解慢性疼痛。为了解决这些问题，我们 将承担三个具体目标：1.确定NMDAR上的域 负责EphB-NMDAR的交互。2.检验VLK的假设 指导EphB2上Y504的磷酸化。3.确定功能 VLK在疼痛可塑性中的意义。这些目标加在一起将创造一个新的 将提供对EphB-NMDAR作用的更深入了解的知识 疼痛中的相互作用并使理解基本机制取得进展 在慢性疼痛状态的背后。

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.