NOCICEPTION AND NMDA RECEPTOR PHOSPHORYLATION

描述（改编自研究者摘要）：慢性或持续性 疼痛在美国是一个主要的健康问题，这导致了医疗 护理和生产力损失数十亿美元。两个症状 慢性或持续性疼痛，导致最多的投诉 患者的症状包括异常性疼痛（对正常非疼痛刺激的疼痛）和 痛觉过敏（对疼痛刺激的反应增强的疼痛感）。 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的最新研究 表明异常性疼痛和痛觉过敏的显著比例是 由脊髓NMDA受体介导。这项工作表明，有一个 脊髓NMDA受体活性的功能变化 持续的伤害性刺激。NMDA受体受多种 包括磷酸化。受体的磷酸化导致 受体活性的增加。NMDA的两个亚基 受体（NR 1和NR 2）具有几种激酶的共有位点， 从脊髓中的一些激酶中分离出来， 异常性疼痛和痛觉过敏。因此，本项目的主要假设是， NMDA受体通过持续性伤害感受而磷酸化。为了验证这一 然而，作为一名新的研究者，PI需要开发新的 他实验室里的技术。由于需要开发新技术， 本申请的范围已经被缩小到测试假设， NMDA受体的NR 1亚基在持续的 伤害感受这一小笔赠款申请将：1）允许PI发展， 测试免疫沉淀技术对NR 1亚基的特异性 转染HEK-293细胞，2）将这些技术转移到研究 NR 1亚基在体内，和3）评估NR 1磷酸化的变化， 对伤害性刺激的反应全面了解 NMDA受体对疼痛反应的磷酸化是这一过程的最终目标。 项目这些知识应该会导致对脊髓疼痛有价值的见解 并希望能找到新的有效疗法。

DESCRIPTION (Adapted from the Investigator's Abstract): Chronic or persistent pain is a major health problem in the United States, which results in medical care and productivity losses in the billions of dollars. Two symptoms of chronic or persistent pain, which result in the greatest number of complaints from sufferers, are allodynia (pain to normally non-painful stimuli) and hyperalgesia (enhanced sensation of pain in response to painful stimuli). Recent work with antagonists for the N-methyl-D-aspartate (NMDA) receptor demonstrates that a significant proportion of allodynia and hyperalgesia is mediated by spinal cord NMDA receptors. This work suggests that there is a functional change in the activity of the spinal cord NMDA receptors in response to persistent nociceptive stimuli. NMDA receptors are regulated by a number of factors, including phosphorylation. Phosphorylation of the receptors results in an increase in the activity of the receptors. The two subunits of the NMDA receptor (NR1 and NR2) have consensus sites for several kinases, and activity from some of these kinases in the spinal cord has been associated with allodynia and hyperalgesia. Thus, the major hypothesis of this project is that NMDA receptors are phosphorylated by persistent nociception. To test this hypothesis, however, the PI, who is a new investigator, needs to develop new techniques in his laboratory. Because of the need to develop new techniques, the scope of this application has been narrowed to testing the hypothesis that the NR1 subunit of the NMDA receptor is phosphorylated during persistent nociception. This small grant application will: 1) allow the PI to develop and test the specificity of immunoprecipitation techniques on NR1 subunits transfected into HEK-293 cells, 2) transfer these techniques to the study of NR1 subunits in vivo, and 3) evaluate changes in NR1 phosphorylation in response to nociceptive stimuli. A complete understanding of the dynamics of NMDA receptor phosphorylation in response to pain is the ultimate goal of this project. This knowledge should lead to valuable insights into spinal cord pain processing and, hopefully, to new effective therapies.