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Neuronal Plasticity and Signaling in Neuropathic Pain

神经病理性疼痛中的神经元可塑性和信号传导

基本信息

批准号：
8839310
负责人：
Hui-Lin Pan
金额：
$ 35.52万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-15 至 2016-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8839310
关键词：
Adverse effects Analgesics Animal Model Biochemical Genetics Calcineurin Calcineurin inhibitor Clinical Control Groups Development Drug usage Genetic Techniques Glutamates Goals Graft Rejection Health Immunosuppressive Agents Lead Maintenance Mediating Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor A1 NR1 gene Neuronal Plasticity Nociception Operative Surgical Procedures Organ Transplantation Patients Peripheral nerve injury Phosphorylation Phosphorylation Site Pilot Projects Play Posterior Horn Cells Protein phosphatase Proteins Rattus Regulation Resistance Role Serine Signal Transduction Site Spinal Spinal Cord Synapses Synaptic Transmission Synaptic plasticity Syndrome Testing Threonine Tissues Traumatic Nerve Injury allodynia attenuation casein kinase II central sensitization chronic neuropathic pain dorsal horn improved interdisciplinary approach nerve injury neurotransmission novel strategies painful neuropathy postsynaptic prevent receptor function transmission process treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Neuronal Plasticity and Signaling in Neuropathic Pain Project Summary Activity-dependent synaptic plasticity at the spinal cord level is fundamentally important to the development of neuropathic pain caused by traumatic nerve injury and surgery. N-methyl-D-aspartate (NMDA) receptors in the spinal dorsal horn are critically involved in central sensitization and maintenance of neuropathic pain. However, the mechanisms of potentiated NMDA receptor activity in the spinal cord after nerve injury remain poorly understood. Although increased phosphorylation of NMDA receptors after nerve injury is known, the upstream mechanisms of increased NMDA receptor activity in neuropathic pain remain to be determined. In our preliminary studies, we found that inhibition of the protein kinase CK2 in the spinal cord completely reversed increased NMDA receptor activity and produced long-lasting attenuation of allodynia caused by nerve injury. In this application, we will use an animal model of neuropathic pain to test the central hypothesis that nerve injury increases CK2 activity in the spinal cord, which facilitates phosphorylation of the NR1 subunit of NMDA receptors and potentiates NMDA-mediated synaptic transmission in neuropathic pain. The specific aims of this application are to (1) define the role of imbalance between the CK2(phosphorylation) and calcineurin(de-phosphorylation) activities in augmented NMDA-mediated synaptic transmission at the spinal cord level and neuropathic pain; (2) determine the level of CK2 activity and its role in increased phosphorylation of the NR1 subunit of NMDA receptors in the spinal cord after nerve injury; and (3) identify the protein interaction between NR1 and CK2 subunits, the CK2 phosphorylation sites on the NMDA receptor, and their roles in regulation of increased NMDA receptor activity in neuropathic pain. The role of CK2 in the development of synaptic plasticity in the spinal cord induced by nerve injury has not been recognized previously. We expect that new findings from this proposal will be critical not only to the significant improvement of our understanding of the molecular mechanisms of neuropathic pain but also to the development of new strategies to treat neuropathic pain. Because directly blocking NMDA receptors produces intolerable side effects, targeting CK2 and its specific NMDA receptor phosphorylation sites could represent novel strategies for reducing the NMDA receptor activity and neuropathic pain.

描述（由申请人提供）：神经性疼痛中的神经可塑性和信号传导项目概述脊髓水平的活动依赖性突触可塑性对于由创伤性神经损伤和手术引起的神经性疼痛的发展至关重要。脊髓背角的N-甲基-D-天冬氨酸（NMDA）受体在神经病理性疼痛的中枢致敏和维持中起重要作用。然而，神经损伤后脊髓中NMDA受体活性增强的机制仍然知之甚少。虽然已知神经损伤后NMDA受体磷酸化增加，但神经病理性疼痛中NMDA受体活性增加的上游机制仍有待确定。在我们的初步研究中，我们发现抑制脊髓中的蛋白激酶CK 2完全逆转了NMDA受体活性的增加，并产生了神经损伤引起的异常性疼痛的持久衰减。在本申请中，我们将使用神经性疼痛的动物模型来测试神经损伤增加脊髓中的CK 2活性的中心假设，其促进NMDA受体的NR 1亚基的磷酸化并增强神经性疼痛中NMDA介导的突触传递。本申请的具体目的是（1）定义CK 2和CK 3之间不平衡的作用，（磷酸化）和钙调神经磷酸酶（2）确定神经损伤后脊髓中CK 2活性水平及其在NMDA受体NR 1亚基磷酸化增加中的作用;以及（3）确定NR 1和CK 2亚基之间的蛋白质相互作用、NMDA受体上的CK 2磷酸化位点以及它们在神经病理性疼痛中NMDA受体活性增加的调节中的作用。CK 2在神经损伤诱导的脊髓突触可塑性发育中的作用以前未被认识。我们希望，新的发现，从这个建议将是至关重要的，不仅显着提高我们的理解神经性疼痛的分子机制，但也发展新的战略来治疗神经性疼痛。由于直接阻断NMDA受体会产生不可耐受的副作用，因此靶向CK 2及其特异性NMDA受体磷酸化位点可能是降低NMDA受体活性和神经性疼痛的新策略。