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）：神经性疼痛项目中的神经元可塑性和信号传导摘要在脊髓水平上的活动依赖性突触可塑性对于因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。脊髓角中的N-甲基-D-天冬氨酸（NMDA）受体至关重要地参与了中央敏化和维持神经性疼痛。然而，神经损伤后脊髓中增强的NMDA受体活性的机制仍然鲜为人知。尽管已知神经损伤后NMDA受体的磷酸化增加，但神经性疼痛中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，我们发现脊髓中蛋白激酶CK2的抑制完全逆转了NMDA受体活性的增加，并导致神经损伤引起的异常性疾病的持久衰减。在此应用中，我们将使用神经性疼痛的动物模型来检验中心假设，即神经损伤会增加脊髓中的CK2活性，从而促进NMDA受体NR1亚基的磷酸化，并增强NMDA介导的神经病疼痛中的NMDA介导的突触传播。该应用的具体目的是（1）定义CK2（磷酸化）和钙调神经磷酸酶（去磷酸化）活性之间在脊髓水平和神经性疼痛下的NMDA介导的突触传播中的不平衡作用；（2）确定CK2活性的水平及其在神经损伤后NMDA受体NR1亚基增加的磷酸化中的作用；（3）确定NR1和CK2亚基之间的蛋白质相互作用，NMDA受体上的CK2磷酸化位点以及它们在调节神经性疼痛中NMDA受体活性增加的作用中。先前尚未识别出CK2在神经损伤引起的脊髓中突触可塑性发展中的作用。我们预计，该提案中的新发现将不仅对我们对神经性疼痛分子机制的理解的显着改善至关重要，而且对于治疗神经性疼痛的新策略的发展。由于直接阻断NMDA受体会产生无法忍受的副作用，因此靶向CK2及其特定的NMDA受体磷酸化位点可以代表减少NMDA受体活性和神经性疼痛的新型策略。