The role of the N-methyl-D-aspartate receptor NR1 subunit in peripheral nerve injury-induced mechanical allodynia, glial activation and chemokine expression in the mouse
The role of the N-methyl-D-aspartate receptor NR1 subunit in peripheral nerve injury-induced mechanical allodynia, glial activation and chemokine expression in the mouse
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DOI：
10.1016/j.neuroscience.2004.01.024
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发表时间：
2004-01-01
期刊：
影响因子：
3.3
通讯作者：
Deleo, JA
中科院分区：
文献类型：
--
作者：
Bursztajn, S;Rutkowski, MD;Deleo, JA
N-甲基-D-天冬氨酸受体（NMDAR）与持续性疼痛状态的机制密切相关。本研究的目的是确定是否NMDAR NR-1，在调节NMDAR通道复合物的关键亚基是直接有助于周围神经损伤诱导的异常性疼痛的发病和传播，以及是否N-甲基-D-天冬氨酸（NMDA）信号与脊髓趋化因子（趋化细胞因子）的表达和胶质细胞活化相互作用。我们使用基因工程雄性小鼠，这些小鼠的正常NR 1基因被敲除，并以正常水平（NR 1 +/+，野生型）或低水平（NR 1 +/-，敲除）表达修饰的NR 1基因。每只小鼠均经历外周神经损伤，其中腰5脊髓节段（L5）神经被横切。在术后第1、3、5、7、10、14、17和21天使用0.008和0.015 g von Frey细丝评估机械性异常性疼痛。在第21天处死小鼠，并使用RNA酶保护测定分析收获的L5脊髓的趋化因子表达。在另一项研究中，在周围神经损伤后7天，使用免疫组织化学评估了两组的胶质细胞表达。与野生型小鼠相比，NR 1 +/-小鼠表现出降低的机械性异常性疼痛。然而，即使NMDA受体信号传导显著受损，仍有触觉超敏反应的证据。使用RPA分析，我们发现与NR 1 +/+小鼠相比，NR 1 +/-小鼠中的mRNA趋化因子表达降低。野生型和敲除小鼠之间的小胶质细胞或星形胶质细胞表达没有明显差异。这些数据提供了重要的见解级联事件涉及NMDAR功能和脊髓趋化因子和神经胶质细胞的生产在神经病理性疼痛状态之间的动态相互作用。结果支持了趋化因子信号在脊髓中释放谷氨酸的发现。(C)2004年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The N-methyl-D-aspartate receptor (NMDAR) has been strongly implicated in mechanisms of persistent pain states. The purpose of the present study was to determine whether the NMDAR NR-1, a key subunit in regulation of NMDAR channel complex is directly contributing to the onset and propagation of peripheral nerve injury-induced allodynia and whether N-methyl-D-aspartate (NMDA) signaling interacts with spinal chemokine (chemotactic cytokines) expression and glial activation. We used genetically engineered male mice that had their normal NR1 gene knocked out and expressed a modified NR1 gene at either normal level (NR1 +/+, wild type) or at a low level (NR1+/-, knock down). Each mouse underwent a peripheral nerve injury in which the lumbar 5 spinal segment (L5) nerve was transected. Mechanical allodynia was assessed using 0.008 and 0.015 g von Frey filaments on days 1, 3, 5, 7, 10, 14,17 and 21 post-surgery. Mice were killed on day 21 and the harvested L5 spinal cord was analyzed for chemokine expression using RNAse protection assay. In a separate study, glial expression using immunohistochemistry was assessed in both groups 7 days following peripheral nerve injury. The NR1+/- mice displayed decreased mechanical allodynia in comparison to their wild type counterparts. However, even with dramatically impaired NMDA receptor signaling, there was still evidence of tactile hypersensitivity. Using the RPA analysis, we found decreases in mRNA chemokine expression in the NR1+/- mice as compared with NR1 +/+ mice. There were no apparent differences in microglial or astrocytic expression between the wild type and knock down mice. These data provide important insights into the cascade of events involving the dynamic interaction between NMDAR function and spinal chemokine and glial production in neuropathic pain states. The results support the findings that chemokine signaling releases glutamate in the spinal cord. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.