Loss of NR1 Subunit of NMDARs in Primary Sensory Neurons Leads to Hyperexcitability and Pain Hypersensitivity: Involvement of Ca2+-Activated Small Conductance Potassium Channels
Loss of NR1 Subunit of NMDARs in Primary Sensory Neurons Leads to Hyperexcitability and Pain Hypersensitivity: Involvement of Ca2+-Activated Small Conductance Potassium Channels
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DOI：
10.1523/jneurosci.0454-13.2013
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发表时间：
2013-08-14
影响因子：
5.3
通讯作者：
Ji, Ru-Rong
中科院分区：
文献类型：
--
作者：
Pagadala, Promila;Park, Chul-Kyu;Ji, Ru-Rong
已经确定NMDAR的激活在脊髓突触可塑性中起重要作用（即，中枢致敏）和组织损伤后的疼痛超敏反应。尽管NMDAR在DRG初级感觉神经元中显著表达，但外周NMDAR在调节内在神经元兴奋性和疼痛敏感性中的独特作用尚未得到很好的理解，部分原因是缺乏选择性分子工具。为了解决这个问题，我们使用Advillin-Cre驱动程序选择性地删除DRG神经元中NMDARs的NR 1亚基。在NR 1条件性基因敲除（NR 1-cKO）小鼠中，DRG神经元中不存在NR 1表达，但在脊髓神经元中保持正常; NMDA诱导的电流也在这些小鼠的DRG神经元中消除。令人惊讶的是，NR 1-cKO小鼠与野生型同窝仔相比，表现出机械和热超敏反应。NR 1缺陷DRG神经元表现出兴奋性增加，如动作电位频率增加所示，以及脊髓切片中兴奋性突触传递增强，如微型EPSC频率增加所示。这种超兴奋性可以通过NMDAR拮抗剂APV和Ca 2+激活的慢传导K+（SK）通道阻断剂apamin再现。此外，NR 1阳性DRG神经元共表达SK 1/SK 2，并且在这些神经元中，NMDA升高apamin敏感的后超极化电流，而APV抑制apamin敏感的后超极化电流。我们的研究结果揭示了迄今未被怀疑的作用，NMDARs在控制初级感觉神经元的内在兴奋性可能通过Ca 2+激活SK通道。我们的研究结果也引起了人们对NMDAR拮抗剂作为疼痛和其他神经系统疾病治疗的潜在相反作用的关注。
It is well established that activation of NMDARs plays an essential role in spinal cord synaptic plasticity (i.e., central sensitization) and pain hypersensitivity after tissue injury. Despite prominent expression of NMDARs in DRG primary sensory neurons, the unique role of peripheral NMDARs in regulating intrinsic neuronal excitability and pain sensitivity is not well understood, in part due to the lack of selective molecular tools. To address this problem, we used Advillin-Cre driver to delete the NR1 subunit of NMDARs selectively in DRG neurons. In NR1 conditional knock-out (NR1-cKO) mice, NR1 expression is absent in DRG neurons but remains normal in spinal cord neurons; NMDA-induced currents are also eliminated in DRG neurons of these mice. Surprisingly, NR1-cKO mice displayed mechanical and thermal hypersensitivity compared with wild-type littermates. NR1-deficient DRG neurons show increased excitability, as indicated by increased frequency of action potentials, and enhanced excitatory synaptic transmission in spinal cord slices, as indicated by increased frequency of miniature EPSCs. This hyperexcitability can be reproduced by the NMDAR antagonist APV and by Ca2+-activated slow conductance K+ (SK) channel blocker apamin. Furthermore, NR1-positive DRG neurons coexpress SK1/SK2 and apamin-sensitive afterhyperpolarization currents are elevated by NMDA and suppressed by APV in these neurons. Our findings reveal the hitherto unsuspected role of NMDARs in controlling the intrinsic excitability of primary sensory neurons possibly via Ca2+-activated SK channels. Our results also call attention to potential opposing effects of NMDAR antagonists as a treatment for pain and other neurological disorders.