Neuropathic Pain Memory Is Maintained by Rac1-Regulated Dendritic Spine Remodeling after Spinal Cord Injury
Neuropathic Pain Memory Is Maintained by Rac1-Regulated Dendritic Spine Remodeling after Spinal Cord Injury
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DOI：
10.1523/jneurosci.3142-08.2008
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发表时间：
2008-12-03
影响因子：
5.3
通讯作者：
Hains, Bryan C.
中科院分区：
文献类型：
--
作者：
Tan, Andrew M.;Stamboulian, Severine;Hains, Bryan C.
局部突触强度的增加构成了中枢神经系统学习和记忆的突触基础，也可能通过突触后树突结构的重新形成或细化，有助于脊髓损伤（SCI）后神经性疼痛的维持。为了确定SCI诱导的树突状脊柱重塑是否有助于神经元高兴奋性和神经性疼痛，我们在假手术、挫伤性脊髓损伤和用选择性Rac1激活抑制剂NSC23766治疗的脊髓损伤后1个月，分析了成年大鼠脊柱形态、定位和背角（DH）神经元的功能影响。脊髓损伤后，与对照神经元相比，位于IV-V层的DH神经元表现出脊柱密度增加，脊柱重新分布和成熟，这与计算机模拟中EPSCs的增强和体内单位记录中对无害和有害外周刺激的过度兴奋反应有关。脊髓损伤动物还表现出触觉异常性痛和热痛觉过敏症状。抑制小gtp结合蛋白Rac1可以改善脊髓损伤后脊柱形态的变化，减轻损伤引起的宽动态范围神经元的高兴奋性，并在3天内逐渐增加疼痛阈值。这表明Rac1是一个重要的细胞内信号分子，参与脊髓损伤后与慢性神经性疼痛相关的脊髓树突状脊柱病理。我们的报告为学习和记忆与神经性疼痛之间的新概念桥梁提供了有力的证据。
Localized increases in synaptic strength constitute a synaptic basis for learning and memory in the CNS and may also contribute to the maintenance of neuropathic pain after spinal cord injury (SCI) through the de novo formation or elaboration of postsynaptic dendritic structures. To determine whether SCI-induced dendritic spine remodeling contributes to neuronal hyperexcitability and neuropathic pain, we analyzed spine morphometry, localization, and functional influence in dorsal horn (DH) neurons in adult rats 1 month after sham surgery, contusion SCI, and SCI treated with a selective inhibitor of Rac1 activation, NSC23766. After SCI, DH neurons located in lamina IV-V exhibited increased spine density, redistributed spines, and mature spines compared with control neurons, which was associated with enhancement of EPSCs in computer simulations and hyperexcitable responsiveness to innocuous and noxious peripheral stimuli in unit recordings in vivo. SCI animals also exhibited symptoms of tactile allodynia and thermal hyperalgesia. Inhibition of the small GTP-binding protein Rac1 ameliorated post-SCI changes in spine morphology, attenuated injury-induced hyperexcitability of wide-dynamic range neurons, and progressively increased pain thresholds over a 3 d period. This suggests that Rac1 is an important intracellular signaling molecule involved in a spinal dendritic spine pathology associated with chronic neuropathic pain after SCI. Our report provides robust evidence for a novel conceptual bridge between learning and memory on the one hand, and neuropathic pain on the other.