Distinct roles of srGAP3-Rac1 in the initiation and maintenance phases of neuropathic pain induced by paclitaxel
Distinct roles of srGAP3-Rac1 in the initiation and maintenance phases of neuropathic pain induced by paclitaxel
复制标题
srGAP3-Rac1 在紫杉醇诱导的神经病理性疼痛的起始和维持阶段中的独特作用
DOI：
10.1113/jp279525
复制
发表时间：
2020-05-01
影响因子：
5.5
通讯作者：
Ouyang, Handong
中科院分区：
文献类型：
--
作者：
Chen, Zihang;Zhang, Subo;Ouyang, Handong
脊髓背角srGAP 3（slit-robo GT3活化蛋白3）在神经病理性疼痛的起始阶段增加，在维持阶段减少。然而，Rac 1的活性，这可以减少srGAP 3，降低在起始阶段和增加在维持phase.增加srGAP 3在起始阶段促进新的不成熟的树突棘挑起神经病理性疼痛。维持期srGAP 3的降低可增强Rac 1的活性，促进树突棘的成熟和神经病理性疼痛的持续; SrGAP 3小干扰RNA仅在起始期给药才能改善神经病理性疼痛。Rac 1抑制剂只有在维持期给药才能改善神经病理性疼痛，联合靶向srGAP 3和Rac 1可以产生最佳的镇痛效果。神经病理性疼痛包括起始期和维持期，每一个阶段都有不同的病理生理过程。了解这两个阶段中的突触可塑性和分子事件与探索神经病理性疼痛的精确治疗策略有关。在本研究中，我们表明，树突棘密度增加，在脊髓背角的紫杉醇诱导的神经性疼痛的起始阶段和脊柱的成熟率增加，在维持阶段。srGAP 3（slit-robo GT3活化蛋白3）的增加促进树突棘在起始阶段发芽。在维持阶段，srGAP 3降低以上调Rac 1活性，这促进肌动蛋白聚合和树突棘成熟，从而促进神经性疼痛的持续。在起始阶段敲低srGAP 3或在维持阶段抑制Rac 1可减轻神经性疼痛。srGAP 3在起始阶段和Rac 1在维持阶段的联合干预显示出对神经性疼痛的更好的镇痛功效。本研究证实了srGAP 3-Rac 1在神经病理性疼痛的两个阶段中树突棘可塑性中的作用，并因此为神经病理性疼痛的不同阶段提供了治疗策略。
Key pointsSpinal cord dorsal horn srGAP3 (slit-robo GTPase activating protein 3) increases in the initiation phase of neuropathic pain and decreases in the maintenance phase. However, Rac1 activity, which can be reduced by srGAP3, decreases in the initiation phase and increases in the maintenance phase.The increased srGAP3 in the initiation phase promotes new immature dendritic spines instigating neuropathic pain. Decreased srGAP3 in the maintenance phase enhances Rac1 activity facilitating maturation of dendritic spines and the persistence of neuropathic pain.SrGAP3 small interfering RNA can ameliorate neuropathic pain only when administrated in the initiation phase. The Rac1 inhibitor can ameliorate neuropathic pain only when administrated in the maintenance phase.Combined targeting of srGAP3 in the initiation phase and Rac1 in the maintenance phase can produce optimal analgesic efficacy.Neuropathic pain includes an initiation phase and maintenance phase, each with different pathophysiological processes. Understanding the synaptic plasticity and molecular events in these two phases is relevant to exploring precise treatment strategies for neuropathic pain. In the present study, we show that dendritic spine density increases in the spinal dorsal horn in the initiation phase of neuropathic pain induced by paclitaxel and that the spine maturity ratio increases in the maintenance phase. Increased srGAP3 (slit-robo GTPase activating protein 3) facilitates dendritic spine sprouting in the initiation phase. In the maintenance phase, srGAP3 decreases to upregulate Rac1 activity, which facilitates actin polymerization and dendritic spine maturation and thus the persistence of neuropathic pain. Knockdown of srGAP3 in the initiation phase or inhibition of Rac1 in the maintenance phase attenuates neuropathic pain. Combined intervention of srGAP3 in the initiation phase, and Rac1 in the maintenance phase shows better analgesic efficacy against neuropathic pain. The present study demonstrates the role of srGAP3-Rac1 in dendritic spine plasticity in the two phases of neuropathic pain and, accordingly, provides treatment strategies for different phases of neuropathic pain.