Distinct roles of srGAP3‐Rac1 in the initiation and maintenance phases of neuropathic pain induced by paclitaxel

Abstract

Key points Spinal cord dorsal horn srGAP3 increases in the initiation phase of neuropathic pain and decreases in the maintenance phase. However, Rac1 activity which can be reduced by srGAP3, decreased in the initiation phase and increased 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 siRNA 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. Abstract 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. Here, we showed that dendritic spine density increased in the spinal dorsal horn in the initiation phase of neuropathic pain induced by paclitaxel and that the spine maturity ratio increased in the maintenance phase. Increased srGAP3 facilitated dendritic spine sprouting in the initiation phase. In the maintenance phase, srGAP3 decreased to upregulate Rac1 activity which facilitated actin polymerization and dendritic spine maturation thereby the persistence of neuropathic pain. Knockdown of srGAP3 in the initiation phase or inhibition of Rac1 in the maintenance phase attenuated neuropathic pain. Combined intervention of srGAP3 in the initiation phase, and Rac1 in the maintenance phase had better analgesic efficacy against neuropathic pain. This research demonstrated the role of srGAP3‐Rac1 in dendritic spine plasticity in the two phases of neuropathic pain, and based on which, provides treatment strategies for different phases of neuropathic pain. This article is protected by copyright. All rights reserved