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 (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. 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. 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.

Just in time! Identification of a novel mechanism for treating PIPN

“…In addition, further investigations using ex vivo slice preparations to determine the electrophysiological changes induced by sequential srGAP3-RAC1 inhibition will be essential. The findings reported by Chen et al (2020) provide a novel basis for future work exploring the temporal mechanisms underlying paclitaxel induced peripheral neuropathy.…”

“…These findings portray functionally coupled, but temporally distinct, roles for srGAP3 and RAC1 in the modulation of PIPN. This interplay was clearly demonstrated in the final experiment by Chen et al (2020) in which srGAP3 was knocked down using siRNA during the initiation phase and RAC1 activity was suppressed with NSC23766 during the maintenance phase. The results reveal a robust reduction in mechanical allodynia, approaching baseline levels, on day 30 following paclitaxel administration.…”

“…Going forward, targeting these proteins for the development of novel therapies addressing PIPN could prove promising and potentially translatable. Although current pharmacological tools exist for targeting RAC1, Chen et al (2020) used genetic approaches for interfering with srGAP3. These techniques are not as easily translated into humans and future work aimed at developing a small molecule to target srGAP3 could be transformative for the treatment of paclitaxel induced peripheral neuropathy.…”

“…In this issue of The Journal of Physiology, an elegant series of experiments performed by Chen et al (2020) found that srGAP3 levels in the dorsal horn of the spinal cord increased during the initiation phase of PIPN, which correlated with dendritic spine density and maturity. This result is consistent with previous studies showing that PIPN results in enhanced numbers of spines, as well as increased spine maturity, which together act to facilitate synaptic transmission.…”

“…This suggests that srGAP3 is a mediator of neuropathic pain through the regulation of dendritic spine formation and maturation in the early stages of PIPN. To investigate the maintenance phase of PIPN, which is most clinically relevant, Chen et al (2020) turned their attention to a different target: RAC1. SrGAP3 inhibits the activity of RAC1, which has been shown to be involved in neuropathic pain following nerve injury.…”