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GCN2 regulates paclitaxel-induced neuropathic pain

ABSTRACT: Neuropathic pain is a significant clinical challenge affecting patients treated with the chemotherapeutic paclitaxel. Current therapeutic options for paclitaxel-induced neuropathy are limited due to an incomplete understanding of its molecular mechanisms. Here, we demonstrate a critical role for the Integrated Stress Response (ISR) in paclitaxel-induced neuropathic pain. Paclitaxel robustly activates the ISR specifically in dorsal root ganglion (DRG) neurons via the upstream kinase GCN2. Activation of GCN2 alone is sufficient to sensitize DRG neurons to depolarization and produce pain-like behaviors in vivo. Critically, paclitaxel-induced DRG neuron sensitization and behavioral mechanical and cold hypersensitivity require GCN2 signaling. Finally, paclitaxel treatment reduces global tRNA charging and abundance, providing a mechanistic basis for GCN2 activation. These findings position GCN2 and the ISR as promising therapeutic targets for the management of paclitaxel-induced neuropathic pain.

ORGANISM(S): Mus musculus

PROVIDER: GSE291827 | GEO | 2025/11/12

REPOSITORIES: GEO

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Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).

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GCN2 regulates paclitaxel-induced neuropathic pain

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