GCN2 regulates paclitaxel-induced neuropathic pain

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. Overall design: To investigate the mechanism of paclitaxel-induced neuropathic pain and GCN2 activation, Male C57BL/6 mice were injected with 4mg/kg paclitaxel injection or vehicle control. One day after injection, mice were sacrificed and DRGs were harvested. Libraries were prepared for multiplex small RNA-seq (MSRseq) and were sequenced using Illumina. Following quality control processing and demultiplexing, libaries were aligned to Mus musculus tRNA genes. Charging and abundance were calculated using custom Python and R scripts.