GCN2 regulates paclitaxel-induced neuropathic pain.

background and purposeNeuropathic pain is debilitating and pervasive. Chemotherapeutic agents commonly induce chronic neuropathic pain. Paclitaxel is a prototypical example, causing painful peripheral neuropathy in a majority of patients. Paclitaxel triggers persistent changes in the excitability of sensory neurons resulting in hypersensitivity to sensory cues. The molecular mechanisms underlying paclitaxel-induced maladaptive plasticity are unclear. Here, we demonstrate a role for the Integrated Stress Response (ISR)-a key translational control mechanism-and its activating kinase, general control non-derepressible 2 kinase (GCN2), in paclitaxel-induced neuropathic pain (PINP). EXPERIMENTAL APPROACH: We used genetic and pharmacological techniques, including sensory neuron-specific GCN2 conditional knockout mice and the selective GCN2 inhibitor GCN2-IN-7. Behavioural assays assessed mechanical and cold hypersensitivity, while primary DRG neuron cultures were used to evaluate neuronal excitability via calcium imaging and protein translation by puromycin incorporation (surface sensing of translation, SUnSET). tRNA charging and abundance were measured using MSR-seq. KEY

resultsPaclitaxel robustly activated the ISR via GCN2 in mouse DRG sensory neurons, shown by increased eIF2α phosphorylation, elevated ATF4 levels and reduced global translation rates. Genetic deletion or pharmacological inhibition of GCN2 blocked paclitaxel-induced sensory neuron sensitisation and significantly attenuated mechanical and cold hypersensitivity in vivo. Mechanistically, paclitaxel reduced global tRNA charging and abundance in DRGs, providing a molecular basis for GCN2 activation. CONCLUSIONS AND IMPLICATIONS: These findings demonstrate that GCN2-dependent ISR activation is critical for PINP. Targeting GCN2 may represent a promising therapeutic strategy for preventing or alleviating chemotherapy-induced peripheral neuropathy, potentially improving patient quality of life and chemotherapy tolerance.