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Updated: Sep 11, 2025
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Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies
Published on: October 6, 2022
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GCN2 regulates paclitaxel-induced neuropathic pain
Alexander R Mikesell1, Angela R Meyer1, Guadalupe García1
1Department of Anesthesiology, University of Wisconsin - Madison, Madison, Wisconsin, USA.
British Journal of Pharmacology
|August 13, 2025
Summary
The Integrated Stress Response (ISR), activated by general control non-derepressible 2 kinase (GCN2), plays a key role in paclitaxel-induced neuropathic pain. Inhibiting GCN2 may treat chemotherapy-induced peripheral neuropathy.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy, like paclitaxel, frequently causes debilitating neuropathic pain.
- Paclitaxel induces persistent changes in sensory neuron excitability, leading to hypersensitivity.
- The molecular mechanisms driving paclitaxel-induced neuropathic pain (PINP) remain unclear.
Purpose of the Study:
- To investigate the role of the Integrated Stress Response (ISR) and its kinase, general control non-derepressible 2 kinase (GCN2), in PINP.
- To elucidate the molecular mechanisms underlying paclitaxel-induced sensory neuron sensitization.
Main Methods:
- Utilized sensory neuron-specific GCN2 conditional knockout mice and the GCN2 inhibitor GCN2-IN-7.
- Assessed mechanical and cold hypersensitivity through behavioral assays.
- Evaluated neuronal excitability and protein translation in DRG neuron cultures; measured tRNA charging and abundance.
Main Results:
- Paclitaxel activated the ISR via GCN2 in mouse DRG sensory neurons, evidenced by increased eIF2α phosphorylation and ATF4 levels.
- Genetic deletion or pharmacological inhibition of GCN2 prevented sensory neuron sensitization and reduced hypersensitivity in vivo.
- Paclitaxel reduced global tRNA charging and abundance, providing a mechanism for GCN2 activation.
Conclusions:
- GCN2-dependent ISR activation is essential for PINP.
- Targeting GCN2 presents a potential therapeutic strategy for chemotherapy-induced peripheral neuropathy.
- This approach could improve patient quality of life and chemotherapy tolerance.
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