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Updated: Aug 11, 2025
Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies
Published on: October 6, 2022
Phosphate NIMA-Related Kinase 2-Dependent Epigenetic Pathways in Dorsal Root Ganglion Neurons Mediates
Ming-Chun Hsieh1, Cheng-Yuan Lai2, Wen-Long Cho2
1From the Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
Background:
The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established.
Methods:
Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain. The protein expression levels in the dorsal root ganglion (DRG) of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by von Frey tests and hot plate tests.
Results:
PTX increased phosphorylation of the important microtubule dynamics regulator NEK2 in DRG neurons and induced profound neuropathic allodynia. PTX-activated phosphorylated NEK2 (pNEK2) increased jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, to specifically catalyze the demethylation of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3) at the Trpv1 gene, thereby enhancing transient receptor potential vanilloid subtype-1 (TRPV1) expression in DRG neurons. Moreover, the pNEK2-dependent PTX response program is regulated by enhancing p90 ribosomal S6 kinase 2 (RSK2) phosphorylation. Conversely, intrathecal injections of kaempferol (a selective RSK2 activation antagonist), NCL 00017509 (a selective NEK2 inhibitor), NEK2-targeted siRNA, GSK-J4 (a selective JMJD3 inhibitor), or capsazepine (an antagonist of TRPV1 receptor) into PTX-treated rats reversed neuropathic allodynia and restored silencing of the Trpv1 gene, suggesting the hierarchy and interaction among phosphorylated RSK2 (pRSK2), pNEK2, JMJD3, H3K27me3, and TRPV1 in the DRG neurons in PTX-induced neuropathic pain.
Conclusions:
pRSK2/JMJD3/H3K27me3/TRPV1 signaling in the DRG neurons plays as a key regulator for PTX therapeutic approaches.
Insights
Paclitaxel (PTX) causes neuropathic pain by increasing phosphorylated NIMA-related kinase 2 (NEK2) in dorsal root ganglion neurons. This pathway involves pRSK2, JMJD3, and TRPV1, and targeting it may treat PTX-induced pain.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Paclitaxel (PTX) is a crucial chemotherapy drug.
- PTX commonly causes peripheral neuropathy, impacting patient quality of life.
- The role of NIMA-related kinase 2 (NEK2) in PTX-induced neuropathic pain is unclear.
Purpose of the Study:
- To investigate the mechanistic role of NEK2 in paclitaxel-induced neuropathic pain.
- To elucidate the signaling pathway involved in PTX-induced peripheral neuropathy.
Main Methods:
- Neuropathic pain was induced in Sprague-Dawley rats using PTX.
- Protein expression in dorsal root ganglion (DRG) was analyzed.
- Nociceptive behaviors were assessed using von Frey and hot plate tests.
Main Results:
- PTX elevated phosphorylated NEK2 (pNEK2) in DRG neurons, causing neuropathic pain.
- pNEK2 increased jumonji domain-containing 3 (JMJD3), leading to demethylation of H3K27me3 at the Trpv1 gene and enhanced TRPV1 expression.
- Inhibition of RSK2, NEK2, JMJD3, or TRPV1 reversed PTX-induced allodynia and normalized Trpv1 gene expression.
Conclusions:
- The pRSK2/JMJD3/H3K27me3/TRPV1 signaling pathway in DRG neurons is a key regulator of PTX-induced neuropathic pain.
- This pathway represents a potential therapeutic target for managing PTX side effects.
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