S-ketamine mitigates paclitaxel-induced pain-related anxiety-like behavior through downregulation of mGluR5 and activation of the BDNF/TrkB signaling pathway
Jing Cao, ZiYuan Wang, GeGe Lv, XingLiao Luo, MengYue Wang, JingYu Hui, Mengmeng Li, Yong Yang, YongHong Yang, Yi Hu, Qiang Lin
Frontiers in Neurology April 23, 2026 DOI: 10.3389/fneur.2026.1801549 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mice with paclitaxel-induced peripheral neuropathy |
| Intervention | S-ketamine |
| Measures | electronic von Frey test, elevated plus maze (EPM), open field test (OFT) |
| Topics | Anxiety Esketamine Ketamine |
| Key findings | S-ketamine alleviated paclitaxel-induced mechanical allodynia and anxiety-like behaviors in mice, effects associated with downregulation of mGluR5, reduced pyramidal neuron firing, enhanced theta-gamma coupling, and upregulation of BDNF/TrkB in the prelimbic cortex. |
Abstract
Background: Paclitaxel (PTX), a broad-spectrum anti-tumor drug, is extensively employed as a first-line chemotherapy for solid tumors, including lung and breast cancers. However, it induces chemotherapy-related pain and anxiety in over 53% of patients. S-ketamine, the S-enantiomer of ketamine, exerts rapid antidepressant effects. In this study, we established a PTX model to examine the effects of S-ketamine on pyramidal neurons in the prelimbic cortex (PrL) and the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway, specifically investigating the role of metabotropic glutamate receptor 5 (mGluR5).
Methods: A PTX-induced peripheral neuropathy and pain-related anxiety mouse model was established by intraperitoneal injection of PTX. Mechanical allodynia was assessed using the electronic von Frey test. Anxiety-like behaviors were evaluated using the elevated plus maze (EPM) and open field test (OFT) after S-ketamine treatment. After behavioral testing, electrophysiological recordings, immunofluorescence staining, and Western blotting analyses were performed, specifically targeting the PrL subregion of the medial prefrontal cortex (mPFC).
Results: Compared with PTX-treated mice, S-ketamine administration resulted in significant improvements across behavioral, molecular, and electrophysiological dimensions: significantly increased mechanical withdrawal thresholds indicated alleviated neuropathic pain; Increased central area distance/total distance ratio in the OFT and prolonged open arm time in the EPM demonstrated reduced anxiety-like behaviors; concomitant decreases in mGluR5 expression and pyramidal neuron firing rates were observed alongside enhanced theta-gamma phase-amplitude coupling, and upregulation of BDNF and TrkB expression in the PrL was detected.
Conclusion: S-ketamine mitigates PTX-induced mechanical allodynia and anxiety-like behaviors, an effect that is closely associated with the downregulation of mGluR5 and the concurrent modulation of the BDNF/TrkB signaling pathway in the PrL of the mPFC.