S-ketamine mitigates paclitaxel-induced pain-related anxiety-like behavior through downregulation of mGluR5 and activation of the BDNF/TrkB signaling pathway

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.