Dexmedetomidine attenuates oxaliplatin-induced neuropathic pain by modulating the TLR4/NF-κB pathway to reduce spinal inflammation and oxidative stress

Purpose

This study aimed to investigate the effects of Dexmedetomidine (Dex) on oxaliplatin-induced neuropathic pain and its underlying mechanisms.

Methods

A murine model of oxaliplatin-induced neuropathic pain was established using intraperitoneal injections of oxaliplatin. Dex was administered at different doses, and behavioral tests were performed to assess pain. Spinal cord tissues were analyzed for inflammatory cytokines, oxidative stress markers, and key signaling molecules related to the toll-like receptor 4 (TLR4)/nuclear factor kappa B using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry. In addition, in vitro experiments were conducted using TNF-α-stimulated C6 glial cells to further assess the anti-inflammatory effects of Dex.

Results

Dex significantly alleviated oxaliplatin-induced neuropathic pain, as shown by an increase in paw withdrawal thresholds and a marked reduction in spontaneous flinching. Molecular analyses further demonstrated that Dex treatment reduced interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) expression, as well as malondialdehyde (MDA) and cyclooxygenase-2 (COX2) in the spinal cord. Concurrently, there was a notable enhancement in the activity of Manganese superoxide dismutase (Mn-SOD) and glutathione (GSH), suggesting improved antioxidative defense. Additionally, Dex reduced spinal inflammation and oxidative stress by downregulating TLR4 expression and inhibiting NF-κB activation. Consistent with these findings, Dex also suppressed NF-κB phosphorylation and cytokine expression in TNF-α-treated C6 cells in vitro.

Conclusions

Dex significantly reduced oxaliplatin-induced neuropathic pain by downregulating TLR4 expression and inhibiting NF-κB activation.