Abstract
Oxaliplatin is a platinum-based chemotherapeutic agent treating colorectal and gastric cancer. The most common dose-limiting adverse event of oxaliplatin treatment is chronic neuropathic pain, while the detailed mechanisms remain unknown. The present study investigated the molecular mechanisms of microglial regulation of the oxaliplatin-induced neuropathic pain. Intrathecal (I.t.) treatment with inducible nitric oxide synthetase (iNOS) inhibitor 1400W attenuated the oxaliplatin-induced cold and mechanical hypersensitivity. In addition, pharmacological and chemogenetical inhibition of macrophage/microglia also attenuated the oxaliplatin-induced cold and mechanical hyperalgesia. I.t. treatment with STAT3 inhibitor stattic attenuated the oxaliplatin-indued cold and mechanical hypersensitivity. Oxaliplatin induced the increased phosphorylation of neural STAT3 in the dorsal root ganglion (DRG), which was attenuated by i.t. pretreatment with 1400W. Since STAT3 phosphorylation was regulated by PTEN, effects of oxaliplatin on the PTEN activity in the DRG were examined. PTEN expression was decreased by oxaliplatin treatment. Our present study suggested that oxaliplatin induces neural STAT3 activation through the iNOS induction by macrophage/microglial activation in the DRG, which resulted in the oxaliplatin-induced neuropathic pain.
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