EXPRESS: Preoperative reactive oxygen species exacerbate postoperative hyperalgesia by aggravating neuroinflammation through galectin-3

Patients with preoperative pathological conditions such as anxiety, depression, and sleep disorders experience more severe postoperative pain, suggesting that preoperative pathological changes in patients may affect postoperative pain. However, the potential pathophysiological changes associated with postoperative pain remain unknown. Here, this study initially employed clinical research to investigate potential pathophysiological changes related to postoperative pain. Subsequently, animal behavioral experiments and mechanistic explorations were conducted accordingly. Pregnant women undergoing cesarean sections who could provide preoperative cerebrospinal fluid were selected as subjects. Preoperative cerebrospinal fluid proteomics, postoperative pain intensity, and neutrophil-to-lymphocyte ratio (NLR) were analyzed. Rats were used to model the corresponding preoperative pathological state. Mechanical pain thresholds were measured after plantar incision and spinal cords were harvested for analysis. Clinical studies showed that one-quarter of the proteins positively correlated with postoperative pain were related to reactive oxygen species (ROS). Furthermore, the NLR-Ratio, reflecting postoperative inflammation level, increased with the severity of postoperative pain. Establishing a preoperative ROS-increased model with oxidant t-BOOH enhanced postoperative acute mechanical hyperalgesia and spinal neuroinflammation in rats. Conversely, preoperative administration of antioxidant VE, reducing ROS, alleviated postoperative hyperalgesia and spinal neuroinflammation. galectin-3 inhibitors mitigated postoperative hyperalgesia and neuroinflammation in the preoperative ROS-increased model. Additionally, The effects of galectin-3 on pain sensitization and pro-inflammation in vitro were mediated by the TLR4 receptor. Thus, this study demonstrated that preoperative ROS exacerbated postoperative hyperalgesia via galectin-3-mediated neuroinflammation, suggesting that galectin-3 may be a potential therapeutic target for alleviating postoperative pain in clinical patients.