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Chronic postsurgical pain (CPSP) often occurs after surgery and has a strong impact on patients' daily lives. However, the underlying mechanism of CPSP remains unknown. Here, we used a skin/muscle incision and retraction (SMIR) model to investigate the role of CX3CL1 in SMIR-induced pain and its underlying mechanism. We found that up-regulation of CX3CL1 in the spinal dorsal horn contributed to SMIR-induced mechanical allodynia. The use of a CX3CL1-neutralizing antibody to block CX3CL1 attenuated mechanical allodynia induced by SMIR surgery. We also found that phospho-STAT3 co-localizes with CX3CL1 in spinal neurons after SMIR surgery and that this contributes to SMIR-induced mechanical allodynia. Intrathecal administration of the STAT3 inhibitor S3I-201 suppressed up-regulation of CX3CL1 at both the protein and mRNA levels after SMIR surgery. Chromatin immunoprecipitation further demonstrated that SMIR promotes the recruitment of STAT3 to the cx3cl1 gene promoter (- 1032/- 1022). These findings suggest that activation of STAT3 after SMIR mediates the up-regulation of CX3CL1, leading to mechanical allodynia, and that this upregulation may partly be due to the enhanced recruitment of STAT3 to the cx3cl1 gene promoter after SMIR.

Background Persistent postsurgical pain, as an important clinical problem, seriously affects the quality of life in patients. However, the mechanism underlying persistent postsurgical pain remains largely unclear. The present study aims to elucidate the involvement of toll-like receptor 4 (TLR4) and its interaction with p38 and interleukin [IL]-1β signaling in dorsal root ganglion (DRG) in the persistent postsurgical pain. Methods Skin and muscle incision and retraction (SMIR) surgery-induced paw withdrawal threshold (PWT) change was determined by applying mechanical stimuli to the plantar surface of the hind paw using von Frey hairs. The PE-10 catheter intrathecal placement was used to deliver LPS-RS, interleukin-1 receptor antagonist, or SB203580. Western blot analysis was performed to measure the expression of the TLR4, mitogen-activated protein kinases family, and IL-1β in ipsilateral L3 and L4 DRG. Immunofluorescence staining was performed to further investigate the cell type of TLR4 expression. All data were expressed as means ± standard error of the mean and analyzed using SPSS 13.0. Results The results showed that the SMIR surgery, a rat model of persistent postoperative pain, decreased the ipsilateral 50% PWT, and the decrease lasted for at least 20 d. The expression of TLR4 and phosphorylation of p38 were upregulated in ipsilateral L3 and L4 DRG neurons after SMIR surgery. Pretreatment with LPS-RS, an established TLR4 antagonist, prevented p38 activation and attenuated mechanical allodynia induced by SMIR surgery. In addition, the expression of IL-1β was significantly increased after SMIR surgery. Blocking IL-1β by interleukin-1 receptor antagonist significantly improved the decreased PWT evoked by SMIR. Moreover, inhibition of TLR4 or p38 pathway prevented the IL-1β upregulation and mechanical allodynia induced by SMIR. Conclusions These findings suggest that the activation of p38 and IL-1β signaling pathway via TLR4 mediate mechanical allodynia after SMIR surgery.

Reactive oxygen species (ROS) play a critical role in the pathogenesis of neuropathic pain, but few studies have examined the role of oxidative stress in the mirror-image neuropathic pain (MINP). The present study was to investigate the role of ROS in MINP caused by chronic compression of the dorsal root ganglion (DRG) (CCD) in a rat model. SD rats were randomly divided into sham group and CCD group. CCD was conducted to induce MINP. CCD rats were intraperitoneally injected with α-Phenyl-N-tert-butyl-nitrone (PBN) at 7 days after surgery. Paw withdrawal mechanical threshold (PWMT) was measured at −1, 1, 3, 5 and 7 days after surgery in sham group and CCD group, and at 8 time points after PBN injection. Rats were sacrificed at 3 and 7 days after surgery in sham group and CCD group and at 0.5 and 2 h after PBN injection, and the superoxide dismutase (SOD) and catalase activities, as well as hydrogen peroxide (H2O2) and malonaldehyde (MDA) contents were determined in the contralateral DRGs. Results showed bilateral PWMT reduced significantly in sham group and CCD group, but it returned to nearly normal level in sham group. MDA content, H2O2 content and SOD activity increased significantly, while catalase activity remained unchanged in CCD rats. PBN at 100 mg/kg significantly attenuated bilateral mechanical hyperalgesia accompanied by the improvement of oxidative stress in the contralateral DRGs. Our results demonstrate that ROS produced in the contralateral DRG are involved in the pathogenesis of CCD induced MINP, and ROS scavenger may be a promising drug for the therapy of MINP.