title: p38 and interleukin-1 beta pathway via toll-like receptor 4 contributed to the skin and muscle incision and retraction-induced allodynia.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Critical Care, The First Affiliated Hospital, Second Military Medical University, Shanghai, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology and Critical Care, The First Affiliated Hospital, Second Military Medical University, Shanghai, PR China.
authors.forename: You-shui
authors.initials: YS
authors.lastname: Jiang
authors.affiliation: Department of Pain, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology and Critical Care, The First Affiliated Hospital, Second Military Medical University, Shanghai, PR China. Electronic address: proychxiong@163.com.
authors.forename: Yuan-chang
authors.initials: YC
authors.lastname: Xiong
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D062109:Dermatologic Surgical Procedures; D005727:Ganglia, Spinal / Q000378:metabolism*; D006930:Hyperalgesia / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000601:surgery; D010147:Pain Measurement; D010149:Postoperative Pain / Q000175:diagnosis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D053583:Interleukin-1beta; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Dorsal root ganglion; Postsurgical pain; TLR4; p38 and IL-1β signal pathway