title: The over-production of TNF-α via Toll-like receptor 4 in spinal dorsal horn contributes to the chronic postsurgical pain in rat.
abstract: OBJECTIVE
  Many patients suffer from chronic postsurgical pain (CPSP) following surgery, and the underlying mechanisms are poorly understood. In the present work, using the skin/muscle incision retraction (SMIR) model, the role of spinal TLR4/TNF-α pathway in the induction of CPSP was evaluated.
  
  
  METHODS
  Mechanical allodynia induced by SMIR was established in adult male Sprague-Dawley rats. The von Frey test was performed to evaluate the role of TLR4/TNF-α pathway on the mechanical allodynia. Western-blot and immunohistochemistry methods were adopted to understand the molecular mechanisms.
  
  
  RESULTS
  SMIR surgery decreased the ipsilateral 50 % paw withdrawal threshold, lasting for at least 20 days. Western-blot analysis and immunohistochemistry revealed that SMIR surgery significantly upregulated the expression of TLR4 (p < 0.01) in glial cells on the ipsilateral side of spinal cord and increased TLR4 occurred on day 5 and was maintained to the end of the experiment (day 20). Similarly, tumor necrosis factor-alpha (TNF-α) was significantly increased on days 5, 10, and 20 on the ipsilateral side of spinal dorsal horn following SMIR surgery. Intraperitoneal injection of an inhibitor of TNF-α synthesis thalidomide at 50 or 100 mg/kg dose (but not 10 mg/kg dose) significantly ameliorated the reduced paw withdrawal threshold induced by SMIR surgery. Importantly, intrathecal delivery of a specific TLR4 antagonist (LPS-RS) at dose of 25 μg significantly attenuated mechanical allodynia and prevented the upregulation of TNF-α induced by SMIR surgery.
  
  
  CONCLUSIONS
  These findings suggest that the upregulation of TNF-α via TLR4 contributes to the development of CPSP in spinal dorsal horn.
authors.affiliation: Department of Pain, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan South Road, Urumqi, Xinjiang, 830054, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pain, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan South Road, Urumqi, Xinjiang, 830054, China.
authors.forename: Mingmin
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Sun Yet-Sen University, 58 Zhongshan Rd. 2, Guangzhou, 510080, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Sun Yet-Sen University, 58 Zhongshan Rd. 2, Guangzhou, 510080, China.
authors.forename: Zhongfu
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Sun Yet-Sen University, 58 Zhongshan Rd. 2, Guangzhou, 510080, China.
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Sun Yet-Sen University, 58 Zhongshan Rd. 2, Guangzhou, 510080, China. leezhenyu99@163.com.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000503:physiopathology*; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D010149:Postoperative Pain / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha
keywords: Chronic postsurgical pain; SMIR; TLR4; TNF-α