Yang Sun1, Mingmin Yang1, Hao Tang2, Zhongfu Ma2, Yanbing Liang2, Zhenyu Li3. 1. Department of Pain, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan South Road, Urumqi, Xinjiang, 830054, China. 2. 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. 3. 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.
Abstract
PURPOSE: 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.
PURPOSE: 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.
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