The over-production of TNF-α via Toll-like receptor 4 in spinal dorsal horn contributes to the chronic postsurgical pain in rat.

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.