Andrade Pablo, Hoogland Govert, Del Rosario John S, Steinbusch Harry W, Visser-Vandewalle Veerle, Daemen Marc A
Department of Translational Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands; Department of Neurosurgery, University of Cologne, Cologne, Germany.
J Neurosci Res. 2014 Nov;92(11):1490-8. doi: 10.1002/jnr.23432. Epub 2014 Jun 25.
Inflammation plays a key role in the development of sensitization after peripheral nerve damage. We recently demonstrated that tumor necrosis factor-α receptor (TNFR) levels in the spinal cord correlate with pain sensation in herniated disc patients in a rat chronic constriction injury (CCI) model. By using the sciatic nerve CCI model, we studied the effect of anti-TNF-α treatment on recovery from hypersensitivity and TNFR expression in the dorsal root ganglion (DRG) and dorsal horn (DH). Experimental groups consisted of sham-operated and CCI-operated rats that received two s.c. injections (one immediately after surgery, the other 5 days later), both containing saline, etanercept (3 mg/kg body weight), or infliximab (10 mg/kg body weight). Mechanical allodynia (with von Frey filaments) and thermal hyperalgesia (Hargreaves test) were assessed preoperatively and weekly during the first 4 postoperative weeks. DRG and DH samples were collected 2 and 4 weeks after surgery and analyzed for TNFR1 and TNFR2 protein levels by Western blotting and analyzed for mRNA levels by quantitative real-time polymerase chain reaction. Anti-TNF-α treatment resulted in a significant alleviation of pain. TNFR levels were increased five- to sixfold in CCI rats compared with sham controls. Both treatments significantly diminished these increased levels. Treated animals that showed a ≥50% alleviation of pain exhibited a significantly reduced TNF R1/R2 mRNA ratio compared with treated animals that recovered less well. These results demonstrate that attenuation of TNFR expression is associated with recovery from nerve injury and suggest that this may be one of the working mechanisms of anti-TNF therapies.
炎症在周围神经损伤后致敏的发展中起关键作用。我们最近证明，在大鼠慢性压迫性损伤（CCI）模型中，脊髓中的肿瘤坏死因子-α受体（TNFR）水平与椎间盘突出症患者的疼痛感觉相关。通过使用坐骨神经CCI模型，我们研究了抗TNF-α治疗对背根神经节（DRG）和背角（DH）中痛觉过敏恢复及TNFR表达的影响。实验组包括假手术组和CCI手术组大鼠，它们接受两次皮下注射（一次在手术后立即进行，另一次在5天后），注射物分别为生理盐水、依那西普（3mg/kg体重）或英夫利昔单抗（10mg/kg体重）。术前及术后前4周每周使用von Frey细丝评估机械性异常性疼痛，使用哈格里夫斯试验评估热痛觉过敏。在手术后2周和4周收集DRG和DH样本，通过蛋白质印迹法分析TNFR1和TNFR2蛋白水平，并通过定量实时聚合酶链反应分析mRNA水平。抗TNF-α治疗可显著减轻疼痛。与假手术对照组相比，CCI大鼠的TNFR水平增加了五到六倍。两种治疗均显著降低了这些升高的水平。与恢复较差的治疗动物相比，表示疼痛减轻≥50%的治疗动物的TNF R1/R2 mRNA比值显著降低。这些结果表明TNFR表达的减弱与神经损伤的恢复相关，并提示这可能是抗TNF治疗的作用机制之一。
