Antinociceptive effects of tumor necrosis factor α neutralization in a rat model of antigen-induced arthritis
Antinociceptive effects of tumor necrosis factor α neutralization in a rat model of antigen-induced arthritis
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DOI：
10.1002/art.23608
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发表时间：
2008-08-01
影响因子：
--
通讯作者：
Schaible, Hans-Georg
中科院分区：
文献类型：
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作者：
Boettger, Michael K.;Hensellek, Susanne;Schaible, Hans-Georg
目标。抗炎治疗过程中疼痛的减轻可能是由于炎症过程的减弱和/或直接作用于伤害性神经元的内源性炎症介质的中和。本研究的目的是探讨中和肿瘤坏死因子α的镇痛作用是由于炎症的减轻，还是直接的神经元效应在治疗过程中对疼痛的缓解有显著的贡献。对膝关节慢性抗原诱导性关节炎(AIA)大鼠的运动和疼痛相关行为和组织学进行了评估，并用全身盐水、依那西普或英夫利昔单抗治疗。用免疫组织化学和聚合酶链式反应检测背根神经节内肿瘤坏死因子受体(TNFR)的表达。分别将依那西普和英夫利昔单抗注入正常或炎症膝关节(AIA或高岭土/卡拉胶致炎)，记录膝关节内侧神经传入AS纤维和C纤维的动作电位。在患有AIA的大鼠中，依那西普和英夫利昔单抗均显著减少炎症诱导的运动和疼痛相关行为，而关节肿胀仅略有减轻，组织形态仍显示明显的炎症。大量背根神经节神经元呈TNFRI和TNFRII样免疫反应。关节腔内注射依那西普后30min开始，关节传入对炎症关节的机械刺激反应减弱，但对非炎症关节的机械刺激反应无影响。总体而言，这些数据显示了TNFa中和显著的抗伤害性作用，因此表明减少TNFa对疼痛纤维本身的影响显著有助于缓解疼痛。
Objective. The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor a (TNF alpha) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy.Methods. Locomotor and pain-related behavior and histology were assessed in rats with chronic antigen-induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent AS fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/carrageenan-induced inflammation).Results. In rats with AIA, both etanercept and infliximab significantly decreased inflammation-induced locomotor and pain-related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI- and TNFRII-like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint.Conclusion. Overall, these data show the pronounced antinociceptive effects of TNFa neutralization, thus suggesting that reduction of the effects of TNFa on pain fibers themselves significantly contributes to pain relief.