Involvement of Peripheral and Spinal Tumor Necrosis Factor α in Spinal Cord Hyperexcitability During Knee Joint Inflammation in Rats
Involvement of Peripheral and Spinal Tumor Necrosis Factor α in Spinal Cord Hyperexcitability During Knee Joint Inflammation in Rats
复制标题
DOI：
10.1002/art.38271
复制
发表时间：
2014-03-01
影响因子：
13.3
通讯作者：
Ebersberger, Andrea
中科院分区：
文献类型：
--
作者：
Koenig, Christian;Zharsky, Maxim;Ebersberger, Andrea
Objective.肿瘤坏死因子α（TNF α）不仅在外周组织中产生，而且在脊髓中产生。本研究的目的是解决潜在的外周和脊髓TNF α诱导和维持脊髓兴奋过度，这是一个标志性的疼痛状态在类风湿性关节炎和骨关节炎的关节。在正常条件下和实验性膝关节炎症的存在下，在体内记录脊髓神经元对伤害性膝关节输入的反应。将TNF α、依那西普或TNF受体抗体应用于膝关节或脊髓表面。膝关节腔内注射TNF α可增加脊髓神经元对机械关节刺激的反应，膝关节内注射依那西普可减少炎症诱发的脊髓活动。这些脊髓效应密切反映了外周致敏的诱导和减少。脊髓应用TNF α也增强了对关节刺激的反应，脊髓应用依那西普或抗TNF受体I型显著减弱了炎症诱发的脊髓过度兴奋的产生，其特征在于炎症关节以外的广泛疼痛敏感化。在急性高岭土/角叉菜胶模型中，脊柱应用依那西普并没有降低已建立的过度兴奋性。在抗原诱导的关节炎中，依那西普在第1天降低脊髓反应，但在第3天没有。虽然外周TNF α增加脊髓对关节刺激的反应，但脊髓TNF α支持脊髓过度兴奋的完整模式的产生。然而，已建立的脊髓过度兴奋可能通过不依赖于脊髓TNF α的下游机制来维持。
Objective. Tumor necrosis factor alpha (TNF alpha) is produced not only in peripheral tissues, but also in the spinal cord. The purpose of this study was to address the potential of peripheral and spinal TNF alpha to induce and maintain spinal hyperexcitability, which is a hallmark of pain states in the joints during rheumatoid arthritis and osteoarthritis.Methods. In vivo recordings of the responses of spinal cord neurons to nociceptive knee input under normal conditions and in the presence of experimental knee joint inflammation were obtained in anesthetized rats. TNF alpha, etanercept, or antibodies to TNF receptors were applied to either the knee joint or the spinal cord surface.Results. Injection of TNF alpha into the knee joint cavity increased the responses of spinal cord neurons to mechanical joint stimulation, and injection of etanercept into the knee joint reduced the inflammation-evoked spinal activity. These spinal effects closely mirrored the induction and reduction of peripheral sensitization. Responses to joint stimulation were also enhanced by spinal application of TNF alpha, and spinal application of either etanercept or anti-TNF receptor type I significantly attenuated the generation of inflammation-evoked spinal hyperexcitability, which is characterized by widespread pain sensitization beyond the inflamed joint. Spinally applied etanercept did not reduce established hyperexcitability in the acute kaolin/carrageenan model. In antigen-induced arthritis, etanercept decreased spinal responses on day 1, but not on day 3.Conclusion. While peripheral TNF alpha increases spinal responses to joint stimulation, spinal TNF alpha supports the generation of the full pattern of spinal hyperexcitability. However, established spinal hyperexcitability may be maintained by downstream mechanisms that are independent of spinal TNF alpha.