Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain
Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain
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DOI：
10.1016/j.pain.2010.03.002
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发表时间：
2010-05-01
期刊：
影响因子：
7.4
通讯作者：
Inglis, Julia J.
中科院分区：
文献类型：
--
作者：
McNamee, Kay E.;Burleigh, Annika;Inglis, Julia J.
骨关节炎疼痛的起源知之甚少，但通常认为是由关节神经支配结构（如滑膜、关节囊和骨）内的炎症引起的。我们研究了神经生长因子（NGF）在小鼠OA疼痛发展中的作用，以及可溶性NGF受体TrkAD 5的镇痛功效。通过内侧半月板的不稳定在小鼠中诱导OA，并通过测量后肢重量分布来评估疼痛。从关节中提取RNA，并定量NGF和TNF表达。还评估了肿瘤坏死因子（TNF）和中性粒细胞阻断对NGF表达和疼痛的影响。在手术后（第3天）和OA（16周）疼痛期间，关节中均诱导了NGF，但在疾病的非疼痛阶段（手术后8周）则没有。TrkAd5在两个阶段都能有效抑制疼痛。在术后疼痛阶段的NGF诱导是TNF依赖性的，因为抗TNF减少了关节中的NGF表达并消除了疼痛。然而，TNF在晚期OA关节中不受调节，并且疼痛不受抗TNF治疗的影响。岩藻聚糖通过抑制关节细胞浸润，能够抑制术后疼痛，但不能抑制晚期OA疼痛。这些结果表明，NGF是OA疼痛的重要介质，TrkAd5代表了这种情况下的有效的新型镇痛剂。他们还表明，与术后疼痛不同，OA疼痛的诱导可能不一定是由经典的炎症过程驱动的。(C)2010年国际疼痛研究协会。Elsevier B.V.出版，保留所有权利。
The origin of pain in osteoarthritis is poorly understood, but it is generally thought to arise from inflammation within the innervated structures of the joint, such as the synovium, capsule and bone. We investigated the role of nerve growth factor (NGF) in pain development in murine OA, and the analgesic efficacy of the soluble NGF receptor, TrkAD5. OA was induced in mice by destabilisation of the medial meniscus and pain was assessed by measuring hind-limb weight distribution. RNA was extracted from joints, and NGF and TNF expressions were quantified. The effect of tumour necrosis factor (TNF) and neutrophil blockade on NGF expression and pain were also assessed. NGF was induced in the joints during both post-operative (day 3) and OA (16 weeks) pain, but not in the non-painful stage of disease (8 weeks post-surgery). TrkAd5 was highly effective at suppressing pain in both phases. Induction of NGF in the post-operative phase of pain was TNF-dependent as anti-TNF reduced NGF expression in the joint and abrogated pain. However, TNF was not regulated in the late OA joints, and pain was not affected by anti-TNF therapy. Fucoidan, by suppressing cellular infiltration into the joint, was able to suppress post-operative, but not late OA pain. These results indicate that NGF is an important mediator of OA pain and that TrkAd5 represents a potent novel analgesic in this condition. They also suggest that, unlike postoperative pain, induction of pain in OA may not necessarily be driven by classical inflammatory processes. (C) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.