Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture
Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture
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DOI：
10.1016/j.pain.2007.06.016
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发表时间：
2007-12-15
期刊：
影响因子：
7.4
通讯作者：
Mantyh, Patrick W.
中科院分区：
文献类型：
--
作者：
Jimenez-Andrade, Juan M.;Martin, Carl D.;Mantyh, Patrick W.
目前治疗骨折疼痛的疗法非常有限。一些非甾体抗炎药已被证明会抑制骨愈合，阿片类药物会诱导认知功能障碍和呼吸抑制，这在患有骨质疏松性骨折的老年人中尤其成问题。在本报告中，我们开发了一种小鼠闭合性股骨骨折疼痛模型，其中骨骼疼痛行为如骨折肢体的退缩和守卫被10 mg/kg吗啡逆转。使用这个模型，我们发现，神经生长因子（抗神经生长因子）的单克隆抗体的管理减少了超过50%的脊髓损伤引起的疼痛相关的行为。在骨折后第2天，抗NGF治疗减少了脊髓中的c-Fos和强啡肽的上调。然而，抗神经生长因子治疗并没有减少p-ERK和c-Fos的表达，分别在20和90分钟后，骨折。这表明NGF参与骨折疼痛的维持，而不是急性产生。通过骨痂形成、骨折部位桥接或骨的机械强度测量，抗NGF治疗不抑制骨愈合。由于抗-NGF抗体不能明显地穿过血脑屏障，本数据表明抗-NGF治疗的抗-痛觉过敏作用是由阻断CGRP/trkA阳性纤维的激活和/或敏化引起的，所述CGRP/trkA阳性纤维通常构成支配骨的感觉纤维的大部分。这些结果表明，神经生长因子在驱动骨折疼痛中起着重要作用，并且神经生长因子隔离疗法在减轻这种疼痛中可能是有效的。(c)2007年由Elsevier B. V.代表国际疼痛研究协会出版。
Current therapies to treat skeletal fracture pain are extremely limited. Some non-steroidal anti-inflammatory drugs have been shown to inhibit bone healing and opiates induce cognitive dysfunction and respiratory depression which are especially problematic in the elderly suffering from osteoporotic fractures. In the present report, we developed a closed femur fracture pain model in the mouse where skeletal pain behaviors such as flinching and guarding of the fractured limb are reversed by 10 mg/kg morphine. Using this model we showed that the administration of a monoclonal antibody against nerve growth factor (anti-NGF) reduced fracture-induced pain-related behaviors by over 50%. Treatment with anti-NGF reduced c-Fos and dynorphin up-regulation in the spinal cord at day 2 post-fracture. However, anti-NGF treatment did not reduce p-ERK and c-Fos expression at 20 and 90 min, respectively, following fracture. This suggests NGF is involved in maintenance but not the acute generation of fracture pain. Anti-NGF therapy did not inhibit bone healing as measured by callus formation, bridging of the fracture site or mechanical strength of the bone. As the anti-NGF antibody does not appreciably cross the blood-brain barrier, the present data suggest that the anti-hyperalgesic action of anti-NGF therapy results from blockade of activation and/or sensitization of the CGRP/trkA positive fibers that normally constitute the majority of sensory fibers that innervate the bone. These results demonstrate that NGF plays a significant role in driving fracture pain and that NGF sequestering therapies may be efficacious in attenuating this pain. (c) 2007 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.