Targeting A-type K+ channels in primary sensory neurons for bone cancer pain in a rat model
Targeting A-type K+ channels in primary sensory neurons for bone cancer pain in a rat model
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靶向初级感觉神经元中的 A 型 K 通道治疗大鼠模型中的骨癌疼痛
DOI：
10.1016/j.pain.2011.11.020
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发表时间：
2012-03-01
期刊：
影响因子：
7.4
通讯作者：
Zhang, Yu-Qiu
中科院分区：
文献类型：
--
作者：
Duan, Kai-Zheng;Xu, Qian;Zhang, Yu-Qiu
癌痛是慢性疼痛中最严重的一种，最常见的癌痛是骨癌痛。骨癌疼痛的治疗仍然是一个临床挑战。在这里，我们首次报道了背根神经节（DRG）的a型K+通道参与大鼠骨癌疼痛的神经病变，并且是双氯芬酸的新靶点，双氯芬酸是一种非甾体抗炎药，可用于治疗这种独特的疼痛。骨癌疼痛时DRG神经元a型K+通道发生动态功能变化。主要表达于isolectin b4阳性小DRG神经元的a型K+电流在肿瘤后第14天（PTD 14）增加，在肿瘤后第21天（PTD 21）减弱，但仍保持较高水平。相应地，a型K+通道Kv1.4、Kv3.4和Kv4.3的表达水平在骨癌疼痛期间呈现时间依赖性变化。双氯芬酸增强DRG神经元中的a型K+电流，并以剂量依赖的方式减轻骨癌疼痛。双氯芬酸的镇痛作用可通过a型K+通道阻滞剂4-AP或pandinotoxin-K α逆转或阻断，也可通过靶向大鼠Kv1.4或Kv4.3的siRNA逆转或阻断。反复给予双氯芬酸可减少肿瘤附近软组织肿胀，减轻骨破坏。提示外周a型K+通道参与了大鼠骨癌性疼痛的神经病变。靶向初级感觉神经元中的a型K+通道可能为骨癌疼痛提供一种新的基于机制的治疗策略。(C) 2011年国际疼痛研究协会。Elsevier B.V.版权所有。
Cancer pain is one of the most severe types of chronic pain, and the most common cancer pain is bone cancer pain. The treatment of bone cancer pain remains a clinical challenge. Here, we report firstly that A-type K+ channels in dorsal root ganglion (DRG) are involved in the neuropathy of rat bone cancer pain and are a new target for diclofenac, a nonsteroidal anti-inflammatory drug that can be used for therapy for this distinct pain. There are dynamically functional changes of the A-type K+ channels in DRG neurons during bone cancer pain. The A-type K+ currents that mainly express in isolectin B4-positive small DRG neurons are increased on post-tumor day 14 (PTD 14), then faded but still remained at a higher level on PTD 21. Correspondingly, the expression levels of A-type K+ channel Kv1.4, Kv3.4, and Kv4.3 showed time-dependent changes during bone cancer pain. Diclofenac enhances A-type K+ currents in the DRG neurons and attenuates bone cancer pain in a dose-dependent manner. The analgesic effect of diclofenac can be reversed or prevented by A-type K+ channel blocker 4-AP or pandinotoxin-K alpha, also by siRNA targeted against rat Kv1.4 or Kv4.3. Repeated diclofenac administration decreased soft tissue swelling adjacent to the tumor and attenuated bone destruction. These results indicate that peripheral A-type K+ channels were involved in the neuropathy of rat bone cancer pain. Targeting A-type K+ channels in primary sensory neurons may provide a novel mechanism-based therapeutic strategy for bone cancer pain. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.