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Targeting A-type K+ channels in primary sensory neurons for bone cancer pain in a rat model

Duan, Kai-Zhenga,1; Xu, Qiana,1; Zhang, Xiao-Menga; Zhao, Zhi-Qia; Mei, Yan-Aib; Zhang, Yu-Qiua,*

doi: 10.1016/j.pain.2011.11.020
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Summary Bone cancer induced dynamic changes of A-type K+ channels in dorsal root ganglion neurons. Diclofenac antagonized bone cancer pain by upregulating peripheral A-type K+ channels.

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-Kα, 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.

aInstitute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China

bSchool of Life Sciences, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China

*Corresponding author. Address: Institute of Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China. Tel.: +86 21 55522877; fax: +86 21 55522876.

E-mail: yuqiuzhang@fudan.edu.cn

1These authors contributed equally to this work.

E-mail: yuqiuzhang@fudan.edu.cn

Submitted July 28, 2011; revised October 27, 2011; accepted November 17, 2011.

© 2012 Lippincott Williams & Wilkins, Inc.
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