Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model.

Abstract

Bone cancer pain has a strong impact on the quality of life of patients, but is difficult to treat. Better understanding of the pathogenic mechanisms underlying bone cancer pain will likely lead to the development of more effective treatments. In the present study, we investigated whether inhibition of KCNQ/M channels contributed to the hyperexcitability of primary sensory neurons and to the pathogenesis of bone cancer pain. By using a rat model of bone cancer pain based on intratibial injection of MRMT-1 tumour cells, we documented a prominent decrease in expression of KCNQ2 and KCNQ3 proteins and a reduction of M-current density in small-sized dorsal root ganglia (DRG) neurons, which were associated with enhanced excitability of these DRG neurons and the hyperalgesic behaviours in bone cancer rats. Coincidently, we found that inhibition of KCNQ/M channels with XE-991 caused a robust increase in the excitability of small-sized DRG neurons and produced an obvious mechanical allodynia in normal rats. On the contrary, activation of the KCNQ/M channels with retigabine not only inhibited the hyperexcitability of these small DRG neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in bone cancer rats, and all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. These results suggest that repression of KCNQ/M channels leads to the hyperexcitability of primary sensory neurons, which in turn causes bone cancer pain. Thus, suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of bone cancer pain.

• Authors: Qin Zheng, Dong Fang, Min Liu, Jie Cai, You Wan, Ji-Sheng Han, Guo-Gang Xing
• Journal: Pain (Pain) Vol. 154 Issue 3 Pg. 434-448 (Mar 2013) ISSN: 1872-6623 [Electronic] United States
• PMID: 23352759 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Chemical References

• 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone
• Anthracenes
• Carbamates
• KCNQ2 Potassium Channel
• KCNQ3 Potassium Channel
• Kcnq2 protein, rat
• Kcnq3 protein, rat
• Phenylenediamines
• Potassium Channel Blockers
• ezogabine

Topics

• Animals
• Anthracenes (pharmacology)
• Bone Neoplasms (pathology, physiopathology, secondary)
• Carbamates (pharmacology, therapeutic use)
• Carcinoma (pathology, physiopathology, secondary)
• Down-Regulation
• Female
• Ganglia, Spinal (physiopathology)
• Hot Temperature (adverse effects)
• Hyperalgesia (etiology, physiopathology)
• KCNQ2 Potassium Channel (antagonists & inhibitors, biosynthesis, genetics, physiology)
• KCNQ3 Potassium Channel (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Mammary Neoplasms, Experimental (pathology)
• Neoplasm Transplantation
• Nociception (physiology)
• Pain (etiology)
• Patch-Clamp Techniques
• Phenylenediamines (pharmacology, therapeutic use)
• Potassium Channel Blockers (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sensory Receptor Cells (metabolism, physiology)
• Stress, Mechanical
• Synaptic Transmission
• Tibia (pathology)