title: Suppression of KCNQ/M (Kv7) potassium channels in the spinal cord contributes to the sensitization of dorsal horn WDR neurons and pain hypersensitivity in a rat model of bone cancer pain.
abstract: Primary and metastatic cancers that affect bones are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. In the present study, we investigated whether inhibition of KCNQ/M (Kv7) potassium channels in the spinal cord contributes to the development of bone cancer pain via sensitization of dorsal horn wide dynamic range (WDR) neurons. Using a rat model of bone cancer pain based on intratibial injection of MRMT-1 tumor cells, we observed a significant increase in C-fiber responses of dorsal horn WDR neurons in the MRMT-1 injected rats, indicating sensitization of spinal WDR neurons in bone cancer rats. Furthermore, we discovered that blockade of KCNQ/M channels in the spinal cord by local administration of XE-991, a specific KCNQ/M channel blocker, caused a robust increase in excitability of dorsal horn WDR neurons, while, producing obvious pain hypersensitivity in normal rats. On the contrary, activation of spinal KCNQ/M channels by retigabine, a selective KCNQ/M channel opener, not only inhibited the bone cancer‑induced hyperexcitability of dorsal horn WDR neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in the bone cancer rats, while all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. All things considered, these results suggest that suppression of KCNQ/M channels in the spinal cord likely contributes to the development of bone cancer pain via sensitization of dorsal horn WDR neurons in rats following tumor cell inoculation.
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China.
authors.forename: Dong
authors.initials: D
authors.lastname: Fang
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Liu
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Cancer Center, First Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ren
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China.
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Xing
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001859:Bone Neoplasms / Q000473:pathology; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006930:Hyperalgesia / Q000473:pathology*; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049990:Membrane Transport Modulators / Q000494:pharmacology; D009368:Neoplasm Transplantation; D010146:Pain / Q000473:pathology*; D010655:Phenylenediamines / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D002219:Carbamates; D051656:KCNQ Potassium Channels; D049990:Membrane Transport Modulators; D010655:Phenylenediamines; C101866:ezogabine; D000109:Acetylcholine