title: Targeting A-type K(+) channels in primary sensory neurons for bone cancer pain in a rat model.
abstract: 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.
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China School of Life Sciences, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Kai-Zheng
authors.initials: KZ
authors.lastname: Duan
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Xiao-Meng
authors.initials: XM
authors.lastname: Zhang
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: Yan-Ai
authors.initials: YA
authors.lastname: Mei
authors.forename: Yu-Qiu
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology / Q000627:therapeutic use; D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001703:Biophysics; D001859:Bone Neoplasms / Q000150:complications* / Q000000981:diagnostic imaging; D001842:Bone and Bones / Q000473:pathology; D004008:Diclofenac / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005121:Extremities / Q000000981:diagnostic imaging / Q000473:pathology; D005260:Female; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D037102:Lectins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010146:Pain / Q000209:etiology* / Q000473:pathology*; D017288:Pain Threshold / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D024642:Potassium Channels, Voltage-Gated / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D011859:Radiography; D051381:Rats; D017208:Rats, Wistar; D012604:Scorpion Venoms / Q000494:pharmacology / Q000627:therapeutic use; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D053675:Versicans
chemical_list: D051700:Activating Transcription Factor 3; D000894:Anti-Inflammatory Agents, Non-Steroidal; C497108:Atf3 protein, rat; D006023:Glycoproteins; D037102:Lectins; D009419:Nerve Tissue Proteins; C105110:Pandinus toxin K-alpha; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D034741:RNA, Small Interfering; D012604:Scorpion Venoms; C508324:Vcan protein, rat; D053675:Versicans; D004008:Diclofenac; D015761:4-Aminopyridine