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.
Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Aminopyridine / pharmacology
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4-Aminopyridine / therapeutic use
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Activating Transcription Factor 3 / metabolism
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Behavior, Animal / drug effects
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Biophysics
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Bone Neoplasms / complications*
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Bone Neoplasms / diagnostic imaging
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Bone and Bones / pathology
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Diclofenac / pharmacology
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Diclofenac / therapeutic use
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Extremities / diagnostic imaging
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Extremities / pathology
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Female
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Functional Laterality
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Ganglia, Spinal / pathology*
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Glycoproteins / metabolism
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Hyperalgesia / drug therapy
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Hyperalgesia / physiopathology
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Lectins / metabolism
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Membrane Potentials / drug effects
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Nerve Tissue Proteins / metabolism
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Pain / etiology*
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Pain / pathology*
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Pain Threshold / drug effects
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Patch-Clamp Techniques
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Physical Stimulation
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Potassium Channel Blockers / pharmacology
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Potassium Channel Blockers / therapeutic use
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Potassium Channels, Voltage-Gated / classification
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Potassium Channels, Voltage-Gated / genetics
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Potassium Channels, Voltage-Gated / metabolism*
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RNA, Small Interfering / pharmacology
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RNA, Small Interfering / therapeutic use
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Radiography
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Rats
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Rats, Wistar
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Scorpion Venoms / pharmacology
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Scorpion Venoms / therapeutic use
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Sensory Receptor Cells / drug effects
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Sensory Receptor Cells / metabolism*
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Time Factors
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Versicans
Substances
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Activating Transcription Factor 3
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Anti-Inflammatory Agents, Non-Steroidal
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Atf3 protein, rat
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Glycoproteins
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Lectins
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Nerve Tissue Proteins
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Pandinus toxin K-alpha
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Potassium Channel Blockers
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Potassium Channels, Voltage-Gated
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RNA, Small Interfering
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Scorpion Venoms
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Vcan protein, rat
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Versicans
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Diclofenac
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4-Aminopyridine