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

Pain. 2012 Mar;153(3):562-74. doi: 10.1016/j.pain.2011.11.020. Epub 2011 Dec 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology
  • 4-Aminopyridine / therapeutic use
  • Activating Transcription Factor 3 / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Behavior, Animal / drug effects
  • Biophysics
  • Bone Neoplasms / complications*
  • Bone Neoplasms / diagnostic imaging
  • Bone and Bones / pathology
  • Diclofenac / pharmacology
  • Diclofenac / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Extremities / diagnostic imaging
  • Extremities / pathology
  • Female
  • Functional Laterality
  • Ganglia, Spinal / pathology*
  • Glycoproteins / metabolism
  • Hyperalgesia / drug therapy
  • Hyperalgesia / physiopathology
  • Lectins / metabolism
  • Membrane Potentials / drug effects
  • Nerve Tissue Proteins / metabolism
  • Pain / etiology*
  • Pain / pathology*
  • Pain Threshold / drug effects
  • Patch-Clamp Techniques
  • Physical Stimulation
  • Potassium Channel Blockers / pharmacology
  • Potassium Channel Blockers / therapeutic use
  • Potassium Channels, Voltage-Gated / classification
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism*
  • RNA, Small Interfering / pharmacology
  • RNA, Small Interfering / therapeutic use
  • Radiography
  • Rats
  • Rats, Wistar
  • Scorpion Venoms / pharmacology
  • Scorpion Venoms / therapeutic use
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • Time Factors

Substances

  • Activating Transcription Factor 3
  • Anti-Inflammatory Agents, Non-Steroidal
  • Atf3 protein, rat
  • Glycoproteins
  • Lectins
  • Nerve Tissue Proteins
  • Pandinus toxin K-alpha
  • Potassium Channel Blockers
  • Potassium Channels, Voltage-Gated
  • RNA, Small Interfering
  • Scorpion Venoms
  • isolectin B4-binding glycoprotein, rat
  • Diclofenac
  • 4-Aminopyridine