Voltage-gated Ion Channels in Nociceptors: Modulation by cGMP

J Neurophysiol. 2004 Oct;92(4):2323-32. doi: 10.1152/jn.00355.2004. Epub 2004 Jun 2.

Abstract

In tissue or nerve injury, proinflammatory mediators are released that can modulate a variety of ion channels found in nociceptors. The changes in channel activity, which primarily occurs through changes in intracellular pathways, may lead to the pathological states of hyperalgesia and allodynia. To understand further the regulatory mechanisms underlying the changes in channel activity, we used whole cell patch-clamp recordings from capsaicin-sensitive nociceptive neurons in rat trigeminal ganglion neurons to examine how the cGMP-dependent pathways may regulate ion channel function. Addition of the 8-(4-chlorophenylthio)-3',5' (CPT)-cGMP, a membrane permeant modulator of ion channels, decreased the number of evoked action potentials by 36% and inhibited the tetrodotoxin-resistant (TTX-R) sodium currents and IA potassium currents by 37 and 32%, respectively. Delayed rectifier potassium (IK) currents were unaffected, suggesting that the effects of CPT-cGMP are unlikely to arise from a nonspecific effect on channel activity as a consequence of the adsorption of amphipathic CPT-cGMP molecules to the membrane's bilayer component. This conclusion was reinforced by the lack of changes in gramicidin A channel function in the presence of CTP-cGMP. In summary, the activation of the cGMP-dependent pathways reduces nociceptor excitability, in part, by decreasing the activity of voltage-gated TTX-R sodium channels. This pathway may be a target for efforts to produce selective analgesics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Action Potentials / drug effects
  • Animals
  • Axons / physiology
  • Capsaicin / pharmacology
  • Cells, Cultured
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / pharmacology*
  • Electrophysiology
  • Gramicidin / pharmacology
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology*
  • Ion Channels / drug effects
  • Ion Channels / physiology*
  • Lipid Bilayers
  • Neural Conduction / drug effects
  • Neurons / drug effects
  • Nociceptors / drug effects
  • Nociceptors / physiology*
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Patch-Clamp Techniques
  • Potassium Channel Blockers / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology
  • Trigeminal Ganglion / cytology
  • Trigeminal Ganglion / drug effects
  • Trigeminal Ganglion / physiology

Substances

  • CPT-cGMP
  • Ion Channels
  • Lipid Bilayers
  • Potassium Channel Blockers
  • Sodium Channel Blockers
  • Gramicidin
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Tetrodotoxin
  • Cyclic GMP
  • Capsaicin