Retigabine, the specific KCNQ channel opener, blocks ectopic discharges in axotomized sensory fibres.
The M-current has been proposed as a potential target for analgesia under neuropathic pain conditions. M-currents and/or their molecular correlates, KCNQ proteins, have been demonstrated in key elements of the nociceptive system including spinal and dorsal root ganglion neurons. Here we demonstrate that retigabine, a selective KCNQ channel opener, applied at neuromatose endings modulates the excitability of axotomized fibres inhibiting ectopic discharges. Responses to mechanical and chemical stimulation were obtained from intact and previously axotomized Adelta- and C-fibres using in vitro preparations and extracellular electrophysiological recording techniques. Application of retigabine (10 microM) produced an estimated approximately 80% reduction in the number of discharges produced by mechanical and chemical stimulation of most axotomized fibres tested (24/27). The electrical threshold of stimuli applied to the neuroma was found to increase in the presence of retigabine (+17.5+/-2.3%) and to decrease in the presence of a high potassium medium (-16.5+/-3.7%). This indicates that retigabine produces a hyperpolarization and a subsequent reduction of the excitability in aberrant sensory endings. Application of XE-991 (10 microM), a KCNQ channel blocker, had no effect on responses to stimulation of the neuroma but blocked the effects of retigabine indicating a specific involvement of KCNQ channels. In contrast to the strong effects on ectopic discharges, retigabine did not change responses to stimulation recorded from intact receptors. Results indicate that KCNQ channel opening at axotomized endings may constitute a novel and selective mechanism for modulation of some neuropathic pain symptoms.
Roza
Carolina
C
Dpto. Fisiologia, Edificio de Medicina, Campus Universitario, Universidad de Alcala, Alcala de Henares, Madrid 28871, Spain.
Lopez-Garcia
Jose Antonio
JA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D019771:Axotomy / Q000379:methods; D002219:Carbamates / Q000494:pharmacology*; D005260:Female; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000502:physiology*; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D010655:Phenylenediamines / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*
D002219:Carbamates; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; C101866:ezogabine