Oscillatory mechanism in primary sensory neurones.
Ectopic spike activity, generated at low levels in intact sensory dorsal root ganglia and intensified following axotomy, is an important cause of neuropathic pain. The spikes are triggered by subthreshold membrane potential oscillations. The depolarizing phase of oscillation sinusoids is due to a phasic voltage-sensitive Na(+) conductance (gNa(+)). Here we examine the repolarizing phase for which K(+) conductance (gK(+)) is implicated. In vivo, gK(+) blockers have excitatory effects inconsistent with the elimination of oscillations. Indeed, using excised dorsal root ganglia in vitro, we found that gK(+) block does not eliminate oscillations; on the contrary, it has a variety of facilitatory effects. However, oscillations were eliminated by shifting the K(+) reversal potential so as to neutralize voltage-insensitive K(+) leak channels. Based on these data, we propose a novel oscillatory model: oscillation sinusoids are due to reciprocation between a phasically activating voltage-dependent, tetrodotoxin-sensitive Na(+) conductance and passive, voltage-independent K(+) leak. In drug-free media, voltage-sensitive K(+) channels act to suppress oscillations and increase their frequency. Numerical simulations support this model and account for the effects of gK(+) block. Oscillations in dorsal root ganglia neurones appear to be based on the simplest possible configuration of ionic conductances compatible with sustained high frequency oscillatory behaviour. The oscillatory mechanism might be exploited in the search for novel analgesic drugs.
Amir
Ron
R
Department of Cell and Animal Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
Liu
Chang-Ning
CN
Kocsis
Jeffery D
JD
Devor
Marshall
M
D000818:Animals; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D026902:Potassium Channel Blockers; D011188:Potassium