Consequences of 4-aminopyridine applications to trigeminal root ganglion neurons.
1. The effects of 4-aminopyridine (4-AP) on the electrical properties of 30 trigeminal root ganglion (TRG) neurons were determined from the membrane voltage responses to step and sinusoidal current injections using intracellular microelectrode techniques in in vitro slice preparations (guinea pigs). 2. Comparisons of results from 4-AP applications (0.05-5 mM) with those from tetraethylammonium (TEA) applications (0.1-10 mM) revealed very different actions of these agents. Both agents produced an increase in input resistance and a decrease in threshold for spike generation. Applications of 4-AP increased subthreshold oscillations of the membrane potential and enhanced the repetitive spike firing evoked by intracellular injections of current pulses. However, TEA applications blocked the potential oscillations and did not exaggerate repetitive spike discharges. Spontaneous spike activity or bursts were observed in four neurons that received 4-AP applications. 3. Membrane properties were determined in 20 of the 30 neurons by fitting impedance data in the frequency domain with a four-parameter membrane model by the use of computer-intensive techniques. In the majority of neurons, the time-invariant and time-dependent membrane conductances decreased during 4-AP application. The time constant for the time-dependent conductance also decreased, suggesting that the closing of K+-channels was facilitated in the membrane. 4. Applications of 4-AP in a dose range of 50 microM-5 mM produced rapid (approximately tens of seconds) responses of the neurons, resulting in a dose-dependent increase of the impedance magnitude functions and in a leftward shift of the resonant "humps" to lower frequencies. This shift indicates that the TRG neuronal membrane is capable of producing large voltage responses to current inputs at low frequencies. Recovery from the effects of 4-AP was slow (usually greater than 30 min). 5. Applications of 4-AP at high doses (greater than or equal to 1 mM) and at various imposed membrane potentials in four neurons resulted in poorly reversible unspecific changes in certain membrane parameters (increased input capacitance and conductance) and an insensitivity of the input conductance to the imposed membrane potential. These effects could be interpreted as membrane breakdown. 6. The tendencies of TRG neurons to fire repetitively and in bursts of spikes during 4-AP application result from the increased oscillatory behavior of their membrane potentials and changes in membrane resonance induced by presumed blockade of K+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)
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Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Miura
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Spigelman
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D015761:4-Aminopyridine; D000200:Action Potentials / Q000187:drug effects; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects*; D014276:Trigeminal Nerve / Q000187:drug effects*
D000631:Aminopyridines; D002800:Cholinesterase Inhibitors; D015221:Potassium Channels; D013757:Tetraethylammonium Compounds; D019789:Tetraethylammonium; D015761:4-Aminopyridine