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The Journal of Neuroscience, November 12, 2003, 23(32):10338-10350
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Cellular/Molecular
Role of Tetrodotoxin-Resistant Na+ Current Slow Inactivation in Adaptation of Action Potential Firing in Small-Diameter Dorsal Root Ganglion Neurons
Nathaniel T. Blair and
Bruce P. Bean
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115
When acutely dissociated small-diameter dorsal root ganglion (DRG) neurons were stimulated with repeated current injections or prolonged application of capsaicin, their action potential firing quickly adapted. Because TTX-resistant (TTX-R) sodium current in these presumptive nociceptors generates a large fraction of depolarizing current during the action potential, we examined the possible role of inactivation of TTX-R sodium channels in producing adaptation. Under voltage clamp, TTX-R current elicited by short depolarizations showed strong use dependence at frequencies as low as 1 Hz, although recovery from fast inactivation was complete in  10-30 msec. This use-dependent reduction was the result of the entry of TTX-R sodium channels into slow inactivated states. Slow inactivation was more effectively produced by steady depolarization than by cycling channels through open states. Slow inactivation was steeply voltage dependent, with a Boltzmann slope factor of 5 mV, a midpoint near -45 mV (5 sec conditioning pulses), and completeness of 93% positive to -20 mV. The time constant for entry (200 msec) was independent of voltage from -20 mV to +60 mV, whereas recovery kinetics were moderately voltage dependent (time constant, 1.5 sec at -60 mV and 0.5 sec at -100 mV). Using a prerecorded current-clamp response to capsaicin as a voltage-clamp command waveform, we found that adaptation of firing occurred with a time course similar to that of development of slow inactivation. Thus, slow inactivation of the TTX-R sodium current limits the duration of small DRG cell firing in response to maintained stimuli and may contribute to cross desensitization between chemical and electrical stimuli.
Key words: action potential; dorsal root ganglion; excitability; nociceptor; sodium channel; spike-frequency adaptation; tetrodotoxin
Received Aug 12, 2003;
revised September 5, 2003;
accepted September 22, 2003.
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