We examined the influence of ultrashort pulses (USP) on sensory neurons. Single and high frequency bursts of 12 ns E-fields were presented to rat skin nociceptors that expressed distinct combinations of voltage-sensitive proteins. A single E-field pulse produced action potentials in all nociceptor subtypes at a critical threshold (E(c) ) of 403 V/cm. When configured into high frequency bursts, USP charge integrated to reduce the action potential threshold in a frequency and burst duration-dependent manner with E(c) as low as 16 V/cm (4000 Hz, 25 ms burst). There was no evidence of electroporation at field intensities near the E(c) for nociceptor activation. USP bursts activated a late, persistent Ca(++) flux that was identified as a dantrolene-sensitive Ca(++) -induced Ca(++) release (CICR). Influx of Ca(++) into the cell was required for the CICR and resulted in a reduction of the single pulse E(c) by about 50%.
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