Endothelin-1 (ET-1) selectively enhances the activation gating of slowly inactivating tetrodotoxin-resistant sodium currents in rat sensory neurons: a mechanism for the pain-inducing actions of ET-1.

Endothelin-1 (ET-1) causes pain through activation of nociceptors, by either direct depolarization or increased excitability. Here we examined the effect of ET-1 on nociceptor-associated tetrodotoxin-resistant (TTX-R) sodium currents using whole-cell voltage clamp of acutely dissociated rat dorsal root ganglion (DRG) neurons. DRG neurons that responded had enhanced activation gating when exposed to 10 nm ET-1, as determined by significant shifts in their average activation midpoint potentials (DeltaE(0.5) = -8.0 +/- 0.5 mV) when compared with control (DeltaE(0.5) = -2.2 +/- 0.4 mV; n = 6) and ET-1 unresponsive cells (DeltaE(0.5) = -3.2 +/- 0.2 mV). ET-1 also modified the availability of TTX-R channels, as determined by negative shifts in the average midpoint potential for inactivation of ET-1 responsive cells when compared with controls. These actions of ET-1 occurred predominantly in cells with more slowly inactivating TTX-R currents. Both time-to-peak current and inactivation time constants were shortened by ET-1 in responsive cells. Previous exposure of cells to the endothelin-A (ET(A)) receptor antagonist BQ-123 (1 microm) prevented ET-1-induced shifts in TTX-R activation. In contrast to changes in TTX-R, ET-1 did not modify tetrodotoxin-sensitive currents recorded from DRG neurons. These results demonstrate that the algogenic peptide ET-1 induces ET(A) receptor-mediated, hyperpolarizing shifts in the voltage-dependent activation of TTX-R Na+ channels, a potential mechanism for selective excitation by ET-1 of nociceptors that we observed in vivo.