Endothelin-1 Decreases Excitability of the Dorsal Root Ganglion Neurons via ET Receptor.

Endothelin-1 (ET-1) has been demonstrated to be a pro-nociceptive as well as an anti-nociceptive agent. However, underlying molecular mechanisms for these pain modulatory actions remain unclear. In the present study, we evaluated the ability of ET-1 to alter the nociceptor excitability using a patch clamp technique in acutely dissociated rat dorsal root ganglion (DRG) neurons. ET-1 produced an increase in threshold current to evoke an action potential (I ) and hyperpolarization of resting membrane potential (RMP) indicating decreased excitability of DRG neurons. I increased from 0.25 ± 0.08 to 0.33 ± 0.07 nA and hyperpolarized RMP from -57.51 ± 1.70 to -67.41 ± 2.92 mV by ET-1 (100 nM). The hyperpolarizing effect of ET-1 appears to be orchestrated via modulation of membrane conductances, namely voltage-gated sodium current (I ) and outward transient potassium current (I ). ET-1, 30 and 100 nM, decreased the peak I by 41.3 ± 6.8 and 74 ± 15.2%, respectively. Additionally, ET-1 (100 nM) significantly potentiated the transient component (I ) of the potassium currents. ET-1-induced effects were largely attenuated by BQ-788, a selective ETR blocker. However, a selective ETR blocker BQ-123 did not alter the effects of ET-1. A selective ETR agonist, IRL-1620, mimicked the effect of ET-1 on I in a concentration-dependent manner (IC 159.5 ± 92.6 μM). In conclusion, our results demonstrate that ET-1 hyperpolarizes nociceptors by blocking I and potentiating I through selective activation of ETR, which may represent one of the underlying mechanisms for reported anti-nociceptive effects of ET-1.