Endothelin-1 Decreases Excitability of the Dorsal Root Ganglion Neurons via ETB 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 (Ithreshold) and hyperpolarization of resting membrane potential (RMP) indicating decreased excitability of DRG neurons. Ithreshold 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 (INa) and outward transient potassium current (IKT). ET-1, 30 and 100 nM, decreased the peak INa by 41.3 ± 6.8 and 74 ± 15.2%, respectively. Additionally, ET-1 (100 nM) significantly potentiated the transient component (IKT) of the potassium currents. ET-1-induced effects were largely attenuated by BQ-788, a selective ETBR blocker. However, a selective ETAR blocker BQ-123 did not alter the effects of ET-1. A selective ETBR agonist, IRL-1620, mimicked the effect of ET-1 on INa in a concentration-dependent manner (IC50 159.5 ± 92.6 μM). In conclusion, our results demonstrate that ET-1 hyperpolarizes nociceptors by blocking INa and potentiating IKT through selective activation of ETBR, which may represent one of the underlying mechanisms for reported anti-nociceptive effects of ET-1.