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Endothelin-1 (ET-1),an endogenous vasoactive peptide,has been found to play an important role in peripheral pain signaling.Acidsensing ion channels (ASlCs) are key sensors for extracellular protons and contribute to pain caused by tissue acidosis.It remains unclear whether an interaction exists between ET-1 and ASICs in primary sensory neurons.In this study,we reported that ET-1 enhanced the activity of ASICs in rat dorsal root ganglia (DRG) neurons.In whole-cell voltage-clamp recording,ASIC currents were evoked by brief local application of pH 6.0 exteal solution in the presence of TRPV1 channel blocker AMG9810.Pre-application with ET-1 (1-100 nM) dose-dependently increased the proton-evoked ASIC currents with an ECso value of 7A2 ± 0.21 nM.Pre-application with ET-1 (30 nM) shifted the concentration-response curve of proton upwards with a maximal current response increase of 61.11％ ± 4.33％.We showed that ET-1 enhanced ASIC currents through endothelin-A receptor (ETAR),but not endothelin-B receptor (ETBR) in both DRG neurons and CHO cells co-expressing ASIC3 and ETAR.ET-1 enhancement was inhibited by blockade of G-protein or protein kinase C signaling.In current-clamp recording,pre-application with ET-1 (30 nM) significantly increased acid-evoked firing in rat DRG neurons.Finally,we showed that pharmacological blockade of ASICs by amiloride or APETx2 significantly alleviated ET-1-induced flinching and mechanical hyperalgesia in rats.These results suggest that ET-1 sensitizes ASICs in primary sensory neurons via ETAR and PKC signaling pathway,which may contribute to peripheral ET-1-induced nociceptive behavior in rats.