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 (I threshold) and hyperpolarization of resting membrane potential (RMP) indicating decreased excitability of DRG neurons. I threshold 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 Na) and outward transient potassium current (I KT). ET-1, 30 and 100 nM, decreased the peak I Na by 41.3 ± 6.8 and 74 ± 15.2%, respectively. Additionally, ET-1 (100 nM) significantly potentiated the transient component (I KT) 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 I Na in a concentration-dependent manner (IC50 159.5 ± 92.6 μM). In conclusion, our results demonstrate that ET-1 hyperpolarizes nociceptors by blocking I Na and potentiating I KT through selective activation of ETBR, which may represent one of the underlying mechanisms for reported anti-nociceptive effects of ET-1.
KeywordsEndothelin-1 Neuropathic pain ETBR DRG neurons Sodium currents Potassium currents Anti-nociception IRL-1620
Action potential duration
Decay phase time constant
Delayed rectifier potassium current
Dorsal root ganglion
Endothelin A receptor
Endothelin B receptor
Fast transient potassium currents
Phosphate buffer saline
Resting membrane potential
Standard error of mean
Tetraethyl ammonium chloride
Time to peak
Sodium current reversal potential
The authors thank the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Government of India, for the financial support.
SSS and JNS conceptualized the study design. NKM and KS carried out the experiments. NKM, KS, and JNS analyzed the data. NKM, JNS, SSS, and AG wrote the final version of the manuscript.
Compliance with Ethical Standards
All experimental protocols were approved by the Institutional Animal Ethics Committee, National Institute of Pharmaceutical Education and Research, SAS Nagar, India.
Conflict of Interest
The authors declare that they have no conflict of interest.
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