Electrophysiology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab, 160062, India.
Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, 60515, USA.
Mol Neurobiol. 2018 May;55(5):4297-4310. doi: 10.1007/s12035-017-0640-1. Epub 2017 Jun 16.
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.
内皮素-1（ET-1）已被证明具有致痛和抗痛作用。然而，这些疼痛调节作用的潜在分子机制仍不清楚。在本研究中，我们使用膜片钳技术在急性分离的大鼠背根神经节（DRG）神经元中评估了 ET-1 改变伤害感受器兴奋性的能力。ET-1 增加了诱发动作电位（I）的阈电流，并使静息膜电位（RMP）超极化，表明 DRG 神经元兴奋性降低。ET-1（100 nM）使 I 从 0.25±0.08 增加到 0.33±0.07 nA，使 RMP 从-57.51±1.70 超极化到-67.41±2.92 mV。ET-1 的超极化作用似乎是通过调节膜电导来协调的，即电压门控钠电流（I）和外向瞬态钾电流（I）。ET-1，30 和 100 nM，分别使 I 的峰值降低 41.3±6.8%和 74±15.2%。此外，ET-1（100 nM）显著增强了钾电流的瞬态成分（I）。BQ-788，一种选择性 ETR 阻断剂，大大减弱了 ET-1 引起的作用。然而，选择性 ETR 阻断剂 BQ-123 并没有改变 ET-1 的作用。选择性 ETR 激动剂 IRL-1620 以浓度依赖性方式模拟了 ET-1 对 I 的作用（IC 159.5±92.6 μM）。总之，我们的结果表明，ET-1 通过选择性激活 ETR 阻断 I 和增强 I 使伤害感受器超极化，这可能是 ET-1 报道的抗痛作用的潜在机制之一。
