Gan Xiong, Wu Jing, Ren Cuixia, Qiu Chun-Yu, Li Yan-Kun, Hu Wang-Ping
Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, PR China.
Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, PR China.
Pharmacol Res. 2016 May;107:19-26. doi: 10.1016/j.phrs.2016.02.018. Epub 2016 Mar 3.
Glutamate activates peripheral group I metabotropic glutamate receptors (mGluRs) and contributes to inflammatory pain. However, it is still not clear the mechanisms are involved in group I mGluR-mediated peripheral sensitization. Herein, we report that group I mGluRs signaling sensitizes acid-sensing ion channels (ASICs) in dorsal root ganglion (DRG) neurons and contributes to acidosis-evoked pain. DHPG, a selective group I mGluR agonist, can potentiate the functional activity of ASICs, which mediated the proton-induced events. DHPG concentration-dependently increased proton-gated currents in DRG neurons. It shifted the proton concentration-response curve upwards, with a 47.3±7.0% increase of the maximal current response to proton. Group I mGluRs, especially mGluR5, mediated the potentiation of DHPG via an intracellular cascade. DHPG potentiation of proton-gated currents disappeared after inhibition of intracellular Gq/11 proteins, PLCβ, PKC or PICK1 signaling. Moreover, DHPG enhanced proton-evoked membrane excitability of rat DRG neurons and increased the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, peripherally administration of DHPG dose-dependently exacerbated nociceptive responses to intraplantar injection of acetic acid in rats. Potentiation of ASIC activity by group I mGluR signaling in rat DRG neurons revealed a novel peripheral mechanism underlying group I mGluRs involvement in hyperalgesia.
谷氨酸激活外周I组代谢型谷氨酸受体（mGluRs）并导致炎性疼痛。然而，I组mGluR介导的外周敏化所涉及的机制仍不清楚。在此，我们报告I组mGluRs信号传导使背根神经节（DRG）神经元中的酸敏感离子通道（ASICs）敏化，并导致酸中毒诱发的疼痛。DHPG是一种选择性I组mGluR激动剂，可增强ASICs的功能活性，ASICs介导质子诱导的事件。DHPG浓度依赖性地增加DRG神经元中的质子门控电流。它使质子浓度-反应曲线向上移动，对质子的最大电流反应增加了47.3±7.0%。I组mGluRs，尤其是mGluR5，通过细胞内级联反应介导了DHPG的增强作用。抑制细胞内Gq/11蛋白、PLCβ、PKC或PICK1信号后，DHPG对质子门控电流的增强作用消失。此外，DHPG增强了大鼠DRG神经元质子诱发的膜兴奋性，并增加了酸刺激诱导的去极化幅度和动作电位数量。最后，外周给予DHPG剂量依赖性地加剧了大鼠对足底注射醋酸的伤害性反应。大鼠DRG神经元中I组mGluR信号传导对ASIC活性的增强揭示了I组mGluRs参与痛觉过敏的一种新的外周机制。
