Wu Jing, Wang Jia-Jia, Liu Ting-Ting, Zhou Yi-Mei, Qiu Chun-Yu, Shen Ding-Wen, Hu Wang-Ping
Research Center of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning 437100, Hubei, P.R. China.
Department of Physiology, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning 437100, Hubei, P.R. China.
Oncotarget. 2017 Oct 10;8(54):93051-93062. doi: 10.18632/oncotarget.21805. eCollection 2017 Nov 3.
Peroxisome proliferator-activated receptor-α (PPAR-α), a lipid activated transcription factor of nuclear hormone receptor superfamily, can relieve pain through a rapid-response mechanism. However, little is known about the underlying mechanism. Herein, we report that PPAR-α activation acutely inhibits the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons, in rat dorsal root ganglion (DRG) neurons. Pre-application of PPAR-α agonist GW7647 for 2 min decreased the amplitude of proton-gated currents mediated by ASICs in a concentration-dependent manner. GW7647 shifted the concentration-response curve for proton downwards, with a decrease of 36.9 ± 2.3% in the maximal current response to proton. GW7647 inhibition of proton-gated currents can be blocked by GW6471, a selective PPAR-α antagonist. Moreover, PPAR-α activation decreased the number of acidosis-evoked action potentials in rat DRG neurons. Finally, peripheral administration of GW7647 dose-dependently relieved nociceptive responses to injection of acetic acid in rats. These results indicated that activation of peripheral PPAR-α acutely inhibited functional activity of ASICs in a non-genomic manner, which revealed a novel mechanism underlying rapid analgesia through peripheral PPAR-α.
过氧化物酶体增殖物激活受体-α（PPAR-α）是核激素受体超家族的一种脂质激活转录因子，可通过快速反应机制缓解疼痛。然而，其潜在机制尚不清楚。在此，我们报道PPAR-α激活可急性抑制大鼠背根神经节（DRG）神经元中酸敏感离子通道（ASICs）的功能活性，ASICs是细胞外质子的关键传感器。预先应用PPAR-α激动剂GW7647 2分钟，以浓度依赖的方式降低了ASICs介导的质子门控电流的幅度。GW7647使质子的浓度-反应曲线向下移动，对质子的最大电流反应降低了36.9±2.3%。GW7647对质子门控电流的抑制作用可被选择性PPAR-α拮抗剂GW6471阻断。此外，PPAR-α激活减少了大鼠DRG神经元中酸中毒诱发的动作电位数量。最后，外周给予GW7647剂量依赖性地减轻了大鼠对注射醋酸的伤害性反应。这些结果表明，外周PPAR-α的激活以非基因组方式急性抑制ASICs的功能活性，这揭示了通过外周PPAR-α实现快速镇痛的新机制。
