Research Center of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China.
Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China.
J Neuroinflammation. 2021 Apr 14;18(1):92. doi: 10.1186/s12974-021-02151-w.
Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine involved in pain processing and hypersensitivity. It regulates not only the expression of a variety of inflammatory mediators but also the functional activity of some ion channels. Acid-sensing ion channels (ASICs), as key sensors for extracellular protons, are expressed in nociceptive sensory neurons and contribute to pain signaling caused by tissue acidosis. It is still unclear whether TNF-α has an effect on functional activity of ASICs. Herein, we reported that a brief exposure of TNF-α acutely sensitized ASICs in rat dorsal root ganglion (DRG) neurons.
Electrophysiological experiments on rat DRG neurons were performed in vitro and acetic acid induced nociceptive behavior quantified in vitro.
A brief (5min) application of TNF-α rapidly enhanced ASIC-mediated currents in rat DRG neurons. TNF-α (0.1-10 ng/ml) dose-dependently increased the proton-evoked ASIC currents with an EC value of 0.12 ± 0.01 nM. TNF-α shifted the concentration-response curve of proton upwards with a maximal current response increase of 42.34 ± 7.89%. In current-clamp recording, an acute application of TNF-α also significantly increased acid-evoked firing in rat DRG neurons. The rapid enhancement of ASIC-mediated electrophysiological activity by TNF-α was prevented by p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190, but not by non-selective cyclooxygenase inhibitor indomethacin, suggesting that p38 MAPK is necessary for this enhancement. Behaviorally, TNF-α exacerbated acid-induced nociceptive behaviors in rats via activation of local p38 MAPK pathway.
These results suggest that TNF-α rapidly enhanced ASIC-mediated functional activity via a p38 MAPK pathway, which revealed a novel peripheral mechanism underlying TNF-α involvement in rapid hyperalgesia by sensitizing ASICs in primary sensory neurons.
肿瘤坏死因子-α（TNF-α）是一种参与疼痛处理和过敏反应的促炎细胞因子。它不仅调节各种炎症介质的表达，还调节一些离子通道的功能活性。酸感应离子通道（ASICs）作为细胞外质子的关键传感器，在伤害感受神经元中表达，并有助于组织酸中毒引起的疼痛信号转导。目前尚不清楚 TNF-α 是否对 ASICs 的功能活性有影响。本文报道 TNF-α 短暂暴露可急性敏化大鼠背根神经节（DRG）神经元中的 ASICs。
在体外对大鼠 DRG 神经元进行电生理实验，并在体外量化乙酸诱导的疼痛行为。
TNF-α （5min）短暂应用可迅速增强大鼠 DRG 神经元中的 ASIC 介导电流。TNF-α（0.1-10ng/ml）剂量依赖性地增加质子诱发的 ASIC 电流，EC 值为 0.12±0.01nM。TNF-α 使质子浓度-反应曲线向上移位，最大电流反应增加 42.34±7.89%。在电流钳记录中，TNF-α 的急性应用也显著增加了大鼠 DRG 神经元的酸诱发放电。p38 丝裂原活化蛋白激酶（MAPK）抑制剂 SB202190 可阻止 TNF-α 对 ASIC 介导的电生理活性的快速增强，但非选择性环氧化酶抑制剂吲哚美辛不能阻止，这表明 p38 MAPK 对此增强是必需的。行为上，TNF-α 通过激活局部 p38 MAPK 通路加剧了酸诱导的大鼠疼痛行为。
这些结果表明，TNF-α 通过 p38 MAPK 通路迅速增强 ASIC 介导的功能活性，这揭示了 TNF-α 通过敏化初级感觉神经元中的 ASICs 参与快速痛觉过敏的外周新机制。
