TNF-α acutely enhances acid-sensing ion channel currents in rat dorsal root ganglion neurons via a p38 MAPK pathway

Background Tumor necrosis factor-alpha (TNF-alpha) 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-alpha has an effect on functional activity of ASICs. Herein, we reported that a brief exposure of TNF-alpha acutely sensitized ASICs in rat dorsal root ganglion (DRG) neurons. Methods Electrophysiological experiments on rat DRG neurons were performed in vitro and acetic acid induced nociceptive behavior quantified in vitro. Results A brief (5min) application of TNF-alpha rapidly enhanced ASIC-mediated currents in rat DRG neurons. TNF-alpha (0.1-10 ng/ml) dose-dependently increased the proton-evoked ASIC currents with an EC50 value of 0.12 +/- 0.01 nM. TNF-alpha 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-alpha also significantly increased acid-evoked firing in rat DRG neurons. The rapid enhancement of ASIC-mediated electrophysiological activity by TNF-alpha 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-alpha exacerbated acid-induced nociceptive behaviors in rats via activation of local p38 MAPK pathway. Conclusions These results suggest that TNF-alpha rapidly enhanced ASIC-mediated functional activity via a p38 MAPK pathway, which revealed a novel peripheral mechanism underlying TNF-alpha involvement in rapid hyperalgesia by sensitizing ASICs in primary sensory neurons.

Automated summary

TNF-α rapidly enhances ASIC-mediated functional activity through a p38 MAPK pathway, sensitizing ASICs in primary sensory neurons and exacerbating pain.