Acute P38-Mediated Enhancement of P2X3 Receptor Currents by TNF-α in Rat Dorsal Root Ganglion Neurons.

purposeTumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine and involves in a variety of pain conditions. Some findings suggest that TNF-α may act directly on primary afferent neurons to induce acute pain hypersensitivity through non-transcriptional regulation. This study investigated whether TNF-α had an effect on functional activity of P2X3 receptors in primary sensory neurons. Herein, we report that a brief (5 min) application of TNF-α rapidly enhanced the electrophysiological activity of P2X3 receptors in rat dorsal root ganglia (DRG) neurons.

methodsElectrophysiological recordings were carried out on rat DRG neurons, and nociceptive behavior was quantified in rats.

resultsA brief (5 min) exposure of TNF-α rapidly increased P2X3 receptor-mediated and α,β-methylene-ATP (α,β-meATP)-evoked inward currents in a dose-dependent manner. The potentiation of P2X3 receptor-mediated ATP currents by TNF-α was voltage-independent. TNF-α shifted the concentration-response curve for α,β-meATP upwards, with an increase of 31.57 ± 6.81% in the maximal current response to α,β-meATP. This acute potentiation of ATP currents by TNF-α was blocked by p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190, but not by non-selective cyclooxygenase inhibitor indomethacin, suggesting involvement of p38 MAPK, but not cyclooxygenase. Moreover, intraplantar injection of TNF-α and α,β-meATP produced a synergistic effect on mechanical allodynia in rats. TNF-α-induced mechanical allodynia was also alleviated after local P2X3 receptors were blocked.

conclusionThese results suggested that TNF-α rapidly sensitized P2X3 receptors in primary sensory neurons via a p38 MAPK dependent pathway, which revealed a novel peripheral mechanism underlying acute mechanical hypersensitivity by peripheral administration of TNF-α.