Leukotriene B4 potentiates acid-sensing ion channel currents in mouse dorsal root ganglion neurons

Leukotriene B4 (LTB4) is a lipid mediator generated from arachidonic acid. Studies have shown that LTB4 plays a role in the pain process. However, little is known about the underlying molecular and cellular mechanisms. The present data demonstrated a functional link between LTB4 and acid-sensing ion channels (ASICs) in mouse dorsal root ganglion (DRG) neurons. LTB4 potentiated acid-activated ASIC currents in a concentration-dependent and pH-independent manner. The potentiating effect of LTB4 on ASIC currents was mediated by BLT1 receptors but not by BLT2 receptors. The LTB4-induced potentiation of ASIC currents was prevented by the ERK1/2 inhibitor U0126 and the JNK inhibitor SP600125, but not by the p38 inhibitor SB202190, indicating involvement of intracellular ERK1/2 and JNK signaling. Moreover, LTB4 potentiated the burst of action potentials evoked by acidic stimuli in mouse DRG neurons. Behaviorally, intraplantar injection of LTB4 exaggerated spontaneous nociceptive behaviours evoked by subsequent acid challenge in WT mice, and developed attenuated mechanical hyperalgesia in ASIC3 KO mice. Our results suggested that LTB4 potentiated the electrophysiological activity of ASICs via BLT1 receptors as well as the ERK1/2 and JNK signaling pathways, which might open promising new perspectives for pain treatment associated with tissue acidification.