Histamine is known to excite a subset of C-fibers and cause itch sensation. Despite its well-defined excitatory action on sensory neurons, intracellular signaling mechanisms are not understood. Previously, we demonstrated that bradykinin excited sensory neurons by activating TRPV1 via the phospholipase A2 (PLA2) and lipoxygenase (LO) pathway. We, thus, hypothesized that histamine excited sensory neurons via the PLA 2/LO/TRPV1 pathway. Application of histamine elicited a rapid increase in intracellular Ca2+ ([Ca2+]i) that desensitized slowly in cultured dorsal root ganglion neurons. Histamine-induced [Ca2+]i was dependent on extracellular Ca2+ and inhibited by capsazepine and by SC0030, competitive antagonists of TRPV1. Quinacrine and nordihydroguaiaretic acid, a PLA2 and an LO inhibitor, respectively, blocked the histamine-induced Ca2+ influx in sensory neurons, while indomethacin (a cyclooxygenase inhibitor) did not. We thus conclude that histamine activates TRPV1 after stimulating the PLA2/LO pathway, leading to the excitation of sensory neurons. These results further provide an idea for potential use of TRPV1 antagonists as anti-itch drugs.
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