This paper is in honor of Manfred Zimmermann’s 70th birthday.

Abstract

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 PLA₂/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.