Histamine-induced Ca2+ influx via the PLA2/lipoxygenase/TRPV1 pathway in rat sensory neurons

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

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Acknowledgements

This study was supported by the National Creative Research Initiatives of the Ministry of Science and Technology of Korea.

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      Although the activation of pruriceptive (itch sensitive) sensory neurons is also related to the activation of ion channels partially overlapping with the nociceptor channels, they are typically activated via an indirect way: pruritic ligands bind to their metabotropic receptors thereby activating the pruritic channels via downstream signaling pathways [8,9]. A particular role of the heat-pain mediating TRPV1 and TRPA1 was also described in the transduction of histaminergic and non-histaminergic itch [11,12,33–36]. TRPM3 was recently identified as a heat sensitive TRP channel expressed by somatosensory neurons of the trigeminal and dorsal root ganglia (TGs and DRGs).

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

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