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.

Nat Commun. 2012 Mar 20;3:746. doi: 10.1038/ncomms1749.

Güler AD, Rainwater A, Parker JG, Jones GL, Argilli E, Arenkiel BR, Ehlers MD, Bonci A, Zweifel LS, Palmiter RD.

Source

Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, 1959 NE Pacific Street, Box 357370, Seattle, Washington 98195, USA.

Abstract

The ability to control the electrical activity of a neuronal subtype is a valuable tool in deciphering the role of discreet cell populations in complex neural circuits. Recent techniques that allow remote control of neurons are either labor intensive and invasive or indirectly coupled to neural electrical potential with low temporal resolution. Here we show the rapid, reversible and direct activation of genetically identified neuronal subpopulations by generating two inducible transgenic mouse models. Confined expression of the capsaicin receptor, TRPV1, allows cell-specific activation after peripheral or oral delivery of ligand in freely moving mice. Capsaicin-induced activation of dopaminergic or serotonergic neurons reversibly alters both physiological and behavioural responses within minutes, and lasts ~10 min. These models showcase a robust and remotely controllable genetic tool that modulates a distinct cell population without the need for invasive and labour-intensive approaches.