TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch 

by Jenny Wilzopolski ^1,2,3,*, Manfred Kietzmann ¹, Santosh K. Mishra ², Holger Stark ⁴, Wolfgang Bäumer ^2,3 and Kristine Rossbach¹

¹Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany

²Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA

³Department of Veterinary Medicine, Institute of Pharmacology and Toxicology, Freie Universität Berlin, 14195 Berlin, Germany

⁴Institute of Pharmaceutical and Medical Chemistry, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany

^*Author to whom correspondence should be addressed. Academic Editors: Emanuela Masini, Laura Lucarini and Alessandro AlaimoBiomolecules2021, 11(8), 1166; https://doi.org/10.3390/biom11081166Received: 13 July 2021 / Revised: 31 July 2021 / Accepted: 4 August 2021 / Published: 6 August 2021(This article belongs to the Special Issue New Developments in Histamine Research)

Abstract: Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the trans- mission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.

Keywords: histamine; histamine H1 receptor; histamine H4 receptor; itch; signal transduction; TRPV1; TRPA1; dorsal root ganglion neurons (DRG); Ca2+-imaging