The TRPM3 ion channel mediates nociception but not itch evoked by endogenous pruritogenic mediators

Abstract

During the molecular transduction of itch, the stimulation of pruriceptors on sensory fibers leads to the activation or sensitization of ion channels, which results in a consequent depolarization of the neurons. These ion channels mostly belong to the transient receptor potential (TRP) channels, which are involved in nociception and thermosensation. In particular, TRPV1 and TRPA1 were described in the transduction of both thermal nociception as well as histaminergic and non-histaminergic itch. The thermosensitive TRPM3 plays an indispensable role in heat nociception together with TRPV1 and TRPA1. However, the role of TRPM3 in the development of pruritus has not been studied yet. Therefore, in this study we aimed at investigating the potential role of TRPM3 in the transduction of pruritus and pain by investigating itch- and nociception-related behavior of Trpm3^+/+ and Trpm3^-/- mice, and by studying the activation of somatosensory neurons isolated from trigeminal ganglia upon application of algogenic and pruritogenic substances. Activators of TRPM3 evoked only nocifensive responses, but not itch in Trpm3^+/+ animals, and these nocifensive responses were abolished in the Trpm3^-/- strain. Histamine and endogenous non-histaminergic pruritogens induced itch in both Trpm3^+/+ and Trpm3^-/- mice to a similar extent. Genetic deletion or pharmacological blockade diminished TRPM3 mediated Ca²⁺ responses of sensory neurons, but did not affect responses evoked by pruritogenic substances. Our results demonstrate that, in contrast to other thermosensitive TRP channels, TRPM3 selectively mediates nociception, but not itch sensation, and suggest that TRPM3 is a promising candidate to selectively target pain sensation.

Keywords: Cheek model; Endogenous pruritogens; Itch; Nociception; TRP channels; TRPM3.