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.
Highlights
Pain and itch are associated with clearly different subjec tive sensations, their general definitions emphasize common features: both can be described as an unpleasant sensation associated with pro tective somatosensory responses [1]
These nocifensive responses were abolished in Trpm3− /− animals, clearly indicating that pregneno lone sulfate (PregS)- and CIM0216-induced nociception is mediated by TRPM3 in the cheek
We found that TRPM3 agonists, as well as the TRP vanilloid 1 (TRPV1) agonist Caps behaved as algogenic substances in Trpm3+/+ animals i.e. they induced mainly nociception and hardly any itch
Summary
Pain and itch are associated with clearly different subjec tive sensations, their general definitions emphasize common features: both can be described as an unpleasant sensation associated with pro tective somatosensory responses [1]. The activation of nociceptors is initiated by the opening of nociceptive ion channels, including thermosensitive transient receptor po tential (TRP) channels, acid sensing ion channels (ASICs) [14] or P2X ionotropic purinoreceptors [15,16,17], which results in depolarization and consequent discharge of the nociceptive neurons. These ion channels can be directly activated by painful stimuli (extreme temperatures, acidosis or pain-evoking chemical ligands) or indirectly, via intracellular signaling pathways initiated by algogenic or inflammatory signals [18]. A particular role of the heat-pain mediating TRPV1 and TRPA1 was described in the transduction of histaminergic and non-histaminergic itch [11,12,33,34,35,36]
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