Antagonizing trpa1 receptors counteracts non-histaminergic itch in humans

Background and aims: Chronic itch is a common symptom of several pathological conditions with a lifetime prevalence of about 20%. In most conditions chronic itch follows a histamine-independent pathway, involving a subgroup of polymodal C-fibers that can be experimentally activated by the application of BAM8-22, an agonist of Mas-related G protein-coupled receptor X1 (MrgprX1). Moreover, the TRPA1 receptor downstream activation can likewise be involved in non-histaminergic itch generation. This study aimed to evaluate the interaction between MrgprX1 and TRPA1 by modulating BAM8-22-induced non-histaminergic itch by TRPA1 antagonist A-967079.

Methods: Twenty-two healthy subjects were randomized, using a single-blinded protocol. Four areas on the forearms were selected and treated as follows: vehicle+BAM8-22, A-967079+BAM8-22, A-967079+BAM8-22 (applied after 5 minutes), and A-967079+inactivated cowhage spicules. A-967079 (0.5 mg/ml) and vehicle were intradermally injected (0.1 ml), while BAM8-22 was applied through inactivated cowhage spicules coated with while BAM8-22 (2 mg/ml). After spicules application, itch intensity was scored with a visual analog scale for 9 minutes followed by the assessment of the mechanically evoked itch.

Results: Itch evoked by ‘A-967079+BAM8-22 (after 5 min)’ resulted in a lower intensity than ‘vehicle+BAM8-22’ (p<0.05). Moreover, the mechanically evoked itch was lower in ‘A-967079+BAM8-22 (after 5 min)’ and ‘A-967079+inativated spicules’ areas compared to ‘vehicle+BAM8-22’ (p<0.05).

Conclusions: A-967079 reduced the itch intensity and the mechanically evoked itch in BAM8-22-induced non-histaminergic itch. This study confirmed the involvement of TRPA1 receptors in the signal pathway of non-histaminergic itch generation and hence the block of TRPA1 receptors can be a promising option for treating chronic itch.