Interleukin-31 Induces Itch-Related Responses with Precursor Behaviors in Mice and Its Suppression by the Dopamine D2/D3 Receptor Agonist Ropinirole

Recent research has revealed that human itch manifests in a variety of distinct phenotypes, such as muzumuzu (creepy-crawly itch, a bit like tickling). We have also demonstrated that scratching behaviors induced by pruritogens in mice are sometimes preceded by specific precursor behaviors, such as shivering or forelimb grooming, whereas in other cases, these precursors are absent. These findings suggest that mice, like humans, exhibit characteristic itch-related behaviors. In the present study, we focused on interleukin-31 (IL-31), which has been implicated in atopic dermatitis-associated itch, and investigated whether precursor behaviors were observed during IL-31-induced itch-related behaviors in mice. Male ICR mice were used in this study. Following intradermal injection of IL-31, subsequent behaviors were recorded with a digital video camera, and scratch behaviors were counted based on the presence or absence of precursor behaviors. Intradermal IL-31-induced scratching with precursor behaviors was significantly higher than that without them. Dopamine D2 receptor agonists are reported to be effective against restless sensations. Ropinirole, a dopamine D2/D3 receptor agonist, significantly suppressed IL-31-induced scratching with precursor behaviors. Interestingly, ropinirole also attenuated IL-31-induced scratching without precursor behaviors. Histamine induces scratching that is unaccompanied by precursor behaviors compared to those accompanied by them. Ropinirole also inhibited histamine-induced scratching, both with and without precursor behaviors. In conclusion, these findings provide the first evidence that IL-31-induced itch-related responses are primarily characterized by precursor behaviors. Moreover, the fact that ropinirole significantly suppressed both IL-31- and histamine-induced scratching suggests that ropinirole holds therapeutic promise for managing diverse itch signaling pathways.