Nitrogen gas-derived cold atmospheric plasma suppresses pruritus through modulation of peripheral sensory neurons and keratinocytes.

Chronic pruritus is a highly prevalent symptom that markedly impairs the quality of life in both humans and animals. Although pharmacological therapies, including Janus kinase (JAK) inhibitors, are widely used for itch management, long-term treatment is associated with adverse effects and increased patient burden. Therefore, the development of non-pharmacological antipruritic approaches is highly desired. In this study, we investigated the antipruritic effects of nitrogen gas-derived cold atmospheric plasma (N2-CAP) and explored its underlying mechanisms using behavioral and calcium imaging analyses. Intradermal administration of an N2-CAP-treated solution (CAP water) significantly suppressed histamine- and serotonin-induced scratching and capsaicin-induced pain-related behaviors in mice. In vitro calcium imaging revealed that CAP water significantly reduced dorsal root ganglion (DRG) neuronal responses to histamine, serotonin, capsaicin, allyl isothiocyanate (AITC), and compound 48/80. Furthermore, CAP water modulated pruritogen-induced Ca2+ responses in human keratinocytes (HaCaT cells) and canine keratinocytes (CPEK cells), suggesting that N2-CAP influences neurocutaneous signaling pathways in both human and veterinary species. In a mouse model of allergic contact dermatitis, intradermal administration of CAP water significantly reduced scratching behavior, with an efficacy comparable to that of oclacitinib, a clinically used JAK inhibitor. Moreover, CAP treatment suppressed histamine- and AITC-induced DRG neuronal activation more strongly than did oclacitinib. Collectively, these findings demonstrated that N2-CAP exerts antipruritic effects by modulating peripheral sensory neurons and epidermal keratinocytes. Therefore, N2-CAP may represent a novel non-pharmacological or adjunctive therapeutic strategy for chronic pruritus in both human and veterinary medicine.