Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (Na-V) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, Na(V)1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing Na-V-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, beta-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in Na-V channel-mediated itch signalling. Na(V)1.7(-/-) showed substantial scratch reduction mainly towards strong pruritogens. Na(V)1.8(-/-) impaired histamine and 5-HT-induced scratching while Na(V)1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of Na(V)1.7 and indicated an overall contribution of Na(V)1.9. Beside the proposed general role of Na(V)1.7 and 1.9 in itch signalling, scrutiny of time courses suggested Na(V)1.8 to sustain prolonged itching. Therefore, Na(V)1.7 and 1.9 may represent targets in pruritus therapy.