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

Helen Kühn,Peter Reeh,Katharina Wolf,Andreas E Kremer,Markus F Neurath,Lisa Gebhardt,Leonie Kappes,Michael J M Fischer

doi:10.1038/s41598-020-59092-2

Helen Kühn, Peter Reeh + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-59092-2

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Abstract

Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (NaV) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, NaV1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing NaV-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, β-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in NaV channel-mediated itch signalling. NaV1.7−/− showed substantial scratch reduction mainly towards strong pruritogens. NaV1.8−/− impaired histamine and 5-HT-induced scratching while NaV1.9 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 NaV1.7 and indicated an overall contribution of NaV1.9. Beside the proposed general role of NaV1.7 and 1.9 in itch signalling, scrutiny of time courses suggested NaV1.8 to sustain prolonged itching. Therefore, NaV1.7 and 1.9 may represent targets in pruritus therapy.

Highlights

Pruritus, commonly referred to as itch, can appear as agonizing symptom of dermatological, systemic and psychogenic disorders[1]
While an isolated analysis of individual NaV channels is sufficient to determine a role of NaV subtypes in acute itch, the complexity of itch signalling with a possible complementing function of NaV channels, as indicated by recent in vitro studies[18], remains elusive
Scratch behaviour upon diverse acute itch stimuli was assessed in NaV1.7−/−, NaV1.8−/−, NaV1.9−/− knockout mice and congenic wild type animals in order to explore which NaV channels are required for itch signalling

Summary

Introduction

Commonly referred to as itch, can appear as agonizing symptom of dermatological, systemic and psychogenic disorders[1]. A major role in histamine-independent itch signalling can be attributed to Mas-related G protein-coupled receptors (MRGPR) This family of G protein-coupled receptors (GPCRs) mediates acute scratch behaviour towards pruritogens such as bovine adrenal medulla 8–22 peptide (BAM8-22)[4], chloroquine[5], β-alanine[6] and the tethered PAR2 ligand SLIGRL7. Complementary physiological studies have shown that these channels modulate pain signalling[20,21,22] For their indispensable role in the generation and propagation of action potentials, www.nature.com/scientificreports these NaV subtypes have been suggested as potential drug targets for blunting sensory perceptions. NaV1.9 knockout mice showed reduced scratch behaviour upon treatment with histamine, chloroquine and BAM8-2228 This suggests that NaV1.7 and NaV1.9 are involved in acute itch signalling. We show here that various pruritogens require different NaV channels to mediate an itch stimulus while neuronal activation is unaltered in primary sensory neurons of the respective knockout animals

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