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

Abstract

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, β-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.Pruritus, commonly also referred to as itch, can appear as agonizing symptom of dermatological, systemic and psychogenic disorders 1 . Despite its high impact on the quality of life, treatment options remain limited. One obstacle in the development of new drugs arises from the diversity of signalling pathways triggering itch. Aside histamine, which was the first known pruritogen 2,3 , pruritus can be elicited by various histamine-independent pruritogens with diverse chemical structures acting on a wide range of receptors. 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 SLIGRL 7 . Additionally, pruritogens like 5-hydroxytryptamine (5-HT) 8 , and lysophosphatidic acid (LPA) 9 signal via activation of their specific receptors.Pruritogens can activate GPCRs located on nerve endings of unmyelinated primary sensory neurons, resulting in a rise of cytosolic calcium levels both via the inositol phospholipid signalling pathway 10-13 and via transient receptor potential ion channels (TRP) 14 . Upon membrane depolarization, voltage-gated sodium channels (Na V ) are opened, triggering the initiation and propagation of action potentials. The function of Na V channels is determined by the pore-forming alpha-subunit of which nine subtyp...

FGF13 Is Required for Histamine-Induced Itch Sensation by Interaction with NaV1.7

“…In mice, selective Na V 1.7 inhibitors suppressed itch behaviors induced by histamine (Graceffa et al, 2017;Chandra et al, 2020). Na V 1.7 KO mice in which the functional expression of Na V 1.7 being prevented in DRG and trigeminal ganglia neurons exhibited strong scratching reduction toward many pruritogens, such as C48/80, 5-HT, CQ, endothelin, and histamine (Kühn et al, 2020). Particularly, a tamoxifen-inducible Na V 1.7 KO mouse allowing adult-onset deletion of SCN9A-encoding Na V 1.7 also appeared lack of scratching behavior induced by histamine (Flinspach et al, 2017).…”

A plant‐derived TRPV3 inhibitor suppresses pain and itch

“…to play role in itching (Devigili et al, 2014;Kuhn et al, 2020;Peng et al, 2015;Shiratori-Hayashi et al, 2019). Application of 50-μM citrusinine-II on these channels had no obvious activity (Figure 2f-i).…”

“…After excluding the effect of channel desensitization, 50-μM citrusinine-II showed no significant inhibition of TRPV2 (Figure 2e). In addition, other ion channels such as ASIC3, P2X3, Na v 1.7 and Na v 1.8 channels have been reported to play role in itching (Devigili et al, 2014;Kuhn et al, 2020;Peng et al, 2015;Shiratori-Hayashi et al, 2019). Application of 50-μM citrusinine-II on these channels had no obvious activity (Figure 2f-i).…”

Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis

“…The release of the neuropeptide calcitonin-gene related peptide (CGRP) induced by P-CTX-1 in mouse skin-nerve preparations was shown to involve Na v 1.9 and the combined activation of Na v 1.7 and Na v 1.1 [ 144 ]. Although the Na v isotypes mediating the pruritus induced by CTXs remain to be identified, the roles of Na v 1.7 and Na v 1.9 have been revealed in acute itch from other etiologies [ 167 , 168 , 169 , 170 , 171 ]. Interestingly, Na v 1.7 is required for the release of another neuropeptide, substance P (SP), in the spinal cord from electrically stimulated DRG neurons, and the subsequent wind-up, i.e., increased dorsal horn neuron excitability following repeated C-fiber stimulation [ 172 ].…”