Itch suppression in mice and dogs by modulation of spinal \u03b12 and \u03b13GABAA receptors

William T Ralvenius,Hendrik Wildner,Michael Detmar,Uwe Rudolph,Martina Pagani,Jed Lee Hubbs,Nina Fischer,Ana Rostaher,Mario A Acuña,Elena Neumann,Simon Schwager,Dietmar Benke,Katrin Frauenknecht,Claude Favrot,Hanns Ulrich Zeilhofer,Adriano Aguzzi

doi:10.1038/s41467-018-05709-0

Abstract

Chronic itch is a highly debilitating condition affecting about 10% of the general population. The relay of itch signals is under tight control by inhibitory circuits of the spinal dorsal horn, which may offer a hitherto unexploited therapeutic opportunity. Here, we found that specific pharmacological targeting of inhibitory α2 and α3GABAA receptors reduces acute histaminergic and non-histaminergic itch in mice. Systemic treatment with an α2/α3GABAA receptor selective modulator alleviates also chronic itch in a mouse model of atopic dermatitis and in dogs sensitized to house dust mites, without inducing sedation, motor dysfunction, or loss of antipruritic activity after prolonged treatment. Transsynaptic circuit tracing, immunofluorescence, and electrophysiological experiments identify spinal α2 and α3GABAA receptors as likely molecular targets underlying the antipruritic effect. Our results indicate that drugs targeting α2 and α3GABAA receptors are well-suited to alleviate itch, including non-histaminergic chronic itch for which currently no approved treatment exists.

Highlights

Chronic itch is a highly debilitating condition affecting about 10% of the general population
We investigated the presence of α1, α2, α3, and α5GABAAR subunits on spinal axon terminals of primary MrgprA3 positive pruritoceptors and on spinal gastrin releasing peptide (GRP) neurons (Fig. 2)
Both MrgprA3 fibers and GRP neurons are concentrated in lamina II8,22, which harbors α2 and/or α3GABAAR subunits at high density[16,17,23]

Summary

Introduction

Chronic itch is a highly debilitating condition affecting about 10% of the general population. Other work addressed neuronal pathways involved in the spinal relay of itch These studies identified excitatory interneurons expressing gastrin releasing peptide (GRP)[9] or the GRP receptor (GRPR) 10,11 as key elements of this process. These itch-relay pathways appear to be under tight control by dorsal horn inhibitory neurons. We first used genetically modified mice to identify α2/α3 containing GABAARs as key elements of spinal itch control Building on this result we assessed potential antipruritic actions of an α2/α3GABAAR selective compound Building on this result we assessed potential antipruritic actions of an α2/α3GABAAR selective compound (TPA023B; ref. 19) and showed that it reduced acute histaminedependent and histamine-independent itch in mice and chronic itch in mice and dogs without apparent side effects

Methods

Results

Conclusion