Itch suppression in mice and dogs by modulation of spinal α2 and α3GABAA receptors

William T. Ralvenius, Elena Neumann, Martina Pagani, Mario A. Acuña, Hendrik Wildner, Dietmar Benke, Nina Fischer, Ana Rostaher, Simon Schwager, Michael Detmar, Katrin Frauenknecht, Adriano Aguzzi, Jed Lee Hubbs, Uwe Rudolph, Claude Favrot and Hanns Ulrich Zeilhofer ()
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William T. Ralvenius: University of Zürich
Elena Neumann: University of Zürich
Martina Pagani: University of Zürich
Mario A. Acuña: University of Zürich
Hendrik Wildner: University of Zürich
Dietmar Benke: University of Zürich
Nina Fischer: Vetsuisse Faculty
Ana Rostaher: Vetsuisse Faculty
Simon Schwager: Swiss Federal Institute of Technology (ETH) Zürich
Michael Detmar: Swiss Federal Institute of Technology (ETH) Zürich
Katrin Frauenknecht: University of Zürich and University Hospital Zürich
Adriano Aguzzi: University of Zürich and University Hospital Zürich
Jed Lee Hubbs: Swiss Federal Institute of Technology (ETH) Zürich
Uwe Rudolph: McLean Hospital
Claude Favrot: Vetsuisse Faculty
Hanns Ulrich Zeilhofer: University of Zürich

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05709-0

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