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, Hanns Ulrich Zeilhofer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number3230
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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