Itch suppression in mice and dogs by modulation of spinal alpha 2 and alpha 3GABA(A) receptors

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

来源：Nature Communications, 2018, 9(1): 3230.

DOI：10.1038/s41467-018-05709-0

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 alpha 2 and alpha 3GABA(A) receptors reduces acute histaminergic and non-histaminergic itch in mice. Systemic treatment with an alpha 2/alpha 3GABA(A) 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 alpha 2 and alpha 3GABA(A) receptors as likely molecular targets underlying the antipruritic effect. Our results indicate that drugs targeting alpha 2 and alpha 3GABA(A) receptors are well-suited to alleviate itch, including non-histaminergic chronic itch for which currently no approved treatment exists.

• 出版日期2018-8-13