Itch suppression in mice and dogs by modulation of spinal α2 and α3GABA(A) receptors

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 α3GABA(A) receptors reduces acute histaminergic and non-histaminergic itch in mice. Systemic treatment with an α2/α3GABA(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 α2 and α3GABA(A) receptors as likely molecular targets underlying the antipruritic effect. Our results indicate that drugs targeting α2 and α3GABA(A) receptors are well-suited to alleviate itch, including non-histaminergic chronic itch for which currently no approved treatment exists.