Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
Neuroscience Center Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
Nat Commun. 2018 Aug 13;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 α2 and α3GABA receptors reduces acute histaminergic and non-histaminergic itch in mice. Systemic treatment with an α2/α3GABA 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 receptors as likely molecular targets underlying the antipruritic effect. Our results indicate that drugs targeting α2 and α3GABA receptors are well-suited to alleviate itch, including non-histaminergic chronic itch for which currently no approved treatment exists.
慢性瘙痒是一种高度致残的疾病，影响约 10%的普通人群。脊髓背角的抑制性回路对瘙痒信号的传递进行严格控制，这可能提供了一个迄今为止尚未开发的治疗机会。在这里，我们发现，特异性药理学靶向抑制性 α2 和 α3GABA 受体可减少小鼠的急性组胺能和非组胺能瘙痒。选择性 α2/α3GABA 受体调节剂的全身治疗也可缓解特应性皮炎小鼠模型和对屋尘螨敏感的犬的慢性瘙痒，而在长期治疗后不会引起镇静、运动功能障碍或止痒活性丧失。突触间回路追踪、免疫荧光和电生理实验将脊髓 α2 和 α3GABA 受体鉴定为潜在的抗瘙痒作用的分子靶点。我们的结果表明，靶向 α2 和 α3GABA 受体的药物非常适合缓解瘙痒，包括目前尚无批准治疗方法的非组胺能慢性瘙痒。
