HTR7 Mediates Serotonergic Acute and Chronic Itch

Chronic itch is a prevalent and debilitating condition for which few effective therapies are available. We harnessed the natural variation across genetically distinct mouse strains to identify transcripts co-regulated with itch behavior. This survey led to the discovery of the serotonin receptor HTR7 as a key mediator of serotonergic itch. Activation of HTR7 promoted opening of the ion channel TRPA1, which in turn triggered itch behaviors. In addition, acute itch triggered by serotonin or a selective serotonin reuptake inhibitor required both HTR7 and TRPA1. Aberrant serotonin signaling has long been linked to a variety of human chronic itch conditions, including atopic dermatitis. In a mouse model of atopic dermatitis, mice lacking HTR7 or TRPA1 displayed reduced scratching and skin lesion severity. These data highlight a role for HTR7 in acute and chronic itch and suggest that HTR7 antagonists may be useful for treating a variety of pathological itch conditions. •Activation of peripheral HTR7 receptors triggers itch but not pain behaviors•HTR7 promotes opening of the inflammatory ion channel TRPA1•Serotonin- and SSRI-evoked itch is mediated by HTR7 and TRPA1•HTR7 and TRPA1 are required for the development of atopic dermatitis in mice Aberrant serotonin signaling has long been linked to acute and chronic itch disorders. Morita et al. now show that HTR7 is a mediator of serotonergic and SSRI-evoked itch and is required for the development of chronic itch in a mouse atopic dermatitis model.