The plasticity of neuropeptide Y-Y1 receptor system on neurons contributes to mechanical hyperknesis during chronic itch.

In the physiological states, the act of scratching protects the person from harmful substances, while in certain pathological conditions, the patient suffers from chronic itch, both physically and mentally. Chronic itch sufferers are more sensitive to mechanical stimuli, and mechanical hyperknesis relief is essential for chronic itch treatment. While neuropeptide Y-Y1 receptor (NPY-Y1R) system is known to play a crucial role in modulating mechanical itch in physiological conditions, it is elusive how they are altered during chronic itch. We hypothesize that the negative regulatory effect of Y1Rs on neurons, the key neurons that transmit mechanical itch, declines during chronic itch. We combined transgenic mice, chemogenetic manipulation, immunofluorescence, rabies virus circuit tracing, and electrophysiology to investigate the plasticity of Y1Rs on neurons during chronic itch. We found that neurons receive direct input from neurons and that inhibition of neurons induces activation of neurons. Moreover, the expression of Y1Rs on neurons is reduced, and the regulatory effect is also reduced during chronic itch. Our study clarifies the plasticity of Y1Rs on neurons during chronic itch and further elucidates the mechanism by which NPY-Y1R system is responsible for modulating mechanical itch. We highlight Y1Rs as a promising therapeutic target for mechanical hyperknesis during chronic itch.