Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, No.1481, Xinshi North Road, Shanghai 200434, China.
Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, No. 1279, Sanmen Road, Shanghai 200434, China.
Theranostics. 2024 Jan 1;14(1):363-378. doi: 10.7150/thno.89433. eCollection 2024.
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.
在生理状态下，搔抓行为可保护人体免受有害物质的侵害，而在某些病理条件下，患者会遭受慢性瘙痒的折磨，身心俱疲。慢性瘙痒患者对机械刺激更为敏感，机械性超敏缓解对慢性瘙痒的治疗至关重要。虽然神经肽 Y-Y1 受体（NPY-Y1R）系统在调节生理条件下的机械性瘙痒方面起着关键作用，但目前尚不清楚其在慢性瘙痒期间如何发生改变。我们假设，Y1R 对传递机械性瘙痒的关键神经元——神经元的负向调节作用在慢性瘙痒期间会减弱。我们结合转基因小鼠、化学遗传学操作、免疫荧光、狂犬病毒回路追踪和电生理学等方法，研究了慢性瘙痒期间 Y1R 对神经元的可塑性。我们发现神经元接收来自神经元的直接输入，并且抑制神经元会诱导神经元的激活。此外，在慢性瘙痒期间，神经元上 Y1R 的表达减少，其调节作用也减弱。本研究阐明了慢性瘙痒期间 Y1R 对神经元的可塑性，进一步阐明了 NPY-Y1R 系统调节机械性瘙痒的机制。我们强调 Y1R 是治疗慢性瘙痒时机械性超敏的一个有希望的治疗靶点。
