慢性瘙痒，和慢性疼痛一样，是一种疾病状态，尚缺乏有效的治疗手段。阐明瘙痒信息的传递与调控神经环路及其可塑性变化是揭示慢性瘙痒机制的前提。申请人在发现“痛觉超敏闸门”(J Clin Invest. 2013）的脊髓神经环路的基础上，结合疼痛可作为一种反刺激缓解瘙痒这一现象，提出反刺激可缓解瘙痒的机制假说：反刺激抑制瘙痒是通过脊髓背角两级抑制性神经元的调控实现的。反刺激可以升高脊髓eCBs水平，激活GlyT2+神经元终末的CB1R，甘氨酸释放减少，对下游的GABA能神经元的抑制作用减弱，GABA能神经元对经典痒觉通路的GRPR+ 神经元抑制增强，起到止痒作用。本课题拟联合应用双膜片钳技术、光遗传学、分子生物学和行为学等技术，以细胞特异性基因敲除小鼠为研究平台，深入研究瘙痒信息的传递与调控环路及其在慢性瘙痒状态下的可塑性变化，为阐明慢性痒的“痒-抓挠-痒”恶性循环的脊髓机制提供结构与功能基础。

Chronic pruritus, similar to chronic pain, is considered to be a state of diseases and lacks effective treatment. Discovering the functional organization and plasticity of itch processing circuits in spinal dorsal horn is the premise for elucidating the mechanisms of chronic pruritus. Based on the discovery of "allodynia gate" circuit in spinal dorsal horn (J Clin Invest. 2013), and the notion that pain can be used as a counterstimulus to alleviate pruritus, we propose herein a hypothesis on how the counterstimulus alleviate pruritus: the counterstimulus elevates the content of endocannabinoids （eCBs） in spinal dorsal horn, which activates CB1 receptors （CB1R）on the spinal inhibitory glycinergic （GlyT2+）neurons and then decreases the release of glycine. The inhibitory effect of GlyT2+ neurons on their downstream GABAergic neurons was weakened, and the inhibition of GABAergic neurons on GRPR+ neurons of itch pathways was enhanced. The present proposal will utilize paired patch-clamp whole-cell recordings, pharmacogenetics, optogenetics, molecular biology and behaviour techniques to study the functional organization and plasticity of spinal itch processing circuits in transgenic mice and conditional CB1 KO mice. This project will provide the clues for the interpretation of “itch scratching cycle” during chronic pruritus.