Preprint / Version 1

A dedicated inhibitory circuit for gating itch in the spinal cord

This article is a preprint and has not been certified by peer review.

Authors

    Kai-Feng Shen,  
    Kai-Feng Shen
    • Army Medical University image/svg+xml
    • Washington University School of Medicine
    Rita Bardoni,  
    Rita Bardoni
    Yuxi Zhou,  
    Yuxi Zhou
    Sihan Chen,  
    Sihan Chen
    Jia-Yan Wu,  
    Jia-Yan Wu
    Yali Chen,  
    Yali Chen
    Hui Li,  
    Hui Li
    • Washington University School of Medicine
    • The Fourth Military Medical University
    Juan Liu,  
    Juan Liu
    • Washington University School of Medicine
    Yu Sun,  
    Yu Sun
    • Washington University School of Medicine
    • Shanghai Jiao Tong University School of Medicine
    Andrea Bighinati,  
    Andrea Bighinati
    Ben-Long Liu,  
    Ben-Long Liu
    Jun Wu,  
    Jun Wu
    Na Wang,  
    Na Wang
    • Washington University School of Medicine
    • Shandong Academy of Medical Sciences
    Xiao-Fei Gao,  
    Xiao-Fei Gao
    Joseph Jeffry,  
    Joseph Jeffry
    • Washington University School of Medicine
    Xueting Liu,  
    Xueting Liu
    • Washington University School of Medicine
    • Guangzhou Medical University image/svg+xml
    Xian-Yu Liu,  
    Xian-Yu Liu
    • Washington University School of Medicine
    Zhong-Qiu Zhao,  
    Zhong-Qiu Zhao
    • Washington University School of Medicine
    Fang Gao,  
    Fang Gao
    • Washington University School of Medicine
    • Icahn School of Medicine at Mount Sinai image/svg+xml
    Yingfu Jiao,  
    Yingfu Jiao
    Ailing Tao,  
    Ailing Tao
    Yun-Qing Li,  
    Yun-Qing Li
    • The Fourth Military Medical University
    Weifeng Yu,  
    Weifeng Yu
    Zhou-Feng Chen
    Zhou-Feng Chen
Categories
Neuroscience & Neurology
Keywords
Spinal dorsal horn; inhibitory interneurons; itch; GRPR neurons; substance P; NK3R neurons

Abstract

Various populations of spinal inhibitory neurons have been implicated in itch inhibition, but the precise mechanisms underlying tonic gating of itch and its inhibition by pain remain incompletely understood. Here, we identify a subset of inhibitory interneurons that uniquely express neurokinin receptor 3 (NK3R) in the spinal cord of mice. NK3R neurons receive monosynaptic input from Tac1+ sensory neurons, which release substance P (SP) and project directly to gastrin-releasing peptide receptor (GRPR)-expressing neurons that are dedicated to itch transmission. Silencing of NK3R inhibitory neurons disinhibits GRPR neurons and induces neuropathic itch, whereas their activation profoundly impairs itch but not pain transmission. These findings suggest that spinal NK3R inhibitory neurons serve as a pivotal and specific microcircuit for tonically gating of itch, and that the SP-NK3R-GRPR pathway may underlie the inhibition of itch by pain that activates the primary afferents to release SP onto the spinal cord.

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Shen, K.-F., Bardoni, R., Zhou, Y., Chen, S., Wu, J.-Y., Chen, Y., Li, H., Liu, J., Sun, Y., Bighinati, A., Liu, B.-L., Wu, J., Wang, N., Gao, X.-F., Jeffry, J., Liu, X., Liu, X.-Y., Zhao, Z.-Q., Gao, F., … Chen, Z.-F. (2026). A dedicated inhibitory circuit for gating itch in the spinal cord. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.09.04.000324

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