Intra-somatosensory cortical circuits mediating pain-induced analgesia

Ji-Ye Huang, Yu-Xin Jin, Wan-Ying Dong, Wan Zhao, Ping-Kai Cheng, Jun-Hao Miao, An Liu, Di Wang, Juan Li, Zhi Zhang (), Wenjuan Tao () and Xia Zhu ()
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Ji-Ye Huang: University of Science and Technology of China
Yu-Xin Jin: University of Science and Technology of China
Wan-Ying Dong: University of Science and Technology of China
Wan Zhao: The First Affiliated Hospital of University of Science and Technique of China
Ping-Kai Cheng: University of Science and Technology of China
Jun-Hao Miao: University of Science and Technology of China
An Liu: Anhui Medical University
Di Wang: University of Science and Technology of China
Juan Li: University of Science and Technology of China
Zhi Zhang: University of Science and Technology of China
Wenjuan Tao: Anhui Medical University
Xia Zhu: University of Science and Technology of China

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Pain in one part of the body profoundly diminishes the sensation of pain in other parts of the body in humans. Here, we found that pain-related behaviors in hindpaw are inhibited by noxious stimuli from diverse body regions in mice. Using activity-dependent cell labeling in male FosTRAP2 mice, we captured a neuronal ensemble in the layers 2–4 of secondary somatosensory cortex (S2) that was activated during pain at diverse body regions induced analgesia. Single-cell projection analysis showed that these S2 neurons receive projections from the contralateral S2 and specifically innervate the layer 4 of primary somatosensory cortex (S1). Microendoscopic calcium imaging and chemogenetic manipulation in freely moving mice showed that this S2 → S1 feedforward inhibitory circuit mediates ipsilateral pain-induced analgesia, whereas contralateral S2 innervation of the S2 → S1 circuit mediates contralateral pain-induced analgesia. Our study defines the intra-somatosensory cortical circuits underlying “pain inhibiting pain”, expanding the scope of known circuit mechanisms involved in pain relief.

Date: 2025
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DOI: 10.1038/s41467-025-57050-y

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