Intra-somatosensory cortical circuits mediating pain-induced analgesia

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 Fos^TRAP2 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.