Distinct supraspinal neural pathways underlie licking-induced alleviation of pain sensation and aversion in male mice.

Licking as a form of tactile input is widely employed to assess pain levels, suggesting that it may be a restorative behavior in response to injury. However, the exact brain neural mechanisms underlying licking-induced analgesia remain to be elucidated. In this study, we establish a mouse research paradigm to investigate licking-induced analgesia and report that licking behavior significantly reduces pain sensation and pain-related aversion in male mice by triggering the activation of glutamatergic neurons within the gracile nucleus (Gr). Furthermore, we describe the efferent projections from the Gr to the zona incerta (ZI). Importantly, glutamatergic and GABAergic ZI neurons with Gr input (GrZI) neuronal ensembles are efferent to the hindlimb region of the primary somatosensory cortex (S1HL) and the ventral tegmental area (VTA), which regulate the sensory and affective components of licking-induced analgesia, respectively. These findings unveil critical cross-modal supraspinal pathways that enable tactile input to differentially regulate the sensory and affective components of nociception.