An attention-demanding hunting paradigm engages the superior colliculus-zona incerta circuit mediating analgesia in male mice.

Attention distraction mitigates pain, yet its neural basis remains elusive. We established cricket hunting as an attention-demanding paradigm that alleviates acute and chronic pain in male mice. Activity tagging revealed that cricket hunting activated a subset of glutamatergic neurons in the superior colliculus (SC). Selective stimulation of these hunting-activated neurons alleviated chronic hyperalgesia, primarily mediated by their projections to the zona incerta (ZI). Notably, repeated engagement, either through the hunting paradigm or by repeatedly activating hunting-activated SC-ZI projections, induced sustained analgesia (lasting at least 6 hours), linked to potentiated glutamatergic inputs to ZI GABAergic neurons. Furthermore, SC-ZI projections originating from SC neurons expressing tachykinin precursor 1 (Tac1) selectively elevated neuropathic pain thresholds via substance P release and neurokinin 1 (NK1) receptor-dependent excitatory synaptic transmission onto ZI GABAergic neurons. Together, we show that a specific SC-ZI circuit drives attention-induced analgesia, highlighting the SCTac1-ZI pathway as a therapeutic target for chronic pain.