A molecular and spinal circuit basis for the functional segregation of itch and pain

Neurons expressing gastrin-releasing peptide receptor (Grpr+) have long been considered dedicated to itch, yet broad activation also evokes pain-related behavior. Whether Grpr+ neurons are required for pain, and how itch- and pain-related functions are organized within this population remain unresolved.

Here, we show that Grpr+ neurons comprise functionally distinct subpopulations defined by tachykinin-1 (Tac1) and correspond to species-conserved transcriptomic subtypes. Convergent loss- and gain-of-function approaches show the Tac1− subpopulation is required for chemical itch, whereas a bombesin-insensitive, Tac1 enriched population is necessary for mechanical hypersensitivity across diverse injury states. Computationally identified enhancers provide subtype-enriched genetic access, confirming their roles in itch, mechanical hypersensitivity, and sustained pain.