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

The dorsal horn is remarkably diverse, yet how this cellular complexity enables discrimination of sensory modalities remains a fundamental question. Neurons expressing the 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 that 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. The findings resolve functional diversity within the Grpr+ population, including identification of a convergent node for mechanical hypersensitivity, and provide subtype-enriched tools for further investigation.