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

Abstract

Summary The dorsal horn is remarkably diverse, yet how this cellular complexity enables discrimination of sensory modalities remains a fundamental question. 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. 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.