Transcriptomically distinct subtypes of Grpr+ dorsal horn neurons, distinguished by Tac1 expression and corresponding to species-conserved Exc-SKOR2 and Exc-LMO3 populations, mediate functionally segregated sensory modalities with Grpr+Tac1- neurons necessary for chemical itch and Grpr+Tac1+ neurons necessary for mechanical allodynia across diverse injury types, a functional segregation that can be therapeutically exploited through computationally designed genomic enhancers for modality-specific intervention.

Recent advances reveal an extensive cellular diversity within the dorsal horn. How this complexity processes distinct sensations, like itch and pain, remains a fundamental question. We discovered hidden within a population of neurons expressing the gastrin-releasing peptide receptor (Grpr+), thought to be itch-specific, are highly homologous yet functionally distinct subtypes distinguished by expression of Tachykinin-1 (Tac1). While the Tac1- subtype mediates itch, the Tac1+ subtype mediates mechanical allodynia across diverse pain states. Inhibitory populations and differential sensitivities to GRP serve as key modulators of the Grpr+ neuron subtypes, shaping modality specific output. Leveraging computationally designed genomic enhancers to silence the Tac1- population reverses itch while silencing the Tac1+ subtype reverses mechanical allodynia broadly. The work demonstrates the nuance of differential sensory modality coding within the dorsal horn and the power of genomic enhancer-based strategies for modality-specific targeting.