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

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.