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Pain and itch processing by subpopulations of molecularly diverse spinal and trigeminal projection neurons

Significance To generate modality-specific percepts (e.g., pain vs. itch), the brain must interpret the activity that arises from the output cells (projection neurons) of the dorsal horn of the spinal cord, which receive and then transmit pain- or itch-provoking stimuli. However, neither the extent to which projection neurons relay modality-specific messages nor the molecular makeup of these neurons is clear. Here, we report that the projection neurons are, in fact, diverse, not only molecularly but also functionally. By focusing on genes expressed by projection neurons within the neurokinin-1 receptor (NK1R) and non–NK1R-expressing populations, we also demonstrate considerable functional heterogeneity among these subsets, including nociceptive (pain)-specific, pruriceptive (itch)-specific, and polymodal (both pain and itch) subsets of projection neurons. A remarkable molecular and functional heterogeneity of the primary sensory neurons and dorsal horn interneurons transmits pain- and or itch-relevant information, but the molecular signature of the projection neurons that convey the messages to the brain is unclear. Here, using retro-TRAP (translating ribosome affinity purification) and RNA sequencing, we reveal extensive molecular diversity of spino- and trigeminoparabrachial projection neurons. Among the many genes identified, we highlight distinct subsets of Cck+-, Nptx2+-, Nmb+-, and Crh+-expressing projection neurons. By combining in situ hybridization of retrogradely labeled neurons with Fos-based assays, we also demonstrate significant functional heterogeneity, including both convergence and segregation of pain- and itch-provoking inputs into molecularly diverse subsets of NK1R- and non–NK1R-expressing projection neurons.