The Molecular and Cellular Basis of Regional Itch Differences

Itch is a complex, noxious sensation associated with many skin and systemic conditions, which varies in intensity and quality across different body regions. Despite its prevalence, the molecular and cellular mechanisms underlying regional itch differences remain poorly understood. Here, we investigate the neural basis of regional itch differences, focusing on the role of neuropeptides and histamine receptors expression. Using a combination of behavioral, pharmacological, genetic, histological, and molecular approaches, we identified distinct regional differences in itch response between the cheek and dorsal nape (neck). Our findings reveal that Substance P modulates itch in the cheek, while histamine receptor 1 (HRH1) is the primary receptor mediating itch but not pain in the cheek. We also discovered regional differences in sensory neuron subpopulations, with increased co-expression of HRH1 and neuropeptides in trigeminal ganglion neurons. In brief, we provide new insights into the molecular and cellular mechanisms underlying regional itch differences, highlighting the importance of considering regional variations in itch response to develop effective treatments.