ABSTRACT

Chronic itch, a distressing sensory perception often accompanying various dermatological and systemic conditions, significantly impacts the quality of life of affected individuals. A prominent feature of the chronic itch is hair-touch-induced itch (mechanical itch) sensitization, in which normally innocuous hair touch elicits itch. While significant progress has been made in understanding mechanical itch circuits in the central nervous system, detailed molecular, cellular, and circuitry of mechanical itch in the peripheral nervous system remain poorly understood. Here, using mouse intersectional genetic strategy, electrophysiological recordings, behavioral study, and in situ hybridization techniques, we identified a unique population of mechanical itch sensory neurons in dorsal root ganglia expressing Toll-like receptor 5 and Calbindin1 (Tlr5+/Calb1+) that innervate to the special hairs at the skin, termed 'vellus-like hairs’ in mice that is equivalent to human vellus hair. Mice with ablated Tlr5+/Calb1+ neurons showed significantly reduced scratching behavior under chronic itch conditions, indicating Tlr5+/Calb1+ DRG neurons play an important role in chronic itch as well. To dissect the molecular and cellular events within Tlr5+/Calb1+ DRG neurons that contribute to mechanical itch sensitization in chronic itch, we utilized single-cell RNA sequencing to examine the transcriptional landscape of chronic itch, revealing differentially expressed ion channels and cytokines that may serve as potential targets. Our findings shed light on the molecular and cellular events occurring at the periphery level of the nervous system, providing valuable insights into the development of novel treatments for chronic itch that can alleviate the burden of chronic itch, ultimately improving the lives of those affected by this debilitating condition.