BPS2026 – TRPV4 channels expressed in trigeminal AB low-threshold mechanoreceptors modulate chronic itch

Itch is a common clinical problem that severely impacts quality of life. However, effective treatments are scarce due to the limited understanding of its molecular and cellular mechanisms. TRPV4 is known to initiate itch in keratinocytes, but its role in sensory neurons is largely unknown. There is evidence to suggest that it may modulate neuronal itch pathways; however, its exact function and mechanisms remain unclear. In order to characterize TRPV4 expression in trigeminal neurons, we performed in situ hybridization and Ca 2+ imaging using the genetically encoded indicator GCaMP6f. To investigate the impact of neuronal TRPV4 deletion on itch, we performed behavioral tests in a mouse model of atopic dermatitis. Although TRPV4 is known to be expressed in small-diameter sensory neurons that co-express TRPV1, particularly within the trigeminal ganglion, we found that a significant proportion of TRPV4-positive neurons also belong to mechanosensitive subtypes characterized by TrkB expression. Using a neuron-specific conditional knockout mouse model targeting both small- and large-diameter sensory neurons, we demonstrated that TRPV4 plays a dual role in a model of atopic dermatitis. TRPV4 deletion resulted in reduced mechanical allknesis, but paradoxically increased and prolonged spontaneous scratching behavior during chronic itch. Together, our data reveal an unexpected function of TRPV4 in modulating itch via mechanosensitive sensory neurons. We propose that TRPV4 plays a crucial role in engaging spinal inhibitory circuits in itch processing and that its absence disrupts the feedback mechanisms that normally restrain pruritic signaling.