Neural mechanism signals the body to stop scratching

TRPV4, an ion channel, is found in neurons classically associated with touch, called Aβ low-threshold mechanoreceptors. New research indicates that TRPV4 can generate itch, but it also helps trigger a negative feedback signal, a neural message that tells the spinal cord and brain that scratching has been sufficient. Image Courtesy of Roberta Gualdani

Researchers have discovered that the ion channel TRPV4 plays a critical role in regulating the body's built-in "stop-scratching" circuit—a finding that has significant implications for the treatment of chronic itch conditions such as atopic dermatitis and psoriasis.

The research was presented at the 70th Biophysical Society Annual Meeting in San Francisco. Dr. Roberta Gualdani, a professor at the University of Louvain in Brussels, and her team engineered a genetic mouse model that selectively deleted TRPV4 only in sensory neurons. That approach circumvented a key limitation of earlier studies in which the channel was removed from all tissues.​

"We were initially studying TRPV4 in the context of pain," Dr. Gualdani explained in a press release. "But instead of a pain phenotype, what emerged very clearly was a disruption of itch, specifically, how scratching behaviour is regulated."

Using genetic tools, calcium imaging, and behavioural assays, the researchers demonstrated that TRPV4 is expressed in Aβ low-threshold mechanoreceptors (Aβ-LTMRs), as well as in subsets of sensory neurons linked to itch and pain pathways, including those expressing TRPV1. When a chronic itch condition resembling atopic dermatitis was induced, mice lacking neuronal TRPV4 scratched less frequently, but each bout lasted significantly longer than normal.

"At first glance, that seems paradoxical," Dr. Gualdani said. "But it actually reveals something very important about how itch is regulated."

The data indicate that TRPV4 in mechanosensory neurons helps trigger a negative feedback signal—a neural message informing the spinal cord and brain that scratching has been sufficient. Without this signal, the sensation of relief is blunted and scratching continues excessively.

These findings do complicate the therapeutic picture: While TRPV4 in keratinocytes appears to promote itch sensations, the same channel in neurons helps restrain them.

"This means that broadly blocking TRPV4 may not be the solution," Dr. Gualdani noted.

"Future therapies may need to be much more targeted—perhaps acting only in the skin, without interfering with the neuronal mechanisms that tell us when to stop scratching."

This dual role of TRPV4 suggests that cell-type-specific pharmacological strategies may be necessary to develop the next generation of antipruritic therapies, she said.