Have you ever wondered why scratching sometimes makes itching even worse? The neurotransmitter serotonin has been fingered as one troublemaker as the brain tries to control pain caused by scratching. But the underlying mechanisms of the vicious itch-scratch cycle are more complicated than one chemical.
Now, scientists at the Washington University School of Medicine have identified a “miswiring” of nerve fibers that creates “short circuiting” in touch-sensing skin cells called Merkel cells, according to a new study published in Science Translational Medicine.
The mechanism promoted the itch-scratch cycle in mice, the researchers showed, and they now proposed that the findings could inform the development of new anti-itching therapies in various skin conditions such as eczema.
Using a mouse model of dry skin-associated chronic itch, the researchers found that activation of the Piezo2 ion channel in Merkel cells is key in the generation of itch. Crippling Piezo2 from Merkel cells reduced persistent scratching among the animals.
A group of MRGPRA3-expressing nerve fibers, which primarily mediate the perception of pain and itch, was found to act downstream of the Merkel cell-related itch signaling, the team showed.
The scientists then used super-resolution microscopy with 3D reconstruction to visualize the interactions between Merkel cells and MRGPRA3-expressing nerves. The mice’s dry skin showed abnormal changes in the structure of the MRGPRA3 nerve endings directed toward Merkel cells. Specifically, the endings appeared to migrate toward Merkel cells in the chronic itch skin but not in the steady state.
This structural “miswiring” of Merkel cells with nerve endings showed “how chronic itch can alter the normal function of skin cells to propagate the vicious itch-scratch cycle,” the team wrote in the study, which has Jing Feng, Ph.D., as the first author.
Washington University's Center for the Study of Itch & Sensory Disorders that Feng belongs to has been working to elucidate the mechanisms behind itching for a long time.
In a 2014 study published in the journal Neuron, scientists from the center found that serotonin facilitates itch transmission. The chemical did that by activating Gastrin-releasing peptide receptor (GRPR) neurons through a receptor called 5-HT1A. The team at that time proposed blocking the crosstalk between 5-HT1A and GRPR as a potential anti-itching strategy.
This time, Feng and colleagues suggested that the miswiring mechanism found in mice might also point to future itch treatment in humans partly because the human MRGPRX1 protein shares similar properties with mouse MRGPRA3.
“For the first time, we identified Merkel cells as the main center for these touch-itch conversions … and I think these could be therapeutic targets to break the itch-scratch cycle in the future,” Feng said in an interview with Science in a podcast.