Neuronal Circuit Likely Behind Chronic Itch in MS and Other Diseases Identified

The nerve cell circuit, stretching from the skin to the spinal cord, is likely responsible for the persistent itching sensation that can afflict people with multiple sclerosis (MS) and other conditions, a study found.

The discovery was made in mice and as such is still preliminary, but researchers say this work may lead to specific treatments for chronic itch.

The study, “Identification of a Spinal Circuit for Mechanical and Persistent Spontaneous Itch,” was published in the journal Neuron.

People with MS can experience a range of altered and unpleasant sensations — frequently described as a tingling, itching, burning or aching feeling, or a “girdling” sensation across the body (popularly called the “MS hug”). These sensations are collectively known as dysesthesia. They are caused by damage to nerves that perturbs the normal transmission of messages to and from the brain.

Chronic itch, that which lasts for six or more weeks, also troubles people with conditions such as eczema, nerve damage caused by diabetes (diabetic neuropathy), and cancer.

Patients can show extra sensitivity to what’s called mechanical itch — which normally comes from a light brushing or poking against the skin — as well as to persistent spontaneous itch. (Chemical itch, in contrast, is a response to things like an insect bite and linked to activation of the histamine system.)

The underlying neural circuits are not well-defined, and no effective treatments exist.

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Researchers at the University of Michigan investigated in detail the mechanisms behind chronic mechanical itch, looking for possible treatment approaches.

To narrow down which nerve cells (neurons) account for mechanical itch, they individually removed nine distinct groups of spinal neurons from mice.

One, called excitatory interneurons, had high levels of a protein called Urocortin 3 (Ucn3); these neurons were central for the transmission of both acute and persistent mechanical itch.

“Behavioral analysis after the ablations of these neuronal subsets revealed that Ucn3 neurons are the mechanical itch transmission neurons,” Mahar Fatima, PhD, a study co-author, said in a university news release.

Removing the other spinal neuronal groups did not “affect the transmission of mechanical itch,” Fatima added.

According to the team, a mechanical itch starts upon activation of specialized sensory cells found in skin, called Toll-like receptor 5-positive low-threshold mechanoreceptors. These cells react to a light touch, passing the message along to Ucn3 interneurons in the spinal cord.

Researchers also found a third important player, called inhibitory interneurons expressing neuropeptide Y (NPY). These nerve cells control Ucn3 neuronal activity; that is, they control how much skin “tickling” is needed to cause itching. In other words, the researchers said, these inhibitory interneurons are “the gatekeepers” of sensitivity to itch. If they are defective, a person could experience chronic itch.

To confirm that this neuronal circuit was indeed responsible for mechanical itch, the team manipulated mice to either lack Ucn3 neurons or to shut down their activity.

Mice so altered stopped responding to a light tickle behind the ear, even though they still reacted to a chemical that triggers itching. This indicated that the chemical and mechanical itch pathways are separate, and that Ucn3 neurons are solely contributing in the latter pathway, the researchers said.

In each of various experiments, the mice’s ability to sense touch, pain, or thermal sensation were not affected, demonstrating the specific role of these neurons in itching.

Further mice experiments suggested that under chronic itch conditions, NYP interneurons do not work properly, preventing Ucn3 neurons from stopping as they should, and making them more prone to being overactive.

This, the research team said, may explain why patients with chronic itch have heightened sensitivity and a tendency for persistent spontaneous itch. Consistent with this hypothesis, removing Ucn3 neurons from mice prevented mechanical itch sensitization and persistency in the animals.

“Itching is one of the major symptoms in most skin disorders and other neurologic disorders,” Bo Duan, the study’s senior leader, said. “This is one mechanism we needed to understand to develop a new treatment for patients with chronic itch.”