A New Understanding of Itch

Everyone deals with itch at some point. Usually, it’s relatively minor, such as a mosquito bite, a brush with poison oak, or chicken pox. These are acute itch — uncomfortable, yes, but soon a distant memory. However, itch has a much darker side — the chronic variety. Chronic itch can last for months or years, generate infections, and even rewire the brain. Also, chronic itch may follow different signaling pathways than acute itch. In other words, we may be treating it all wrong.

A woman examining her shoulder itch
Examining biological pathways that govern itch may result in a new generation of therapies.

“Chronic itch affects our sleep because it often happens at night,” said Gil Yosipovitch, M.D., professor of dermatology and director of the Miami Itch Center at the University of Miami Miller School of Medicine. “It affects relationships and can cause depression. It’s comparable to chronic pain.”

Dr. Yosipovitch has been studying itch for years. In two recent articles, he and colleagues examined the biological pathways that govern itch and a new generation of therapies that could provide relief.

The first article, published online November 5 in the Journal of Investigative Dermatology, examines itch signaling in scabies patients and a pig model. Scabies, which affects nearly 150 million people around the world each year, is caused by small mites and generates an itchy rash that is extremely contagious. Naturally, patients scratch, which can lead to open sores and systemic infections.

For years, clinicians have prescribed antihistamines to address the itch, but this treatment has had limited success. Now, Dr. Yosipovitch, French researcher Olivier Chosidow, M.D., Ph.D., and their colleagues have shown that the itch signals associated with scabies follow an entirely different pathway — a non-histaminergic pathway mediated by tryptase, a serine protease enzyme that stimulates protease-activated receptor 2 (PAR2). Other important itch receptors they found to be highly associated with scabies itch were ion channel protein receptors TRPV1 and TRPA1. Coincidentally, these receptors also react to chili peppers (TRPV1) and wasabi (TRPA1).

“The data suggests we have been treating these patients incorrectly,” Dr. Yosipovitch said. “This opens a new area to explore how itch is mediated in scabies and other parasitic diseases, which can help us develop better treatments.”

In another important article, published in the November issue of the Journal of Allergy and Clinical Immunology, Dr. Yosipovitch, research fellow Takashi Hashimoto, M.D., Ph.D., and medical student Jordan Rosen take a deep dive into itch-generating signals, from the skin to the brain, and potential treatments in the pipeline.

The review discusses the two types of itch neurons — histaminergic and nonhistaminergic. Going after nonhistaminergic targets could help millions of people suffering from chronic itch, as this pathway is relevant to the majority of chronic itch types; acute itch is more associated with histamine.

“These findings could impact treatment in the majority of skin diseases and have implications in underlying systemic diseases, such as end-stage renal failure,” Dr. Yosipovitch said. “Itch is also common in liver disease and for patients with lymphomas and leukemias. The list goes on and on.”

The review also illuminated how reflexively scratching stimulates reward centers in the brain, giving it an addictive quality. Even when patients want to stop scratching, they can’t. Also, nerves can become over-sensitized, generating itch signals even when there are no itch stimuli.

Understanding how itch signals are transmitted is giving researchers and drug developers new targets, and new drugs are being developed to help chronic itch patients. Neurokinin 1 inhibitors target receptors for substance P that are involved in itch, as well as kappa opioids, which inhibit itch without the addictive properties of classical mu opioids that are currently of major public concern. Other new classes of drugs inhibit itch via immune pathways involving cytokines such as interleukin 31, interleukin 4 and 13, interleukin 17, and JAK STAT inhibitors. Drugs targeting the non-histaminergic pathway would be especially significant for treating scabies itch.

“There is new hope,” Dr. Yosipovitch said. “Chronic itch is becoming a legitimate target for many drug companies. There is a lot of information about multiple targets in the skin, neural system, and even the brain that could reduce itch.”

Tags: itch, Journal of Allergy and Clinical Immunology, Journal of Investigative Dermatology, Miami Itch Center