New nerve protein target to treat chronic itch
Chronic itch or pruritus is the most common symptom in dermatology yet less than 50% of patients will respond to treatment. Much like chronic pain, pruritus is detrimental to patient well-being.
Researchers led by Professor Martin Steinhoff, Director of UCD Charles Institute of Dermatology and director of the dermatology clinic at St. Vincent’s University Hospital have identified a potential target to treat itch in patients who do not respond to anti-histamine drugs.
Itch can be triggered by external stimuli such as allergens, animals, plants, toxins or medication, or due to inflammation, tumour growth, autoimmune disease, liver or kidney dysfunction, for example. These stimuli cause the release of chemical mediators that transmit signals along nerve fibres to the central nervous system (brain and spinal cord), manifesting as itch and prompting uncontrolled scratching behaviour. Chronic itching and scratching leads to a vicious cycle of recalcitrant itch.
Although scientists acknowledge that itch-selective nerve fibres exist in the sensory nervous system, very little is known about the neuronal regulatory circuits and the signalling pathways of itch in the peripheral and central nervous system.
The group of researchers working with Professor Martin Steinhoff to unravel how the itch sensation arises in the body at a molecular level have focused on a protein called endothelin-1 (ET-1). ET-1 is found on a variety of nerve cells like neurons and glial cells. The protein can cause blood vessels to constrict and also trigger pain sensations. If ET-1 works with its corresponding receptor protein, endothelin-A receptor (ETAR), it causes itch. ET-1 is one of the most potent itch inducers in humans; however, its role in itch in the context of the human disease state was unknown until now.
In this study, the Steinhoff group used molecular biology and imaging techniques to identify a key regulator in this itch signalling pathway. The regulator is an enzyme known as endothelin-converting enzyme 1 (ECE-1). It prevents the receptor protein travelling through the cell, terminates the effects of endothelin and consequently stops the feeling of itch. In demonstrating this, the group have also revealed the first endogenous anti-pruritic regulatory circuit of the skin.
Professor Steinhoff explains, “Our results indicate for the first time that the neural peptidase, ECE-1 directly regulates ET-1-induced, histamine-independent pruritus in humans and mice. It implicates this signalling pathway as an important target to treat pruritus particularly for those patients that do not respond to anti-histamine therapy.”
Kido-Nakahara, M et al. Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus. J Clin Invest. doi:10.1172/JCI67323