Pain neurons protect nerve health and offer new therapeutic targets
Researchers at Karolinska Institutet, have uncovered a previously unknown mechanism that helps pain sensing nerve cells stay healthy and respond to injury. The findings, published in Nature Communications, may improve understanding of chronic pain and nerve damage and maintenance of myelin integrity.
A new study shows that a molecule called RNase4, is produced by specialised pain-sensing neurons. It plays a key role in maintaining their normal function and influences both these neurons and the structure of nearby nerve fibers, positioning pain-sensing neurons not only as sensory transducers but also as sentinels of nerve integrity.
The researchers showed that RNase4 is expressed in unmyelinated sensory neurons, including neurons that innervate the auditory organ, and in the pain-sensing neurons that innervate the face, head, dura mater, and the rest of the body. By combining multiple experimental approaches on mice, they demonstrated that loss of RNase4 alters mechanical pain responses and disrupts the myelin structure surrounding neighboring nerve fibers. They also found that RNase4 levels increase after nerve injury, both during the pain phase and the subsequent recovery period.
“Our results point to RNase4 as part of a regulatory pathway that supports nerve integrity. This molecule has not previously been linked to pain sensing neurons, so its presence and role came as a surprise,” says corresponding author Saida Hadjab, head of the Neurobiology of pain & Therapeutics laboratory at the Department of Neuroscience.
Chronic pain is often difficult to treat, partly because the underlying biology is still not fully understood. The findings suggest that pain sensing neurons may take on a more active role in maintaining the health of surrounding nerve tissue.
“This work has enabled us to identify a novel mechanism and position RNase4 as a regulator of afferent neuron integrity and local microenvironment. The localisation of RNase4 and its function in sensory neurons made it directly relevant to hearing dysfunction, headache, and chronic pain,” says Saida Hadjab.
RNase4 shows a comparable expression pattern in human pain-sensing neurons, supporting its potential relevance in humans. While further research is required to develop therapies targeting the RNase4 pathway, these findings provide a strong foundation for advancing the study of myelin integrity and long-lasting pain in humans.See the study for funding and any reported conflicts of interest.
Publication
Ribonuclease 4 Functions in Nociceptor-Mediated Nerve Homeostasis, Xiaona Feng, Kaiwen Zhang, Prach Techameena, Rolen M. Quadros, Csaba Adori, Aliia Murtazina, Igor Adameyko, Sofia Biagini, Ozun Gokce Bayramlik, Francois Lallemend, Channabasavaiah B. Gurumurthy, Saida Hadjab, Nature Communications, online 24 March 2026, doi: 10.1038/s41467-026-70365-8