Chronic pain affects about a quarter of Americans, according to the Centers for Disease Control and Prevention. There is a window of time in which acute pain can be treated before it turns into chronic pain. However, once chronicity has set in, treatments are limited to temporary pain relief through non-steroidal anti-inflammatory drugs or opioids. Opioid medications have a risk of addiction, and the latest recommendations suggest patients not use them for more than two weeks, which does not address long-term pain. Most people seek treatment after chronic pain is already established.
Sometimes chronic pain can be anticipated, like during cancer treatment. About 40% of cancer patients develop neuropathic chronic pain due to chemotherapy, according to a National Institutes of Health systematic database review.
“Chronic pain does not always happen, but when it does, physicians may have to lessen chemotherapy doses, and that could cause dire consequences. Chronic pain prevents them from treating the person in the way that is needed,” said Armen Akopian, PhD, professor in the Department of Endodontics at the UT San Antonio School of Dentistry.
A new pathway to prevention
Scientists at The University of Texas at San Antonio (UT San Antonio) are investigating a major immune system pathway that leads to the development of chronic pain and a drug that has the potential to stop the process in its tracks. Their study, published April 22 in Cell Reports, is the first of its kind to show a path toward the prevention of chronic pain.
The project began when Akopian, a neuroscientist studying chronic pain, came to Alexei Tumanov, MD, PhD, associate professor in the Department of Microbiology, Immunology and Molecular Genetics at the Joe R. and Teresa Lozano Long School of Medicine, with some puzzling findings.
Targeting lymphotoxin-beta receptor
The study focuses on an immunologic drug that was developed years ago as a treatment for autoimmune diseases. After early clinical trials, the drug was found to be ineffective for the treatment of rheumatoid arthritis, but scientists believed it might work for the prevention of chronic pain.
The drug blocks a specific cytokine receptor called the lymphotoxin-beta receptor, which triggers a neuroimmune pathway of peripheral sensitization that leads to inflammation and pain.
Tumanov said lymphotoxin, the ligand for the lymphotoxin beta receptor, was discovered several decades ago when it showed some activity against tumor cells, similar to the tumor necrosis factor. While they have similarities in structure and function, lymphotoxin biology is very different.
Animal model studies show that lymphotoxin is a crucial cytokine in the development, organization and maintenance of lymphoid organs. Lymphoid organs are important for generating the immune response and for communication between different cell types.
Connecting the immune system and pain
A few years ago, Akopian noticed unusually high expression of the lymphotoxin beta receptor in sensory neurons and came to Tumanov for his perspective.
“We were puzzled as to why this immune molecule is expressed in sensory neurons since we did not think that was a function of this molecule,” said Akopian.
They considered that, along with its job in the immune system, this molecule also serves to regulate sensory neurons.
“This pathway is important in communication from different cell types, not only the immune system, and that is why it is so powerful in circulating pain responses,” Tumanov said.
The team believes that many downstream genes and transcriptional programs are activated after injury or chemotherapy, amplifying the cascade of secondary mediators responsible for the sensitization of sensory neurons. Therefore, blocking the lymphotoxin-beta receptor, the upstream regulator, may prevent the development of chronic pain.
“There are ‘bosses’ who change the processes of many cells. One of these bosses appears to be the lymphotoxin-beta receptor. If you deal with one of these bosses, you cut off the entire chain that produces the adverse effect of pain. It was a simple idea that proved to be correct,” Akopian said.
Looking ahead
The optimization of the dose and delivery of this drug is crucial, Tumanov said, because a systemic immunological blocker could weaken a person’s immune system, reducing the ability to fight infection or cancer.
Tumanov said since the drug was developed for humans and has undergone preliminary clinical trials, scientists are a few steps closer to preventing chronic pain.
The research team will continue to investigate this pathway and the drug’s effects on other types of chronic pain, such as burns or viral infection-induced pain.
“We found that it is better to be more precise and control certain aspects of the immune process related to this specific molecule than total suppression of inflammation,” Akopian said.
Tumanov AV, Mecklenburg JM, Belugin S, Naratadam GT, Barba-Escobedo PA, Todd AW, Koroleva E, Hovhannisyan AH, Shein SA, Tamada K, Zou Y, Lai Z, Akopian AN. Lymphotoxin-beta receptor controls the development of chronic pain. Cell Rep. 2026 Apr 20;45(4):117269. doi: 10.1016/j.celrep.2026.117269. Epub ahead of print. PMID: 42012978.