UAB researchers share a discovery that could pave the way for non‑addictive alternatives to opioid painkillers amid an era of rising overdose deaths.A protein naturally made in the body reduces inflammation and pain after surgery, according to a new preclinical study from investigators at the University of Alabama at Birmingham. Published in Inflammation Research, the report is the first to show a link between the protein, called tristetraprolin, or TTP, and pain relief. The work could lead to the development of alternatives to highly addictive opioids by increasing the levels of TTP or its activity to alleviate pain due to inflammation.
When experiencing pain after surgery, patients are often prescribed powerful opioid pain relievers. These medications are addictive, and patients who have never abused drugs can become dependent on them. In fact, opioid overdoses were responsible for more than 80,000 deaths in 2023 in the United States, according to the U.S. Centers for Disease Control and Prevention.
“The findings from our study revealed that post-surgical pain can be treated by a non-opioid approach and avoid complications related to opioid usage,” said the study’s senior author, Peter King, M.D., professor and vice chair of the Department of Neurology at UAB. He is also affiliated with the Birmingham Veterans Affairs Medical Center, as well as the UAB Killion Center for Neurodegeneration and Experimental Therapeutics and the UAB Department of Cell, Developmental and Integrative Biology.
Balancing act
Surgical procedures can be challenging for the body. Patients often wake up feeling as though they have been in battle, with swelling and pain that can linger for days. Within minutes of an incision, immune cells secrete inflammatory mediators at the surgical site and in the nervous system, triggering inflammation. This response promotes post-surgical pain and can persist beyond a year in up to 30 percent of patients.
The duration of inflammation at the injury site and in the nervous system depends on signals within the immune cells that turn on or shut off production of inflammatory mediators. Two key proteins involved in this signaling, TTP and HuR, regulate the levels of inflammatory mediators by binding to adenine- and uridine-rich elements, or AREs, in their mRNAs.
HuR and TTP binding have opposite effects, and because they bind the same sequence, it is a competition. When the balance tips toward more HuR protein, mRNAs are protected from degradation, more inflammatory proteins are made and inflammation persists. But when more TTP is present and bound to AREs, the mRNAs are degraded, inflammatory proteins are not made and inflammation resolves.
In previous research, King’s team showed that blocking HuR binding reduces inflammation and pain in animal models of many types of neurological injuries. For the current work, his team wanted to see whether the opposite would happen in a TTP knock-out mouse in which immune cells cannot make the protein.
Without TTP, mice with a post-surgical injury were hypersensitive to pain, experienced more swelling and had delayed healing at the injury site than controls. They also had significantly elevated levels of inflammatory mediators, including two that are directly associated with pain. Similar effects were observed far away from the surgical site in the spinal cord and in nerves close to the spinal cord that also contribute to pain. Boosting TTP expression in a different mouse model improved recovery — these mice had significantly less pain and lower levels of inflammatory mediators than controls.
Helping patients
As a medical doctor, King’s goal is to develop therapeutics based on his laboratory research. “One of the goals we have in the next few years is to find small molecules that can directly and specifically increase the expression of TTP or enhance its activity,” King said. His team will also look at TTP activity in animal models of spinal cord injury, traumatic brain injury and stroke, conditions in which inflammation plays a major destructive role early on.
In the meantime, the team already has developed a small molecule inhibitor of HuR that has shown positive results in models of peripheral nerve injury and spinal cord injury. In preclinical models, this inhibitor enters the brain and spinal cord within minutes, making it suitable for rapid delivery by emergency medical technicians. Because inflammation is quickly triggered after spinal cord injury, secondary tissue injury begins immediately. “Time is spine, and arresting the inflammatory response near the onset will improve functional outcomes, including reduced chronic pain,” King said. The team is currently optimizing this drug in preparation for future clinical trials in humans.
The Inflammation Research study, “Myeloid-specific tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses,” was led by corresponding authors King and Abhishek Guha, UAB Department of Neurology.
Co-authors are Robert Sorge, Stacie Totsch and Ava Piper, UAB Department of Psychology in the College of Arts and Sciences; Ying Si, Reed Smith and Mohammed Amir Husain, UAB Department of Neurology, Birmingham Veterans Affairs Medical Center, and UAB Killion Center for Neurodegeneration and Experimental Therapeutics; Sohail Baig, Department of Neurology; and Perry Blackshear, National Institute of Environmental Health Sciences and Duke University.