A Safer Opioid Alternative: New Drug Offers Pain Relief Without Dangerous Side Effects

UF scientists have developed a compound that safely activates delta opioid receptors, offering pain relief without opioid-like side effects.

University of Florida researchers have helped identify a new drug compound that selectively activates pain-regulating receptors in the body, potentially offering a safer alternative to traditional pain medications.

In a study published in Nature Communications and funded by the National Institutes of Health, the team describes how the compound delivers pain relief without the severe side effects often linked to opioid drugs, such as respiratory depression and addiction.

The body uses three types of opioid receptors—mu, delta, and kappa—to manage pain signals, functioning like traffic control systems on a busy highway. Most current pain medications target the mu receptor, which can block pain effectively but often comes with serious risks.

In contrast, the UF scientists are exploring the delta opioid receptor as a promising alternative. By selectively activating this receptor, the new compound may provide effective pain relief while minimizing the dangers associated with conventional opioids.

Promise of Delta Receptors

“Delta receptors are located throughout the body on pathways and neurons that transmit pain signals to the brain,” said Jay McLaughlin, Ph.D., a professor of pharmacodynamics in the UF College of Pharmacy. “Unlike mu receptors, activating delta receptors does not cause respiratory depression. If we can develop drugs that safely target the delta receptor, we might achieve effective pain relief without the lethal concerns.”

The need for safer pain treatments is urgent. According to the Centers for Disease Control and Prevention, nearly a fourth of U.S. adults experienced chronic pain in 2023, with almost one in 10 suffering from pain severe enough to limit daily activities. Studies estimate that the economic burden of chronic pain exceeds $600 billion annually.

“Chronic pain is an ongoing problem that significantly impacts quality of life,” McLaughlin said. “With an aging population, it’s urgent that we identify new pain therapies that minimize harmful side effects.”

Collaborative Research and Breakthrough

For the past three years, a team of scientists at UF, Washington University in St. Louis and the University of Southern California has been studying how opioid receptors work and applying those insights to develop better and safer pain medications.

The main problem with delta receptors has been the potential for seizures, which has stopped these treatments from being widely used. The research team found a way around this by modifying an existing drug to target a specific area of the delta receptor, giving it the ability to provide pain relief without the harmful effects of traditional opioids.

“Applying new insights into receptor function, our novel compound demonstrated pain-relieving effects in mouse models without major opioid-related side effects like respiratory depression,” McLaughlin said. “This is a significant advance in science, because if we can design safer medications using this approach, it could extend beyond pain relief to treating heart disease, blood pressure, and other conditions regulated by receptors with similar functional features.”

McLaughlin emphasized that additional research and clinical trials are needed to validate the safety and effectiveness of targeting delta opioid receptors for treating pain.

Reference: “Structure-guided design of partial agonists at an opioid receptor” by Balazs R. Varga, Sarah M. Bernhard, Amal El Daibani, Saheem A. Zaidi, Jordy H. Lam, Jhoan Aguilar, Kevin Appourchaux, Antonina L. Nazarova, Alexa Kouvelis, Ryosuke Shinouchi, Haylee R. Hammond, Shainnel O. Eans, Violetta Weinreb, Elyssa B. Margolis, Jonathan F. Fay, Xi-Ping Huang, Amynah Pradhan, Vsevolod Katritch, Jay P. McLaughlin, Susruta Majumdar and Tao Che, 13 March 2025, Nature Communications.
DOI: 10.1038/s41467-025-57734-5