Their latest findings were published December 17 in Nature under the title “GTP release-selective agonists prolong opioid analgesic efficacy.” A companion study, “Characterization of the GTPγS release function of a G protein-coupled receptor,” appeared the same day in Nature Communications.

“Our overarching research aims to understand how opioids work so that we can ultimately provide safer options for chronic pain and develop therapies for opioid use disorders,” said senior author Laura M. Bohn, PhD, senior associate dean for Basic and Translational Research and professor of Molecular Pharmacology and Physiology at the USF Health Morsani College of Medicine.

How Opioids Relieve Pain and Cause Harm

The studies focus on a group of experimental pain-relieving compounds that act on mu opioid receptors. These receptors are proteins found on nerve cells that reduce pain signals when activated by opioids such as morphine.

However, activating these receptors also triggers serious side effects. Drugs like morphine can slow breathing, a dangerous effect that contributes to overdose deaths. Dr. Bohn and her team are working to develop compounds that ease pain without causing these harmful reactions. Their research reveals previously unknown ways opioid receptors behave when different drugs bind to them.

New Insights Into Receptor Behavior

Although the research is not expected to produce a new medication right away, it significantly improves scientific understanding of how receptors function, said Edward Stahl, PhD, assistant professor of Molecular Pharmacology and Physiology at the Morsani College of Medicine and a corresponding author on the study, which received funding from the National Institutes of Health.

“Our manuscripts describe a unique way that drugs can control receptors,” Dr. Stahl said. “Fundamentally, knowing more about how receptors work is the first step in understanding how to drug them and how to drug them safer. If this research is further validated, it would add to our textbook knowledge of how receptors function and, more importantly, to our ability to treat human health and disease.”

Reversing the Opioid Signal

When opioids bind to a receptor, they trigger a sequence of events inside the cell that leads to pain relief and side effects. Long-term use of drugs such as morphine, oxycodone, and fentanyl often results in tolerance and dangerous breathing suppression.

The researchers discovered that the earliest step in this signaling process can move in reverse. Some compounds appear to favor this backward reaction instead of pushing the process forward.

“We’ve found that the first step of the chain reaction is reversible, and that some drugs can favor a reverse reaction over the forward reaction,” Dr. Bohn said. “We’ve studied two new chemicals that strongly favor the reverse cycle and, when administered at non-effective doses, can enhance morphine and fentanyl-induced pain relief while not enhancing the respiratory suppression effects.”

Promising Frameworks, Not Final Drugs

The newly studied molecules are not considered drug candidates. At higher doses, they still suppress breathing and have not undergone testing for toxicity or other opioid-related side effects. Even so, they provide valuable guidance for future drug design.

“They do provide the framework for building new drugs,” Dr. Bohn said.

Building on Earlier Breakthroughs

Dr. Bohn’s laboratory previously identified a compound known as SR-17018. Unlike traditional opioids, SR-17018 does not cause breathing suppression or tolerance. It activates the same opioid receptor targeted by morphine, oxycodone, and fentanyl, but it attaches in a different way that leaves the receptor available for the body’s own natural pain-relieving chemicals.

While SR-17018 also favors the reverse signaling direction, researchers believe other features contribute to its improved safety profile.

“For this reason,” Dr. Bohn said, “we will be using our new findings to improve upon SR-17018.”

Broader Implications Beyond Pain Relief

The research could influence drug development beyond opioids. Other receptors, including the serotonin 1A receptor, may also be activated in a reverse direction. According to Dr. Bohn, “this is an important drug target in neuropsychiatric disorders, including depression and psychosis.”

Context Within the Opioid Crisis

These discoveries arrive amid an ongoing public health emergency linked to opioid misuse. Data show that opioids were involved in 68 percent of overdose deaths in 2024, with fentanyl and other synthetic opioids accounting for 88 percent of those fatalities.

Dr. Bohn, an internationally recognized expert in molecular pharmacology and neurobiology, recently joined USF Health. She is widely known for her groundbreaking research on G protein-coupled receptors (GPCRs), the largest class of drug targets in the human body.

Her lab has played a key role in revealing how selective signaling at opioid receptors can reduce pain without causing breathing suppression or tolerance. These findings deepen scientific understanding of opioid biology and move researchers closer to developing safer, non-addictive pain treatments.