By Morgan Nwanguma
Researchers at USF Health have identified a previously unknown way opioid receptors function, an advance that could pave the way for safer pain medications. Their study shows that certain experimental compounds can enhance pain relief without increasing dangerous side effects such as respiratory depression. The findings provide a new framework for designing opioids that are longer-lasting, more effective, and significantly less risky, while also pointing to potential applications in treating other brain disorders.
Overall, the research marks a major step forward in understanding how novel opioid compounds interact with the body. It is fueling hope that future pain therapies can offer strong relief without the life-threatening complications commonly linked to current opioid drugs.
Their most recent findings were published December 17 in Nature and titled “GTP release-selective agonists prolong opioid analgesic efficacy.” An accompanying study, “Characterization of the GTPγS release function of a G protein-coupled receptor,” was published 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 examine a group of experimental pain-relieving compounds that target mu-opioid receptors – proteins on nerve cells that dampen pain signals when activated by opioids such as morphine. While this mechanism is responsible for powerful pain relief, it also underlies serious side effects. Activation of these receptors can slow breathing, a potentially fatal complication that plays a major role in opioid overdose deaths.
Dr. Bohn and her team are seeking to design compounds that preserve pain relief while avoiding these dangerous effects. Their work uncovers previously unrecognized ways opioid receptors respond when different drugs bind to them.
New Insights Into Receptor Behaviour
Although the research is unlikely to yield a new medication in the immediate future, it represents a significant advance in understanding receptor function. According to Edward Stahl, PhD, assistant professor of Molecular Pharmacology and Physiology at the Morsani College of Medicine and a corresponding author of the NIH-funded study, these insights provide a stronger scientific foundation for developing safer opioid therapies.
“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 their receptors, they set off a cascade of cellular events that produce pain relief but also drive harmful side effects. With prolonged use of drugs such as morphine, oxycodone, and fentanyl, this signaling can lead to tolerance and dangerous suppression of breathing.
The researchers found that the very first step in this signaling pathway can, in fact, run in reverse. Certain experimental compounds seem to favour this backward reaction, altering the signal in a way that may reduce risk while preserving pain relief.
“We’ve found that the first step of the chain reaction is reversible, and that some drugs can favour a reverse reaction over the forward reaction,” Dr. Bohn said. “We’ve studied two new chemicals that strongly favour 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 Finished Drugs
The molecules examined in this research are not yet viable drug candidates. At higher doses, they continue to suppress breathing and have not been evaluated for toxicity or other opioid-related adverse effects. Nonetheless, they offer important insights that can guide the development of safer opioids in the future.
“They do provide the framework for building new drugs,” Dr. Bohn said.
Building on Earlier Breakthroughs
Dr. Bohn’s laboratory earlier identified a compound called SR-17018 that behaves differently from conventional opioids. Unlike drugs such as morphine, oxycodone, or fentanyl, SR-17018 does not suppress breathing or lead to tolerance. Although it targets the same opioid receptor, it binds in a distinct manner that allows the receptor to remain accessible to the body’s own natural pain-relieving molecules.
While SR-17018 also promotes reverse signaling, researchers suggest that additional characteristics of the compound play a role in its enhanced 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 implications of this research may extend well beyond opioid therapies. The findings suggest that other receptors such as the serotonin 1A receptor, might also be capable of signaling in a reverse direction. According to Dr. Bohn, this insight could reshape how drugs are designed across a wider range of neurological conditions.
“this is an important drug target in neuropsychiatric disorders, including depression and psychosis.”
Context within the Opioid Crisis
These findings come at a time when opioid misuse remains a major public health crisis. Recent data indicate that opioids were involved in 68 percent of overdose deaths in 2024, with fentanyl and other synthetic opioids responsible for 88 percent of those fatalities.
Dr. Bohn, a globally respected authority in molecular pharmacology and neurobiology, recently joined USF Health. She is best known for her pioneering work on G protein–coupled receptors (GPCRs), the largest family of drug targets in the human body.
Her laboratory has been instrumental in uncovering how selectively directing opioid receptor signaling can relieve pain without triggering respiratory suppression or tolerance. Together, these advances expand scientific insight into opioid biology and bring researchers closer to safer, non-addictive approaches to pain management.
English