Researchers at USF Health report evidence that an early step in mu opioid receptor signaling can run in reverse, and that certain experimental compounds can enhance morphine- and fentanyl-driven pain relief in lab tests without increasing respiratory suppression at very low doses. The findings, published Dec. 17 in Nature and Nature Communications, are framed as a blueprint for designing longer-lasting opioids with fewer risks, though the newly tested molecules are not considered clinical drug candidates.
At the University of South Florida’s (USF) Health Morsani College of Medicine, a team led by Laura M. Bohn, PhD, is investigating how mu opioid receptors—proteins on nerve cells targeted by opioids such as morphine—produce both pain relief and dangerous side effects.
Two related papers published Dec. 17—one in Nature (“GTP release-selective agonists prolong opioid analgesic efficacy”) and a companion study in Nature Communications (“Characterization of the GTPγS release function of a G protein-coupled receptor”)—describe evidence that the earliest step in the receptor’s internal signaling can proceed in reverse. Bohn said the group identified experimental chemicals that strongly favor this reverse direction and, when administered at “non-effective” (very low) doses, can enhance morphine- and fentanyl-induced pain relief without enhancing respiratory suppression.
Edward Stahl, PhD, an assistant professor at the Morsani College of Medicine and a corresponding author on the work, said the studies add to basic understanding of how drugs can control receptors and could eventually support efforts to design safer medicines. The research reported in the university release was supported by the National Institutes of Health.
USF Health also noted that Bohn’s laboratory previously identified an experimental compound called SR-17018, which the university says does not cause breathing suppression or tolerance in the work it cited and binds to the same receptor targeted by commonly used opioids, but in a different way. The new findings, Bohn said, are expected to be used to improve upon SR-17018.
The newly studied molecules described in the Dec. 17 publications are not being presented as finished drug candidates. USF Health said that at higher doses they still suppress breathing and have not been tested for toxicity or other opioid-related side effects, but may still provide a framework for future drug design.
Beyond pain treatment, the researchers said the same reverse-direction signaling concept could have implications for other receptors, including the serotonin 1A receptor, a drug target implicated in neuropsychiatric disorders such as depression and psychosis.
The work was reported against the backdrop of the U.S. overdose crisis. A USF Health release cited data stating opioids were involved in 68% of overdose deaths in 2024 and that fentanyl and other synthetic opioids accounted for 88% of those opioid-related fatalities; public reporting based on provisional CDC estimates has also described a sharp decline in total U.S. overdose deaths in 2024 compared with 2023, while noting that synthetic opioids—particularly fentanyl—remain a leading driver of overdose mortality.
