Researchers from USF Health have made significant progress in understanding how new opioid compounds interact with the body to relieve pain. Their studies offer hope that, in the future, painkillers could effectively manage pain without the life-threatening side effects typical of current opioids.

New Discoveries in Opioid Mechanisms

Recent findings were published on December 17 in the journal Nature under the title “GTP release-selective agonists prolong opioid analgesic efficacy.” At the same time, a related study on the functions of G protein-coupled receptors appeared in Nature Communications. According to Dr. Laura M. Bohn, Professor of Molecular Pharmacology and Physiology, the main goal of the team is to understand how opioids work in order to develop safer treatments for chronic pain and therapies for opioid use disorders in the future.

Focus on Mu-Opioid Receptors

The research centers on experimental pain-relieving compounds that target mu-opioid receptors—proteins on nerve cells that, when activated by opioids like morphine, reduce pain signals. However, activating these receptors can also cause serious side effects, including respiratory depression, which can lead to fatal overdoses. Dr. Bohn’s team is working to create compounds that relieve pain without such negative reactions, uncovering previously unknown behaviors of opioid receptors when interacting with different drugs.

Prospects for Developing Safer Painkillers

While these studies may not immediately lead to new medications, they greatly expand scientific understanding of how receptors function. As Associate Professor Edward Stahl notes, the more is known about receptor mechanisms, the closer scientists get to developing safer ways to target them. If these results are confirmed, they could improve medicine’s ability to treat a variety of conditions.

Reversibility of Signaling Processes

When opioids bind to their receptors, they trigger a cascade of events inside the cell that can result in both pain relief and side effects. Prolonged use of drugs like morphine, oxycodone, and fentanyl often leads to tolerance and dangerous respiratory depression. Researchers have discovered that the earliest stage of this signaling process can be reversible. Some compounds promote a reverse reaction rather than pushing the process forward. Dr. Bohn notes that two new chemical compounds, which favor this reverse cycle, can enhance the pain-relieving effects of morphine and fentanyl at sub-effective doses without increasing respiratory depression.

Limitations and Future Directions

Currently, the studied molecules are not considered drug candidates: at high doses, they still suppress breathing and have not undergone toxicity or side effect testing. Nevertheless, they provide a valuable foundation for future drug development.

Previously, Dr. Bohn’s lab identified the compound SR-17018, which, unlike traditional opioids, does not cause respiratory depression or tolerance. It activates the same opioid receptor as morphine, oxycodone, and fentanyl, but binds differently, leaving the receptor accessible to the body’s own pain-relieving substances. Researchers believe that additional properties of SR-17018 also contribute to its improved safety profile, and they plan to use new data to further refine it.

Significance for Medicine and Society

These discoveries could influence not only the development of opioid drugs but also medications for other purposes. For example, the serotonin 1A receptor, important in treating neuropsychiatric disorders, can also be activated in a reverse direction.

This research is especially relevant amid the ongoing crisis of opioid misuse. In 2024, opioids were involved in 68% of overdose deaths, with fentanyl and other synthetic opioids accounting for 88% of those cases.

Dr. Bohn’s laboratory has played a key role in revealing how selective signal transmission through opioid receptors can relieve pain without causing respiratory depression or tolerance. These findings deepen our understanding of opioid biology and bring scientists closer to creating safer, non-addictive painkillers.