Researchers at USF Health have made a significant discovery, identifying a novel mechanism by which opioid receptors can be manipulated to amplify pain relief without intensifying dangerous side effects like respiratory suppression. Published in Nature, this breakthrough on January 6, 2026, offers a promising framework for developing safer opioid pain relief medications, potentially transforming chronic pain management and reducing overdose risks.
The ongoing opioid crisis underscores an urgent need for effective pain treatments devoid of life-threatening side effects, particularly respiratory depression. Traditional opioids, while potent analgesics, carry a heavy burden of addiction and overdose fatalities, prompting scientists worldwide to seek alternatives. This new understanding of opioid receptor behavior represents a critical step toward achieving that goal.
According to ScienceDaily, the USF Health team’s work, led by senior author Laura M. Bohn, PhD, focuses on understanding how new opioid compounds interact with the body.
Their findings, detailed in a study published in Nature, raise optimism that future pain medications could deliver relief without the severe risks associated with current opioids like morphine and fentanyl.
A new blueprint for safer opioid pain relief
Opioid receptors, proteins on nerve cells, are crucial for pain signal reduction. However, their activation by conventional opioids also triggers detrimental side effects, most notably the slowing of breathing that often leads to overdose deaths. Dr. Bohn’s team is dedicated to designing compounds that alleviate pain while circumventing these harmful reactions.
Their research illuminates previously unknown ways these receptors behave when different drugs bind to them. Edward Stahl, PhD, assistant professor at USF Health and a corresponding author, emphasized that while not immediately yielding a new drug, this work significantly enhances the scientific community’s understanding of receptor function.
He stated, “Fundamentally, knowing more about how receptors work is the first step in understanding how to drug them and how to drug them safer.”
The studies, supported by funding from the National Institutes of Health (NIH), concentrated on experimental pain-relieving compounds acting on mu opioid receptors. These compounds reveal a unique control mechanism over receptors, adding to the foundational knowledge of pharmacology and potentially improving human health treatments.
Reversing the opioid signal for safety
When opioids engage a receptor, they initiate a cascade of intracellular events that result in both pain relief and unwanted side effects. Long-term use of drugs such as oxycodone and fentanyl frequently leads to increased tolerance and dangerous respiratory suppression.
The USF Health researchers uncovered that the initial stage of this signaling sequence can actually operate in reverse.
Dr. Bohn explained that some experimental compounds appear to favor this backward reaction rather than 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,” she noted. Two new chemicals were identified that strongly promote this reverse cycle.
Crucially, when these novel chemicals were administered at non-effective doses, they could enhance the pain relief induced by morphine and fentanyl without exacerbating their respiratory suppression effects. This mechanism offers a groundbreaking approach to developing safer opioid pain relief strategies.
While these newly studied molecules are not yet drug candidates—as they still suppress breathing at higher doses and lack toxicity testing—they provide an invaluable framework for future drug development. Dr. Bohn confirms, “They do provide the framework for building new drugs.”
This builds upon earlier work by Dr. Bohn’s lab, which identified SR-17018, a compound that avoids breathing suppression and tolerance by uniquely interacting with the mu opioid receptor.
This research marks a pivotal moment in pain management, moving beyond the traditional understanding of opioid action. By unveiling a safer way for opioids to relieve pain, scientists are paving the way for a new generation of analgesics that could significantly reduce the societal burden of chronic pain and opioid-related fatalities, offering hope for millions.
