Researchers at the University of South Florida (USF Health) have identified a novel mechanism by which opioid receptors can provide effective pain relief without triggering the most dangerous side effects commonly associated with opioid drugs, such as respiratory suppression and tolerance. The findings represent a significant advance toward the development of safer opioid-based therapies.
Opioids such as morphine, oxycodone, and fentanyl relieve pain by activating μ-opioid receptors in the nervous system. However, this same receptor activation also initiates signaling pathways responsible for life-threatening adverse effects, including slowed breathing, dependence, and overdose. The challenge in opioid pharmacology has been to dissociate analgesia from these harmful outcomes.
The USF Health research team discovered that the earliest step in μ-opioid receptor signaling is reversible. Certain experimental compounds were found to favor a “reverse” signaling process rather than the conventional forward pathway. When administered at sub-effective doses, these compounds enhanced the analgesic effects of standard opioids without intensifying respiratory depression.
The study, published in Nature, demonstrates that selective activation of GTP release at the receptor level can prolong pain relief while avoiding signaling events linked to toxicity. A complementary study published in Nature Communications further characterized this reverse signaling function in G protein-coupled receptors, expanding the broader understanding of receptor pharmacology.
Although the newly identified compounds are not yet suitable as clinical drugs and have not undergone toxicity testing, they provide a critical framework for rational drug design. At higher doses, these compounds still suppress breathing, indicating that further refinement is necessary. Nevertheless, the findings reveal previously unknown receptor behaviors that can be exploited to improve opioid safety.
The research builds on earlier work involving the compound SR-17018, which activates μ-opioid receptors without causing respiratory suppression or tolerance in preclinical models. Unlike traditional opioids, SR-17018 binds in a way that preserves receptor responsiveness to the body’s natural pain-relieving molecules, contributing to its improved safety profile.
Beyond pain management, the discovery has implications for other neurological and psychiatric conditions. Similar reverse signaling mechanisms may operate in receptors involved in depression and psychosis, suggesting broader applications in neuropharmacology.
These findings emerge amid an ongoing opioid crisis, in which synthetic opioids continue to drive the majority of overdose-related deaths worldwide. By redefining how opioid receptors can be controlled at the molecular level, this research offers a promising direction for the development of longer-lasting, more effective, and significantly safer pain treatments.