Scientists at USF Health have achieved a significant breakthrough in deciphering the intricate mechanisms by which opioid compounds engage with the body to alleviate pain, igniting hope for the development of future analgesics that offer relief without the perilous side effects currently associated with opioid medications. This groundbreaking work, detailed in two pivotal studies published on December 17th, illuminates a previously unappreciated aspect of how opioid receptors function, paving the way for a new generation of pain management therapies.
The research, published in the esteemed journal Nature under the title "GTP release-selective agonists prolong opioid analgesic efficacy," and complemented by a related study titled "Characterization of the GTPĪ³S release function of a G protein-coupled receptor" in Nature Communications, delves into the complex molecular choreography that occurs when pain-relieving drugs interact with their targets. The overarching objective, as articulated by 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, is to comprehensively understand opioid action. This fundamental knowledge, she explained, is the bedrock upon which safer options for chronic pain sufferers and effective treatments for opioid use disorder can be built.
At the heart of this investigation lies the mu-opioid receptor, a crucial protein embedded within nerve cells that plays a central role in modulating pain perception. When activated by opioids such as morphine, these receptors initiate a cascade of events that effectively dampen pain signals transmitted throughout the nervous system. However, this therapeutic benefit is frequently shadowed by a spectrum of severe adverse reactions. Among the most life-threatening is respiratory depression, a dangerous slowing of breathing that underpins a significant proportion of opioid overdose fatalities. Dr. Bohn and her dedicated team are meticulously working to engineer compounds that can deliver potent pain relief while sidestepping these debilitating and potentially lethal consequences. Their recent findings reveal nuanced and previously unrecognized behaviors of opioid receptors when different classes of drugs bind to them, offering fresh perspectives on receptor modulation.
Edward Stahl, PhD, Assistant Professor of Molecular Pharmacology and Physiology at the Morsani College of Medicine and a corresponding author on the study, which benefited from funding from the National Institutes of Health, emphasized the foundational importance of these discoveries. While a new medication is not an immediate outcome of this research, the enhanced scientific understanding of receptor function it provides is substantial. "Our manuscripts describe a unique way that drugs can control receptors," Dr. Stahl stated. "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."
The established understanding of how opioids exert their effects involves activating a sequence of intracellular events that ultimately lead to both pain reduction and the undesirable side effects. The chronic administration of widely used opioids like morphine, oxycodone, and fentanyl is often accompanied by the development of tolerance, where higher doses are required to achieve the same level of pain relief, and the persistent risk of severe respiratory suppression. The USF Health researchers have identified a remarkable phenomenon: the initial step in this complex signaling pathway can, under certain conditions, proceed in a reverse direction. Crucially, they have discovered compounds that appear to preferentially engage this backward reaction rather than propelling 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," Dr. Bohn elaborated. "We’ve studied two new chemicals that strongly favor 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." This observation is particularly significant because it suggests a potential avenue for decoupling the analgesic effects from the respiratory depressant properties of opioids.
It is important to underscore that the newly synthesized molecules under examination are not yet considered viable drug candidates for clinical use. At higher concentrations, they still exhibit the capacity to suppress breathing, and they have not undergone comprehensive testing for toxicity or other opioid-related adverse effects. Nevertheless, these experimental compounds serve as invaluable blueprints for the rational design of future opioid-based therapeutics. "They do provide the framework for building new drugs," Dr. Bohn confirmed, highlighting their role as conceptual stepping stones rather than finished products.
This recent work builds upon earlier pioneering discoveries from Dr. Bohn’s laboratory, including the identification of a compound designated SR-17018. In stark contrast to conventional opioids, SR-17018 has demonstrated an absence of respiratory suppression and tolerance. It interacts with the same mu-opioid receptor targeted by traditional analgesics, but its binding modality differs, allowing the receptor to remain available for engagement by the body’s endogenous pain-modulating substances. While SR-17018 also exhibits a preference for the reverse signaling pathway, the researchers posit that additional molecular features contribute to its superior safety profile. "For this reason," Dr. Bohn stated, "we will be using our new findings to improve upon SR-17018." This iterative approach, where new insights inform the refinement of promising leads, is a hallmark of effective drug discovery.
The implications of this research extend beyond the immediate scope of opioid pain relief, offering potential benefits for the development of therapies targeting a broader range of conditions. The identified mechanisms of reversed receptor signaling could be applicable to other G protein-coupled receptors (GPCRs), which constitute the largest class of drug targets in the human body. For instance, the serotonin 1A receptor, a critical target in neuropsychiatric disorders such as depression and psychosis, might also be activated through a reversed signaling pathway. "This is an important drug target in neuropsychiatric disorders, including depression and psychosis," Dr. Bohn noted, pointing to the wide-ranging potential impact of these fundamental discoveries.
These scientific advancements emerge against the backdrop of a pervasive public health crisis driven by the opioid epidemic. Official statistics reveal that opioids played a role in a staggering 68 percent of all overdose deaths in 2024, with synthetic opioids, including fentanyl, accounting for an alarming 88 percent of these fatalities. Dr. Bohn, an internationally recognized authority in molecular pharmacology and neurobiology, recently joined USF Health and is renowned for her seminal contributions to understanding the intricacies of GPCRs. Her laboratory has been instrumental in demonstrating how selective signaling at opioid receptors can achieve pain relief without inducing respiratory depression or tolerance. These ongoing findings not only deepen the scientific community’s comprehension of opioid biology but also bring the development of safer, non-addictive pain treatments closer to realization.
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