Researchers Identify Potentially Safer Approach To Opioid Drug Development

WASHINGTON — Opioids are powerful painkillers, but their use is hindered because patients become tolerant of them, requiring higher doses, and it can cause respiratory depression and death.

In their recent study, researchers at the UC Davis Center for Neuroscience contradict current thinking about how opioid drugs cause tolerance and respiratory depression and suggest a new, balanced approach to developing safer analgesics.

It was published in the journal Neuropsychopharmacology.

“The holy grail of opioid research is to determine the ideal properties of an opioid analgesic for maximizing pain relief while reducing the adverse side effects,” said Jennifer Whistler, senior author on the paper and professor of physiology and membrane biology in the UC Davis School of Medicine.

“This goal has become even more urgent in light of the devastation wreaked by the opioid overdose crises and the failure to identify other non-opioid targets for the treatment of severe and persistent pain.”

Whistler has been researching the neurobiology of addictive disorders and their comorbidities and how to make safer opioids for more than 20 years.

Opioid drugs work by connecting to the mu-opioid receptor (MOR) on cells. This receptor, in turn, signals through G-protein and can also engage a protein called arrestin-3.

The prevailing view has been that engagement of the mu-opioid receptor with arrestin-3 is responsible for the two treatment-limiting side effects of opioids.

The effects ate that the respiratory depressive effects that cause overdose death and the development of analgesic tolerance that leads to dose escalation and increased risk of addiction and overdose death.

This doctrine has led to an almost two-decades-long, evident search for new “ultra G protein biased” opioids that potently activate G protein but do not engage arrestins.

It has also led to the investment of millions of dollars into the clinical development of these new “ultra-biased” opioids. This includes the Food and Drug Administration-approved Oliceridine, which Whistler predicts will have a higher liability to produce tolerance and addiction than our existing opioid therapeutics.

“Contrary to the prevailing hypothesis, we have found that arrestin-3 engagement prevents analgesic tolerance and does not exacerbate respiratory depression,” said Whistler.

“We used a powerful combination of genetic and pharmacological approaches to demonstrate this point.”

The Whistler Lab team challenged the prevailing hypothesis with a panel of six clinically relevant opioid drugs and mice of three distinct genotypes with varying abilities to promote morphine-mediated arrestin-3 engagement.

This genetic and pharmacological approach showed that arrestin-3 recruitment does not promote respiratory depression and that effective arrestin-3 engagement reduced, rather than exacerbated, the development of analgesic tolerance.

Whistler’s data suggest an entirely new approach to the development of opioid therapeutics.

“Specifically, we propose a shift in the effort to develop “balanced” opioid analgesics that strongly promote arrestin-3 engagement, much like our endogenous endorphins do,” said Whistler.

“In light of both the pressing need for new analgesics and the paradigm-shifting nature of our findings, we believe the time has come to try this new approach.”

These studies suggest that future development of safer opioids should focus on identifying such “balanced” opioid ligands that recruit both G protein and arrestin-3, thereby mimicking the signaling profile of most endogenous mu-opioid receptor agonists.

“There are a plethora of biased agonists, including all the opioids we take for pain,” Whistler said.

“We cannot know whether a balanced approach will lead to safer opioids until we have a library of such molecules to test.”

Additional authors on the study are Li He, Sarah W Gooding, Elinor Lewis, Lindsey C. Felth, Anirudh Gaur, all at UC Davis. The work was partly supported by grants from the National Institutes of Drug AbuseNational Institute of Mental Health (both parts of the National Institutes of Health).

The UC Davis Center for Neuroscience is an interdisciplinary research center dedicated to understanding brain function in health and illness.

Teams of internationally recognized scientists lead research programs on a wide range of topics at all brain development, operation, and dysfunction levels.

(With inputs from ANI)

Edited by Saptak Datta and Ritaban Misra



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