Researchers Identify Potentially Safer Approach to Opioid Drug Development

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Opioids are powerful pain relievers, but their use is hampered as patients become tolerant of them, requiring higher and higher doses, and overdoses can cause respiratory depression and death. A recent study by researchers at the UC Davis Center for Neuroscience contradicts existing thinking about how opioid drugs cause respiratory tolerance and depression, and suggests a new balanced approach to developing safer pain relievers. The work is published in Neuropsychopharmacology.

“The holy grail of opioid research is to determine the ideal properties of an opioid pain reliever to maximize pain relief while reducing unwanted side effects,” said Jennifer Whistler, lead author and professor. of Physiology and Membrane Biology at UC Davis School. of Medicine. “This goal has become even more urgent in light of the devastation wrought by opioid overdose crises and the inability to identify other non-opioid targets for the treatment of severe and persistent pain.”

Whistler, who is associate director of the UC Davis Center for Neuroscience, has been researching the neurobiology of addiction disorders and their co-morbidities and how to make opioids safer for more than 20 years.

Search for new opioids with fewer side effects

Opioid drugs work by connecting to the mu opioid receptor (MOR) on cells. This receptor in turn signals through the G protein and can also engage a protein called arrest-3. The prevailing view has been that the engagement of the mu opioid receptor with arrestin-3 is responsible for the two side effects limiting opioid treatment: respiratory depressive effects which cause death from overdose and the development of analgesic tolerance. which leads to an escalation of the dose and an increase in the dose. risk of addiction and death from overdose.

This doctrine has led to a highly visible search of nearly two decades for new “ultra-G protein” opioids that powerfully activate G protein but do not engage arrestins.

It has also led to the investment of millions of dollars in the clinical development of these new “ultra-biased” opioids, including the recently approved FDA-approved Oliceridine, which Whistler says will have a higher responsibility for producing a drug. tolerance and addiction than our existing opioid therapies. .

“Contrary to the prevailing hypothesis, we have found that engaging arrestin-3 prevents tolerance to pain relievers and does not exacerbate respiratory depression,” said Whistler. “We have used a powerful combination of genetic and pharmacological approaches to demonstrate this point.”

The Whistler Lab team challenged the dominant 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. With this genetic and pharmacological approach, they have shown that the recruitment of arrestin-3 does not promote respiratory depression and that effective engagement of arrestin-3 reduces, rather than exacerbates, the development of analgesic tolerance. .

New approach to develop opioid drugs

Whistler’s data suggests an entirely new approach to the development of opioid therapies.

“Specifically, we are proposing a shift in effort to develop ‘balanced’ opioid pain relievers that strongly promote arrestin-3 engagement, much like our endogenous endorphins do,” Whistler said. “Given both the pressing need for new pain relievers 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 those “balanced” opioid ligands that recruit both G protein and arrestin-3, thus mimicking the signaling profile of most. endogenous mu-opioid receptor agonists.

“There is a plethora of biased agonists, including all the opioids we take for pain. We can’t know whether a balanced approach will lead to safer opioids, until we have a library of such molecules to test, ”Whistler said.

Republished courtesy of UC Davis.


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