Study proposes a novel approach for developing safer analgesics

Opioids are potent painkillers; however, their use is hampered as patients become tolerant to them, necessitating more and more doses. Overdoses result in respiratory depression and death.

Painkillers

Painkillers. Image Credit: FotoMirta/Shutterstock.com

Recent research by scientists from the UC Davis Center for Neuroscience contravenes existing opinions on how opioid drugs induce tolerance and respiratory depression. The study also proposes a novel, balanced approach in creating safer analgesics. The research was published on July 13th, 2021, 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. 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.”

Jennifer Whistler, Study Senior Author and Professor, Physiology and Membrane Biology, UC Davis School of Medicine

Whistler is the associate director of the UC Davis Center for Neuroscience and has been exploring the neurobiology of addictive disorders and their comorbidities and means to create safer opioids for over two decades.

Searching for new opioids with fewer side effects

Opioid drugs operate by linking to the mu-opioid receptor (MOR) on cells. This receptor signals through G-protein and also engages a protein named arrestin-3.

The present view is that the engagement of the mu-opioid receptor with arrestin-3 is accountable for the two treatment-limiting side effects of opioids—the respiratory depressive effects that result in overdose death and the progress of analgesic tolerance that drives to dose escalation and heightened risk of addiction and overdose death.

This belief directed to an almost 20-year-long, highly visible hunt for new “ultra G protein biased” opioids that vigorously activate G protein without engaging arrestins.

This also directed to the investment of millions of dollars into the clinical development of these new “ultra-biased” opioids, along with newly FDA-approved Oliceridine, which Whistler anticipates will have a greater liability to develop tolerance and addiction than the present opioid therapeutics.

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

Jennifer Whistler, Study Senior Author and Professor, Physiology and Membrane Biology, UC Davis School of Medicine

Researchers from the Whistler Lab challenged the existing hypothesis with a panel of six clinically appropriate opioid drugs and mice of three distinct genotypes with diverse abilities to encourage morphine-mediated arrestin-3 engagement.

The researchers, in light of this genetic and pharmacological approach, demonstrated that arrestin-3 recruitment does not support respiratory depression and that effective arrestin-3 engagement lessened, rather than aggravated, the formation of analgesic tolerance.

New approach to developing opioid drugs

Whistler’s data indicates a completely new method for the advancement of opioid therapeutics.

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

Jennifer Whistler, Study Senior Author and Professor, Physiology and Membrane Biology, UC Davis School of Medicine

These research works propose that future advancement of safer opioids must concentrate on determining such “balanced” opioid ligands that engage both G protein and arrestin-3, to mirror the signaling profile of a majority of the endogenous mu-opioid receptor agonists.

There are a plethora of biased agonists, including all the opioids we take for pain. We cannot know whether a balanced approach will lead to safer opioids until we have a library of such molecules to test,” concluded Whistler.

Source:
Journal reference:

He, L., et al. (2021) Pharmacological and genetic manipulations at the µ-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice. Neuropsychopharmacology. doi.org/10.1038/s41386-021-01054-x.

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