Research May Lead to Safer Alternatives to Opioids

Arrestin-3, a protein engaged by the mu opioid receptor (MOR) on cells, may prevent analgesic tolerance without exacerbating respiratory depression, contrary to the existing hypothesis on arrestin-3, according to a study published in Neuropsychopharmacology. This research could influence how drug developers consider how opioid drugs cause tolerance and respiratory depression, and it suggests an alternative approach to developing safer analgesics.

"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," Jennifer Whistler, senior author on the paper and professor of physiology and membrane biology in the UC Davis School of Medicine, said in a press release. "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."

Opioid drugs function through connecting to the MOR on cells, which signals through the G-protein and can also engage arrestin-3. The existing understanding of how opioids function suggests engagement of the MOR with arrestin-3 leads to respiratory depressive effects that cause overdose death, as well as the development of analgesic tolerance that leads to dose escalation, increased risk of addiction, and overdose death.

The investigators interrogated this hypothesis by analyzing a panel of 6 clinically relevant opioid drugs using mice of 3 distinct genotypes with varying abilities to promote morphine-mediated arrestin-3 engagement. According to the results of the study, arrestin-3 recruitment does not promote respiratory depression. Further, effective engagement of arrestin-3 reduced the development of analgesic tolerance rather than accelerating it.

“We propose a shift in effort to develop ‘balanced’ opioid analgesics that strongly promote arrestin-3 engagement, much like our endogenous endorphins do," said Jennifer Whistler, PhD, professor of physiology and membrane biology in the UC Davis School of Medicine, in a press release. "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."

The current understanding of how opioids should optimally function has led to a search for opioids that potently activate G protein without engaging arrestins. The study authors said this has, in turn, led to massive investments into the clinical development of “ultra-biased” opioids, including the recently FDA-approved oliceridine. Whistler predicts this drug will have a higher liability to produce tolerance and addiction than existing opioid therapeutics, based on the results of the study.

According to the investigators, the development of safer opioids should focus on identifying balanced opioid ligands that recruit both G protein and arrestin-3 in order to mimic the signaling profile of the majority of 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," Whistler said in the release.

REFERENCE

Potentially safer approach to opioid drug development [news release]. Science Daily; August 24, 2021. Accessed August 27, 2021. https://www.sciencedaily.com/releases/2021/08/210824135355.htm