Opioids are powerful painkillers but their use is hindered because patients become tolerant to them, requiring higher and higher doses, and overdoses can cause respiratory depression and death. A recent study contradicts existing thinking about how opioid drugs cause tolerance and respiratory depression, and suggests a new, balanced 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,» 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, who is associate director of the UC Davis Center for Neuroscience, has been researching the neurobiology of addictive disorders and their comorbidities and how to make safer opioids for more than 20 years.

Searching 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 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 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, highly visible search for new «ultra G protein biased» opioids that potently activate G protein but do not engage arrestins.

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Materials provided by University of California — Davis. Note: Content may be edited for style and length.