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Genetics Partially Explain How People Respond to Oxycodone

Addiction-related behaviors from oxycodone could be due to the protein, RGS9-2.

It’s no secret that prescription painkillers can be highly addictive, but there may be a partial biologic reason for it.

Previous studies have determined that the signaling protein, RGS9-2, plays an imperative role in the brain that leads to addiction-related behaviors. But according to researchers from Icahn School of Medicine at Mount Sinai in New York, New York, the protein does more than that when it comes to the painkiller oxycodone (Oxycontin/Purdue Pharma).

Using mice, the team found that RGS9-2 modulates the oxycodone reward while patients are and are not in pain. When an animal did not have the gene, RGS9KO, which encodes RGS9-2, they had less of a natural tendency for addiction-related behaviors. However, lacking the gene did not impact the analgesic effects of the drug.

Oxycodone works in the areas of the brain for pain relief as well as addiction—which are the same brain receptors where morphine and heroin work. The researchers have shown that RGS9-2 promote the development of morphine tolerance and negatively impacts its analgesic effects. This isn’t the case for all opioids, it actually has the opposite effect by positively impacting the pain relief effects of fentanyl and methadone.

“Although oxycodone produces similar analgesic and behavioral effects to those observed with morphine, our study demonstrates that the intracellular actions of morphine and oxycodone are distinct,” Venetia Zachariou, PhD, associate professor in the Fishberg Department of Neuroscience and The Friedman Brain Institute at Mount Sinai, said in a news release.

The team also found that mice without the RGS9KO gene became tolerant to the analgesic effects of oxycodone sooner than mice who had the gene. This indicates that the protein helps stop that from happening. Not only that, but it appears that the mechanisms control sensitivity oxycodone addiction no matter if patients are in a pain-free or chronic pain state.

“Our work reveals that intracellular factors that prevent the actions of morphine may actually promote the actions of oxycodone. This information is particularly important for pain management strategies, as a common course is to have patients oscillate between oxycodone and morphine to achieve pain relief,” Zachariou said.

The hope with this newfound information will help healthcare providers weigh the benefits and risks of oxycodone for each patient based on the likelihood of developing addiction-related behaviors. This can also help researchers develop novel therapeutic medications based on this pathway.

The study, “RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States,” was published in Neuropsychopharmacology. The news release was provided by Mount Sinai Hospital.

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