LA JOLLA, CA—Even years after they have recovered, a person who once struggled with alcohol or opioid addiction can relapse—and that relapse is more likely to occur during particularly stressful times. Now, Scripps Research scientists have identified an area of the brain that plays a key role in stress-induced oxycodone relapse. Their findings explain why the drug suvorexant, which they previously found to reduce alcohol and oxycodone relapse when administered orally, works so well.
"Having a better understanding of the region(s) in the brain responsible for this kind of relapse is incredibly important as we develop treatments for alcohol use disorder and opioid use disorder," says Scripps Research Associate Professor Remi Martin-Fardon, PhD, senior author of the study published in Journal of Psychopharmacology.
Alcohol use disorder includes chronic heavy alcohol use and binge drinking, while opioid use disorder is the chronic use of opioids that causes significant distress or impairment. Both disorders are considered major public health concerns and affect millions of people a year.
Recently, Martin-Fardon's team showed that when alcohol-dependent rats were given the drug suvorexant (Belsomra®), they drank less alcohol and were less likely to experience stress-induced relapse. Similar experiments suggested that it also could prevent opioid relapse elicited by drug-associated cues.
Suvorexant blocks the neuronal signaling chemical orexin. But orexin acts on the brain in multiple ways, and the researchers wanted to better understand which areas of the brain and molecular pathways were responsible for suvorexant's effect on relapse.
In the new study, the researchers focused on opioid-dependent rats that had learned to press a lever to receive oxycodone but then were abstinent from the opioid for at least 8 days.
Then, the researchers developed a system to expose only one small area of the rats' brains, known as the posterior paraventricular nucleus of the thalamus (pPVT), to suvorexant, rather than giving the drug orally which exposes the entire brain to the drug. The pPVT has been previously shown to play a role in stress, eating and drinking. They found that opioid-dependent rats who were exposed to stress and exposed to suvorexant in the pPVT, pressed the opioid-delivering lever less than half as many times as untreated rats. This diminished drug-seeking behavior, even in the face of stress, showed that suvorexant's ability to prevent relapse was due to its action on orexin signaling in the pPVT.
"In the past, there has been a lot of focus on the role of other areas of the brain in stress-induced relapse," says Jessica Illenberger, a postdoctoral research fellow at Scripps Research and first author of the new paper. "Our work really points the finger at the pPVT, as well as orexin signaling in that brain region, as being important in stress processing and drug-seeking behavior."
Importantly, when the animals were given sweetened condensed milk instead of oxycodone, or when they were reintroduced to drug-associated cues instead of stress, suvorexant in the pPVT did not change their behavior. This suggests that stress-induced oxycodone relapse is mediated by different molecular drivers than stress-induced sugar cravings or other types of oxycodone relapse.
"Relapse is a huge problem for people with opioid use disorder and alcohol use disorder and this gets us one step closer to identifying the proper types of treatment to reduce the risk of relapse," says Illenberger.
The team is now carrying out similar experiments in animal models to determine whether suvorexant also acts through the pPVT in cases of alcohol dependence.
In addition to Martin-Fardon and Illenberger, authors of the study, "Pivotal role of orexin signaling in the posterior paraventricular nucleus of the thalamus during the stress-induced reinstatement of oxycodone-seeking behavior," include Francisco Flores-Ramirez, Glenn Pascasio, Marissa Franco and Brandon Mendonsa of Scripps Research.
This work was supported by the National Institutes of Health (AA026999, AA028549, AA006420, T32 AA007456, DA053443).
