Even after years of recovery, individuals who have struggled with alcohol or opioid addiction may experience a relapse, especially during stressful periods. Scientists have now pinpointed a specific area in the brain that is crucial in stress-induced oxycodone relapse. This discovery sheds light on why the drug suvorexant, known to reduce alcohol and oxycodone relapse when taken orally, is effective.
“Gaining insight into the brain regions responsible for this type of relapse is vital as we develop treatments for alcohol use disorder and opioid use disorder,” explains Scripps Research Associate Professor Remi Martin-Fardon, PhD, the senior author of the study published in Journal of Psychopharmacology.
Alcohol use disorder involves excessive alcohol consumption and binge drinking, while opioid use disorder refers to chronic opioid use leading to significant distress or impairment. These disorders are significant public health issues affecting millions annually.
Recent studies by Martin-Fardon’s team revealed that administering the drug suvorexant (Belsomra®) to alcohol-dependent rats resulted in reduced alcohol consumption and lower chances of stress-induced relapse. Similar experiments indicated its potential in preventing opioid relapse triggered by drug-related cues.
Suvorexant works by blocking the neuronal signaling chemical orexin. Since orexin has various effects on the brain, researchers aimed to understand the specific brain regions and molecular pathways responsible for suvorexant’s impact on relapse.
In their latest research, the team focused on opioid-dependent rats that had been trained to self-administer oxycodone but had abstained from the opioid for at least 8 days.
They devised a method to target a small brain area, the posterior paraventricular nucleus of the thalamus (pPVT), with suvorexant, instead of administering the drug orally, which would affect the entire brain. The pPVT is known to be involved in stress, eating, and drinking behaviors. The study showed that opioid-dependent rats, when exposed to stress and suvorexant in the pPVT, exhibited significantly reduced drug-seeking actions compared to untreated rats. This demonstrated that suvorexant’s ability to prevent relapse was linked to its impact on orexin signaling in the pPVT.
“Historically, the focus has been on other brain regions in stress-induced relapse,” notes Jessica Illenberger, a postdoctoral research fellow at Scripps Research and the lead author of the study. “Our research emphasizes the significance of the pPVT and orexin signaling in that region in stress processing and drug-seeking behavior.”
Notably, when the animals were offered sweetened condensed milk instead of oxycodone or reintroduced to drug-related cues rather than stress, suvorexant in the pPVT did not alter their behavior. This implies that stress-induced oxycodone relapse operates through different molecular mechanisms than stress-induced sugar cravings or other types of oxycodone relapse.
“Relapse poses a significant challenge for individuals with opioid use disorder and alcohol use disorder, and our findings bring us closer to identifying effective treatments to reduce relapse risk,” adds Illenberger.
The team is currently conducting similar experiments in animal models to explore whether suvorexant also influences cases of alcohol dependence through the pPVT.
Aside from Martin-Fardon and Illenberger, other 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 from Scripps Research.
This research received support from the National Institutes of Health (AA026999, AA028549, AA006420, T32 AA007456, DA053443).
