Signs of opioid addiction in the brain, characterized by the number of certain neuron types, were also reversed by DORA-12, and the effect persisted even if DORA-12 had not been given for days. Credit: Neuroscience News
Summary: A recent study highlights a new benefit of quality sleep: deterring opioid relapse. In the study, rats undergoing oxycodone withdrawal received an experimental insomnia treatment. These rats exhibited reduced drug-seeking behavior after the treatment ceased. Such findings could pave the way for human therapies, curbing opioid addiction and relapse.
The experimental insomnia drug, DORA-12, helped opioid-dependent rats to significantly reduce their drug-seeking behavior post-treatment.
Insomnia and other withdrawal symptoms contribute heavily to relapses, suggesting that alleviating such symptoms could decrease relapse likelihood.
Differences were observed between male and female rats in terms of the drug’s efficacy, indicating gender-specific responses to oxycodone and its treatment.
Source: Scripps Research Institute
A good night’s sleep has many proven health benefits, and a new Scripps Research study suggests one more: preventing opioid relapse.
In the new study, published online in Neuropharmacology on August 12, 2023, scientists gave an experimental insomnia treatment to rats experiencing oxycodone withdrawal. The researchers found that the animals were far less likely to seek out drugs again in the future—even after ending the treatment.
These findings could eventually lead to therapies to help prevent opioid addiction or relapse in humans.
“These results are very encouraging,” says Rémi Martin-Fardon, PhD, associate professor of molecular medicine at Scripps Research and senior author of the study. “We hope in the future this compound may be useful for not only treating sleep disorders, but also drug use disorders.”
Opioids including oxycodone are used to treat pain, but carry a risk of misuse and opioid dependence in people who use them regularly. In 2021, opioid overdoses killed more than 80,000 people in the United States, according to the U.S. Centers for Disease Control and Prevention (CDC).
Researchers know that during opioid withdrawal—which can last for days in people who are dependent on the drug—people experience a range of symptoms including nausea, vomiting, sweating, chills, pain, anxiety and insomnia.
Martin-Fardon and Jessica Illenberger, PhD, a postdoctoral research fellow at Scripps Research and first author of the study, wondered whether treating the insomnia associated with opioid withdrawal might help prevent relapse. This is why they turned to an experimental insomnia drug known as DORA-12, which is like the FDA-approved drug Belsomra (suvorexant).
“A lot of drug use and relapse are primarily motivated by a person’s desire to alleviate these withdrawal symptoms,” says Illenberger.
“The idea behind testing this treatment was that if people or animals sleep better during that withdrawal period, then when they wake up, perhaps they won’t feel so much craving and won’t be as likely to relapse.”
In a previous study, the researchers found that suvorexant decreased the amount of oxycodone that opioid-dependent rats self-administered during binge sessions. In the new study, the team focused more on the withdrawal period from oxycodone.
During a 14-day withdrawal period from oxycodone, opioid-dependent rats showed expected withdrawal symptoms, including disturbed circadian rhythms like those seen in insomnia—marked by an increase in activity, eating and drinking during their usual sleeping hours.
However, rats given DORA-12 during this withdrawal period showed patterns of behavior and physiological activities more like animals not dependent on opioids. In addition, when once again exposed to cues they had learned to associate with oxycodone, the rats treated with DORA-12 did not show drug-seeking behavior.
Signs of opioid addiction in the brain, characterized by the number of certain neuron types, were also reversed by DORA-12, and the effect persisted even if DORA-12 had not been given for days.
Interestingly, Martin-Fardon’s group saw slightly different results between male and female animals. Although all rats had less opioid relapse when treated with DORA-12, the drug was less effective in female animals and the changes to neuron numbers seemed to be more pronounced in males.
“I think this is something really important to follow up on,” says Martin-Fardon. “It may be that women are much more sensitive to the effect of oxycodone and different doses of treatment are required.”
More studies are needed to show the utility of DORA-12 or similar insomnia drugs to treat opioid addiction in people. Already, clinical researchers at the Pearson Center for Alcohol and Addiction Research are studying the use of the insomnia drug suvorexant in people with alcohol use disorder.
In addition to Martin-Fardon and Illenberger, authors of the study, “Daily treatment with the dual orexin receptor antagonist DORA-12 during oxycodone abstinence decreases oxycodone conditioned reinstatement,” include Francisco Flores-Ramirez, Glenn Pascasio and Alessandra Matzeu of Scripps Research.
Funding: This work was supported by funding from the Merck Investigator Studies Program (MISP59371), NIH/NIAAA (AA026999, AA028549, AA006420, T32 AA0074560) and NIH/NIDA (DA053443). The DORA-12 was provided by Merck Pharmaceuticals.
About this neuropharmacology and opioid addiction research news
Daily treatment with the dual orexin receptor antagonist DORA-12 during oxycodone abstinence decreases oxycodone conditioned reinstatement
Chronic opioid use disturbs circadian rhythm and sleep, encouraging opioid use and relapse. The orexin (OX) system is recruited by opioids and regulates physiological processes including sleep. Dual OX receptor antagonists (DORAs), developed for insomnia treatment, may relieve withdrawal-associated sleep disturbances. This study investigated whether DORA-12, a recently developed DORA, reduces physiological activity disturbances during oxycodone abstinence and consequently prevents oxycodone-seeking behavior.
Male and female Wistar rats were trained to intravenously self-administer oxycodone (0.15 mg/kg, 21 sessions; 8 h/session) in the presence of a contextual/discriminative stimulus (SD). The rats were subsequently housed individually (22 h/day) to monitor activity, food and water intake. They received DORA-12 (0–30 mg/kg, p.o.) after undergoing daily 1-h extinction training (14 days). After extinction, the rats were tested for oxycodone-seeking behavior elicited by the SD. Hypothalamus sections were processed to assess oxycodone- or DORA-12-associated changes to the OX cell number.
In males, oxycodone-associated increases in activity during the light-phase, reinstatement, and decreases in the number of OX cells observed in the vehicle-treated group were not observed with DORA-12-treatment. Oxycodone-associated increases in light-phase food and water intake were not observed by day 14 of 3 mg/kg DORA-12-treatment and dark-phase water intake was increased across treatment days.
In females, OX cell number was unaffected by oxycodone or DORA-12. Three and 30 mg/kg DORA-12 increased females’ day 7 dark-phase activity and decreased reinstatement. Thirty mg/kg DORA-12 reduced oxycodone-associated increases in light-phase food and water intake. The results suggest that DORA-12 improves oxycodone-induced disruptions to physiological activities and reduces relapse.