Prescription opioid painkillers like oxycodone can be very addictive.
People who use them for a long time often have trouble stopping, even if the drugs start causing problems.
A new study tested a drug that blocks brain signals that keep people wanting opioids.
The drug helped rats stop seeking oxycodone and improved their sleep and eating routines.
This approach may someday help people overcome opioid addiction.
Key Facts:
- Rats given oxycodone for 3 weeks worked hard to get more of it. This models human opioid addiction.
- Taking away the oxycodone caused sleep and eating problems, and rats still sought the drug.
- A new drug that blocks orexin signals involved in addiction and sleep helped this.
- It stopped the rats from seeking more oxycodone and improved their routines.
- It shows promise for helping people overcome opioid addiction.
Source: Neuropharmacology 2023 Nov 15
Prescription Opioids Can Lead to Addiction
Opioids are strong pain relieving drugs.
Common prescription opioids include oxycodone, hydrocodone, and fentanyl.
They activate brain receptors called opioid receptors.
This blocks pain signals and causes relaxation and euphoria.
People prescribed opioids for pain relief can develop an addiction.
Their brains adapt to the constant drug exposure.
Then they need more drug just to feel normal. This causes drug cravings and compulsive use.
Quitting opioids after addiction causes withdrawal symptoms like muscle aches, nausea, anxiety, and sleep problems.
These can drive people to start using again.
About 80% of people relapse after opioid addiction treatment.
New approaches are needed to help people stop abusing opioids.
The Brain’s Orexin System Is Involved in Opioid Addiction
A brain system called the orexin system plays a role in opioid addiction.
Orexin neurons in the hypothalamus release two neuropeptides called orexin-A and orexin-B.
These activate orexin receptors in brain regions involved in motivation, reward, and sleep/wake cycles.
Orexin neurons have opioid receptors. Opioids likely overactivate the orexin system.
This contributes to disrupted sleep and circadian rhythms in addiction.
The orexin system also drives wanting and craving of drugs.
Blocking orexin receptors may help treat addiction.
It could reduce drug seeking and normalize sleep.
A new dual orexin receptor antagonist (DORA) called DORA-12 was tested in addicted rats.
The Experiment: Effect of DORA-12 on Opioid Addiction in Rats
The researchers gave rats extended access to oxycodone self-administration sessions.
This models human opioid addiction.
The rats progressively increased their oxycodone intake over 3 weeks.
Rats given a neutral salt solution instead didn’t increase intake.
Oxycodone was then removed to model withdrawal.
This caused sleep/wake cycle disturbances and conflicted opioid cravings and aversion.
Rats still vigorously sought oxycodone when presented with addiction cues.
One group of rats got daily DORA-12 during withdrawal.
Others got an inactive control or lower DORA-12 doses.
DORA-12 dose-dependently blocked the rats from restarting oxycodone self-administration.
It also normalized their sleep/wake and eating behaviors disrupted by oxycodone dependence.
DORA-12 Reversed Effects of Oxycodone Dependence
The addicted rats had more orexin neuron activation and more orexin neurons than control rats.
DORA-12 dose-dependently reversed this elevated orexin signaling.
It likely normalized function in brain circuits dysregulated by chronic oxycodone exposure.
Oxycodone made the rats more active during their normal rest phase.
DORA-12 at higher doses stopped this overactivity. It shifted the activity back to the normal active phase.
Oxycodone dependence also increased the rats’ daytime food and water intake.
This suggests it dysregulated their metabolic states. The higher DORA-12 dose blocked this excessive intake.
For female rats, oxycodone had less effect on orexin neurons.
But DORA-12 still reduced their oxycodone seeking.
It also increased their activity levels and stabilized their food/water intake at optimal doses.
Orexin Blockade – A Promising Approach to Treating Opioid Addiction
This rat study shows that DORA-12 normalized brain functions and behaviors disrupted by oxycodone dependence.
By stabilizing the orexin system, it reduced compulsive opioid seeking and withdrawal-induced disturbances.
DORA drugs like DORA-12 are promising candidates for managing opioid addiction and reducing relapse risk.
The orexin system is highly conserved across mammals. Rats are useful models for human brains.
Orexin receptor blockade may also benefit opioid addiction treatment by improving sleep quality.
Insomnia during withdrawal often triggers relapse.
DORA drugs are approved sleep aids. Relieving withdrawal insomnia with DORAs could prevent opioid relapse.
Current opioid addiction medications like methadone or buprenorphine help manage cravings and withdrawal during detox.
DORAs may provide additional benefits. Their effects would likely complement existing treatment options.
More human research is needed to confirm DORA drugs’ efficacy for addiction.
Rats exhibit simpler and more reliable drug-seeking behavior than people.
But the approach looks very promising based on this animal study.
It offers fresh hope to the millions suffering from opioid addiction.
References
- Study: Daily treatment with the dual orexin receptor antagonist DORA-12 during oxycodone abstinence decreases oxycodone conditioned reinstatement
- Authors: Jessica M Illenberger et al. (2023)
