A recent study by Scripps Research has identified disruptions in two signaling pathways within a stress-related region of the brain as a factor contributing to relapse in alcohol use disorder (AUD). The findings, published in Frontiers in Pharmacology on November 26, 2025, are based on animal model research and may guide future drug development for AUD.
"We think that alcohol dependence changes these systems, and that's why individuals are prone to seek out alcohol even if they've gone without it for some time," said Rémi Martin-Fardon, associate professor in the Department of Translational Medicine at Scripps Research.
Alcohol use disorder affects nearly 28 million Americans. Although medications such as naltrexone are available to reduce cravings, they have side effects like nausea and do not work for everyone.
The study investigated molecular changes in two neuropeptide systems—orexin and dynorphin—and found that blocking either system individually reduced relapse-like behavior in rats. However, when both signals were blocked together, this effect was lost.
Once control over drinking is lost, regaining it can be difficult. Previous research has shown that stress increases the risk of developing dependence and relapsing after attempts to stop drinking. Alcohol consumption itself also activates the body's stress response systems.
The orexin-dynorphin system is among those affected by AUD. Orexin acts as a "go" signal promoting drug-seeking behavior, while dynorphin serves as a "stop" signal. In cases of excessive drinking, dynorphin signaling appears altered, resulting in unpleasant withdrawal symptoms that motivate continued drinking.
Martin-Fardon's group previously studied this relationship with cocaine addiction but focused on alcohol for this project. The team examined a small area within the thalamus known as the posterior paraventricular nucleus of the thalamus (pPVT), which processes stress signals and receives input from both orexin and dynorphin pathways.
The researchers observed changes in gene expression: alcohol-dependent rats showed increased production of both orexin and dynorphin signals from the hypothalamus. However, neurons in the pPVT expressed fewer receptors for orexin and more for dynorphin.
"What that tells us is that just being dependent on alcohol changes the orexin and dynorphin system, and that these changes persist well into abstinence," said postdoctoral researcher Francisco Flores-Ramirez.
To reach these conclusions, male rats were trained to self-administer alcohol by pressing a lever. After removing access to alcohol, researchers analyzed gene expression in their brains. Some animals received inhibitors targeting orexin or dynorphin signaling within the pPVT. Blocking either signal alone reduced relapse-like behavior under stress; however, inhibiting both simultaneously eliminated this protective effect.
The authors note limitations due to focusing on one brain region and using only male animals. They caution against combining treatments without further research.
"If you want to combine treatments, you have to be very careful," Martin-Fardon said. He added that using different inhibitors or drugs with similar chemistry might still be effective.
The team is now working with colleagues Edward Roberts and Hugh Rosen at Scripps Research to develop selective dynorphin signaling inhibitors intended for quick relief. Martin-Fardon also plans to test combinations involving suvorexant—a drug used for insomnia that blocks orexin signaling—or similar compounds.
