Depression is a growing health problem affecting millions of people around the world.
Although there are many medications available, they often take weeks to work and can cause unpleasant side effects with long-term use.
That’s why scientists are searching for new treatments that act faster and are safer. A research team from Tokyo University of Science may have found one promising option.
In their latest study, published in December 2024 in the journal Molecular Psychiatry, the team led by Professor Akiyoshi Saitoh and researcher Toshinori Yoshioka explored a special group of brain proteins called delta opioid receptors (DOP).
These receptors play an important role in mood regulation. Previous studies showed that certain drugs called DOP agonists—such as KNT-127 and SNC80—can reduce signs of depression and anxiety in animals. But until now, scientists didn’t fully understand how these drugs worked in the brain.
To investigate this, the team used a test called the forced swimming test. This test measures how long a mouse will try to escape from a tank of water. Mice that stop swimming quickly are considered to be showing depression-like behavior.
In the study, mice that received a single dose of the drug KNT-127 before the test spent more time trying to swim, showing fewer signs of helplessness. This suggested an antidepressant-like effect from the drug.
Next, the scientists wanted to understand how this effect happens inside the brain. They focused on a pathway called mTOR, which is known to be involved in fast-acting antidepressant effects.
When the mice were given a drug that blocks the mTOR pathway, the antidepressant-like effects of KNT-127 disappeared. This confirmed that the mTOR pathway plays a key role in the drug’s action.
The team also looked at which brain regions were activated. They found that the antidepressant effects were mainly linked to changes in a brain area called the medial prefrontal cortex (mPFC), a region involved in emotions and decision-making.
In contrast, the anxiety-reducing effects were connected to changes in the amygdala, another area that controls fear and emotions.
Importantly, when the drug was injected directly into a specific part of the mPFC called the infralimbic cortex (IL-PFC), it produced strong antidepressant effects. This brain region in mice is similar to Brodmann Area 25 in humans, which is known to be involved in mood disorders and resistance to standard antidepressant treatments.
Another key discovery was how KNT-127 affects communication between brain cells. The drug boosted glutamate signals—important for brain activity—by reducing the release of GABA, a chemical that usually calms the brain.
Most of the delta opioid receptors were found in a certain type of brain cell called parvalbumin-positive interneurons, which are important for balancing brain activity.
These findings are exciting for several reasons. First, they show exactly how DOP agonists work in the brain, giving scientists a clear target for future drug development. Second, the antidepressant effects were seen regardless of the mouse’s sex, age, or genetic background, meaning the treatment could work for a wide range of people.
Finally, because the IL-PFC is often involved in patients who don’t respond to standard antidepressants, these drugs might offer new hope for those who haven’t found relief with current treatments.
Professor Saitoh says their research could help speed up the development of these drugs for clinical use. If future studies confirm these results in humans, delta opioid drugs like KNT-127 could offer faster and more effective relief for people living with depression.
If you care about mental health, please read studies about Middle-aged women with no kids may have this mental issue and findings of scientists find a cause of mental illnesses induced by childhood abuse.
For more information about mental health, please read studies about Cannabis use disorder linked to increased risk of these mental diseases and findings of Some mental health drugs can cause rapid weight gain.
The study is published in Molecular Psychiatry.
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