As anxiety and depression reach epidemic levels worldwide, the limitations of current treatments—including slow onset of action and undesirable long-term side effects—have left millions in search of better solutions. Now, researchers from Tokyo University of Science (TUS) have found new hope in the form of delta opioid receptor (DOP) agonists. These may be faster and safer alternatives to traditional drugs. Their research, which came out in Molecular Psychiatry on December 6, 2024, shed light on the cellular mechanisms that make DOP agonist antidepressants work. This could lead to a big change in how mental health is treated.Molecular Psychiatry

“Combining the results of this study with our previous findings, we believe that DOP agonists have an unprecedented mechanism of action and have the potential to revolutionise depression treatment with superior efficacy and safety compared to existing drugs,” says Professor Akiyoshi Saitoh, who led the study with Toshinori Yoshioka.

Central to their research is KNT-127, a selective DOP agonist that has shown significant antidepressant and anti-anxiety effects in animal models. Previous experiments using the forced swimming test (FST), a model designed to induce depression-like behaviours in mice, revealed that a single injection of KNT-127 reduced immobility times—a clear sign of antidepressant action. Interestingly, we observed this effect just 30 minutes after administration, which stands in stark contrast to the delayed efficacy of traditional treatments.The study also explored the role of the mechanistic target of rapamycin's (mTOR) signalling pathway, known for its rapid antidepressant effects.

When rapamycin, an mTOR inhibitor, was given to mice before they were treated with KNT-127, it stopped KNT-127 from helping them feel better in the FST. This confirmed that mTOR signalling is crucial to KNT-127’s mechanism of action.

To learn more about KNT-127's effects, scientists looked at parts of the brain that control mood, like the hippocampus, the amygdala, and the medial prefrontal cortex (mPFC). Their findings revealed region-specific mechanisms: antidepressant effects were mediated by Akt signalling in the mPFC, while anxiolytic effects were linked to ERK signalling in the amygdala.

The medial prefrontal infralimbic cortex (IL-PFC), a part of the brain that works like Brodmann Area 25 in humans and rodents, became an important place for action. Researchers injected KNT-127 into the IL-PFC, thereby activating the PI3K and mTOR pathways. This had strong antidepressant effects. Given that the IL-PFC frequently contributes to resistance to conventional therapies, this finding holds promise for treatment-resistant patients.

A study found that KNT-127 stops the release of gamma-aminobutyric acid (GABA), which improves glutamatergic transmission in the IL-PFC. This modulation of neurotransmitter activity underscores the drug’s direct impact on mood regulation. Also, DOPs were mostly found in IL-PFC parvalbumin-positive interneurons. This tells us something new about how the receptor works in certain cells.

Their efficacy across different animal strains, sexes, and ages underscores the broad therapeutic potential of DOP agonists. Another DOP agonist, SNC80, showed similar antidepressant-like effects. This makes the case for these types of compounds as the next generation of mental health treatments stronger.

Prof. Saitoh says, "Our results show that DOP has an antidepressant effect and can greatly improve the clinical development of DOP agonists as medicines due to this." “Moreover, the IL-PFC is involved in resistance to treatment with conventional antidepressants. DOP agonists may, therefore, be more effective in patients who show resistance to existing therapies.”

As the global burden of mental health disorders continues to rise, the discovery of DOP agonists represents a breakthrough in neuroscience and pharmacology. By offering a novel, rapid-acting mechanism with fewer side effects, these compounds could transform the landscape of mental health treatment, bringing new hope to millions worldwide. The next steps will involve clinical trials to validate these findings and further explore their potential in human patients.