A large number of individuals are affected by depression. Prolonged usage of standard antidepressants often results in unwanted side effects, highlighting the urgent need for new therapies that work swiftly and have fewer negative impacts. Researchers at Tokyo University of Science have previously demonstrated the antidepressant-like properties of delta opioid receptor agonists in studies involving animals. Their latest findings shed light on the molecular and cellular mechanisms that underlie these effects, paving the way for future developments in therapy.
The global prevalence of anxiety and depression-related disorders is on the rise. While a variety of treatments are available, current medications come with limitations such as slow onset of action and unwelcome long-term side effects. This situation underscores an urgent need for innovative treatment options that are both fast-acting and less likely to cause adverse effects.
The delta opioid receptor (DOP) plays a vital role in mood regulation, making it a significant target for therapeutic interventions. Research has shown that selective DOP agonists, such as SNC80 and KNT-127, exhibit antidepressant and anti-anxiety effects in animal models. However, the exact molecular mechanisms through which these compounds work remain unclear. Understanding the neurological processes that govern mood regulation and DOP functionality is essential for advancing DOP agonists as promising treatments.
To gain this understanding, Professor Akiyoshi Saitoh and Mr. Toshinori Yoshioka from Tokyo University of Science performed a series of experiments to determine the cellular and molecular factors that contribute to the antidepressant-like effects of KNT-127. In their research, published digitally on December 6, 2024, in Molecular Psychiatry, Prof. Saitoh remarked, “By combining the new findings from this study with our earlier work, we believe that DOP agonists operate through a distinct mechanism of action. This suggests their potential to revolutionize depression treatment with improved efficacy and safety compared to existing medications.”
In their earlier investigations, the researchers employed the forced swimming test (FST), which is designed to elicit depression-like behaviors in non-tested mice, to investigate whether KNT-127 possesses antidepressant-like qualities. They assessed the behaviors of mice treated with KNT-127 against control groups. Notably, a single 30-minute pre-test injection of KNT-127 significantly reduced the time spent immobile, indicating an antidepressant-like effect through DOP activation.
The study also examined the mechanistic target of rapamycin (mTOR) signaling pathway, known for its association with rapid antidepressant effects, to see if it played a role in the efficacy of KNT-127. Mice received an injection of rapamycin, an mTOR pathway inhibitor, before KNT-127 treatment. The findings showed that rapamycin negated the reduced immobility linked to KNT-127 in the FST, highlighting the connection between the antidepressant-like effects of KNT-127 and mTOR signaling.
Further evaluation of protein activation related to mTOR signaling in brain regions associated with mood disorders uncovered unique phosphorylation patterns in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. The research revealed that the antidepressant-like effects predominantly stemmed from Akt signaling in the mPFC, while the reduction in anxiety was correlated with ERK signaling activation in the amygdala.
Additional experiments using a depression model in mice demonstrated that targeted injections of KNT-127 into the medial prefrontal infralimbic cortex (IL-PFC) led to antidepressant effects through the PI3K and mTOR pathways. In rodents, the IL-PFC is functionally similar to Brodmann Area 25 in humans, which is associated with mood regulation. Moreover, the antidepressant-like effects of KNT-127 were observed consistently across various strains, sexes, and ages of the animals. Another DOP agonist, SNC80, also exhibited antidepressant properties, highlighting the broad therapeutic possibilities for DOP agonists.
Furthermore, applying KNT-127 to isolated IL-PFC brain tissue enhanced glutamatergic transmission by inhibiting the release of gamma-aminobutyric acid (GABA), an essential neurotransmitter. This supports the idea that DOP agonists directly influence the IL-PFC. The study further identified most DOP receptors in parvalbumin-positive interneurons within the IL-PFC, providing new insights into the specific expression of DOP in various brain regions and improving our understanding of its mechanisms.
Prof. Saitoh emphasized the clinical significance of their work, stating, “Our findings provide strong evidence for the antidepressant effects of DOP agonists and could greatly inform the clinical development of these compounds. Additionally, the IL-PFC is involved in the resistance seen with traditional antidepressant treatments. Thus, DOP agonists may offer more effective options for patients who do not respond to existing therapies.”
We hope that these insights lead to effective treatment options for those battling depression.
