A new study from the Tokyo University of Science (TUS) has uncovered the molecular mechanisms behind the rapid antidepressant effects of delta opioid receptor (DOP) agonists. The findings, published in Molecular Psychiatry, show that compounds like KNT-127 and SNC80 which activate DOP, are both fast acting and have minimal side effects—a significant potential advantage over current antidepressants which can take weeks to show any benefit and often have significant long-term risks.
The study by Professor Akiyoshi Saitoh and Toshinori Yoshioka from TUS reveals that the DOP agonist KNT-127 produces antidepressant-like effects in animal models by activating specific molecular pathways in the brain. These effects were found to be mediated by the mammalian target of rapamycin (mTOR) signaling pathway, which plays a important role in rapid antidepressant responses.
“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 revolutionize depression treatment with superior efficacy and safety compared to existing drugs,” said Saitoh.
The researchers’ experiments focused on how KNT-127 affects various brain regions associated with mood regulation. Using mouse models of depression, the investigators found that the antidepressant effects of KNT-127 were primarily mediated by Akt signaling in the medial prefrontal cortex (mPFC), a region implicated in emotional processing. In contrast, the anxiolytic (anti-anxiety) effects were linked to the amygdala through a different pathway, involving ERK signaling.
When KNT-127 was administered directly to a region of the brain involved in mood regulation, the medial prefrontal infralimbic cortex (IL-PFC), it produced significant antidepressant effects. This suggests that targeting the IL-PFC could be a promising new approach for treating mood disorders. Previous studies have shown that the IL-PFC is hypoactive and structurally altered in patients with treatment-resistant depression.
The study also demonstrated that KNT-127 enhances glutamatergic transmission while suppressing the release of gamma-aminobutyric acid (GABA) in isolated IL-PFC tissue. This shift towards excitatory neurotransmission in pyramidal neurons may explain the rapid antidepressant effects of DOP agonists.
A central finding of the study was the identification of parvalbumin (PV)-positive interneurons as the primary targets of DOPs in the IL-PFC. These cells help maintain a balance between excitatory and inhibitory signals in the brain. When this balance is disrupted it can result in depression. By activating DOPs in these PV-positive interneurons, KNT-127 appears to restore this balance, facilitating a shift towards more efficient neurotransmission and alleviating depressive symptoms.
The researchers suggest that DOP agonists like KNT-127 could provide a new class of antidepressants that act more quickly and with fewer side effects than existing therapies. Unlike ketamine, another rapid-acting antidepressant that targets mTOR signaling, DOP agonists specifically target PV-positive interneurons in the IL-PFC, offering a potentially safer and more effective alternative.
The study also noted that KNT-127’s effects were consistent across different strains, ages, and sexes of mice used in the study, further supporting the broad therapeutic potential of DOP agonists.
While the exact duration of KNT-127’s effects compared to ketamine remains unclear, the study’s findings offer a fertile area for additional investigation into its potential. The researchers intend to conduct additional studies with a goal of bringing them into clinical practice while also determining whether DOP agonists can help the subset of patients who suffer from treatment-resistant depression.
