Anxiety disorders can have a profound impact on the mental health and quality of life of those affected. Understanding the neural circuits and molecular mechanisms that drive anxiety can aid in the development of effective targeted pharmacological treatments. Delta opioid receptors (DOP), localized in brain regions associated with emotion regulation, play a key role in the development of anxiety. Several studies have demonstrated the therapeutic effects of DOP agonists (synthetic compounds that selectively bind to DOPs and mimic the effect of natural binding compounds) in a wide range of behavioral disorders. One such selective DOP agonist — KNT-127 — shows ‘anxiolytic’ or anxiety-reducing effects in animal models with minimal side effects. However, its mechanism of action is not clearly understood, thus limiting its widespread clinical application.

To fill this gap, Professor Akiyoshi Saitoh, along with Ms. Ayako Kawaminami and a team from Tokyo University of Science, Japan, conducted a series of experiments and behavioral studies on mice. Explaining the rationale behind his work, Professor Sitoh says, “There are currently no therapeutic drugs mediated by delta opioid receptors (DOPs). DOPs may have a different mode of action from existing psychotropics.” exert antidepressant and antianxiety effects through CAR. Therefore, DOP agonists may be useful for treatment-resistant and intractable mental illnesses that do not respond to current treatments.” Their study was published in Neuropsychopharmacology Reports on December 29, 2023.

A neuronal network projecting from the prelimbic cortex (PL) to the basolateral nucleus of the amygdala (BLA) region of the brain is involved in the development of depressive and anxiety symptoms. The research team has previously shown that KNT-127 inhibits the release of glutamate (an important neurotransmitter) in the PL region. Based on this, they hypothesized that DOP activation by KNT-127 suppresses glutamatergic transmission and reduces PL-BLA-mediated anxiety-like behavior. To test this hypothesis, they developed an ‘optogenetic’ mouse model in which they implanted a light-responsive chip into the PL-BLA region of mice and activated the neural circuit using light stimulation. Further, they examined the role of PL-BLA activation on innate and conditioned anxiety-like behavior.

They used the elevated plus maze (EPM) test, which consists of two open arms and two closed arms on opposite sides of a central open field, to assess behavioral anxiety in rats. Specifically, mice with PL-BLA activation spent less time in the central region and the open arm of the maze than controls, which was consistent with innate anxiety-like behavior. Next, the researchers assessed the conditioned fear response of the animals by exposing them to foot shocks and placing them in the same shock chamber the next day without re-exposing them to the current. They recorded the animal’s freezing response, which reflects fear. Notably, animals with PL-BLA activation and controls exhibited similar behavior, suggesting that neural pathways control innate anxiety-like behaviors and conditioned fear responses.

Finally, they evaluated the effects of KNT-127 treatment on the anxiety-like behavior of mice using the EPM test. Notably, animals treated with KNT-127 showed an increase in the percentage of time spent in the open arms and in the central arena of the maze compared to controls. These results suggest that KNT-27 reduces anxiety-like behavior induced by specific activation of the PL-BLA pathway.

Overall, the study demonstrates a role for the PL-BLA neuronal axis in the regulation of innate anxiety, and its potential function in DOP-mediated anxiolytic effects. For the development of new therapeutics targeting DOP in the PL-BLA pathway, further studies are needed to understand the exact underlying molecular and neuronal mechanisms.

Highlighting the long-term clinical applications of their work, Professor Saitoh remarked, “The brain neural circuits focused on in this study are conserved in humans, and research on human brain imaging shows that It has been shown that the PL-BLA region is overactive in patients with depression and anxiety disorders. We are hopeful that suppressing overactivity in this brain region using DOP-targeted therapies will have significant anxiolytic effects in humans. can be compiled.”