Depression continues to grapple a large proportion of the population. Given the side effects associated with the long-term use of conventional antidepressants, there is a need for novel rapid acting therapeutics with minimal side effects. Researchers from Tokyo University of Science have previously demonstrated antidepressant-like effects of delta opioid receptor agonists in rodents. In their latest study, they uncover the molecular and cellular mechanism underlying its action that can advance its therapeutic development. Multiple drugs have been developed to treat these conditions, current medications have several limitations, including slow action and adverse effects with long-term use. This underscores the urgent need for novel, rapidly-acting therapeutic agents with minimal side effects.
The delta opioid receptor (DOR) plays a key role in mood regulation, making it a promising target for therapeutic intervention. Studies have shown that selective DOR agonists (compounds that activate DOR), such as SNC80 and KNT-127, exert antidepressant and anxiolytic effects (anti-anxiety) in animal models. However, the precise molecular mechanisms underlying their actions remain unclear. Understanding the neurological mechanisms that underpin mood regulation and DOR action is crucial for advancing DOR agonists as therapeutic agents. To this end, Professor Akiyoshi Saitoh and Mr. Toshinori Yoshioka from Tokyo University of Science, conducted a series of experiments to elucidate the cellular and molecular processes contributing to the antidepressant-like effects of KNT-127.
In their previous work, the researchers conducted the forced swimming test (FST), which is known to induce depression-like helplessness behavior in untested mice, to investigate whether KNT-127 produces antidepressant-like effects. They compared the response of animals treated with KNT-127 and controls. Notably a single injection of KNT-127, 30 minutes prior to the test, significantly reduced immobility count, reflecting an antidepressant-like effect mediated by DOR stimulation. The mTOR signaling pathway, implicated in rapid antidepressant effects, was investigated for its role in KNT-127’s action. The researchers injected the mice with rapamycin — an mTOR inhibitor — prior to KNT-127 treatment. Indeed, the drug reversed the KNT-127-induced decrease in the FST immobility count, indicating that its effects of were mediated by mTOR signaling.
Next, researchers analyzed the mTOR signaling-related protein activation in brain regions associated with mood disorders and mapped distinct phosphorylation patterns in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. The experiments revealed that the antidepressant-like effects were primarily mediated by the PI3K/Akt signaling in the mPFC, while the anxiolytic effects were associated with activation of the amygdala through ERK signaling. Further studies in a mouse model of depression revealed that when KNT-127 was locally injected into the medial prefrontal infralimbic cortex region (IL-PFC), an anti-depressive effect was produced through the PI3K and mTOR pathway. The IL-PFC in rodents is considered functionally similar to Brodmann Area 25 in humans, which is associated with mood regulation.
Further, the antidepressant-like effects of KNT-127 were independent of the sex or age of the animals, and another DOR agonist, SNC80, also exhibited antidepressant-like effects, highlighting the broad therapeutic potential of DOR agonists. Additionally, KNT-127’s application to isolated IL-PFC brain tissue enhanced glutamatergic transmission by suppressing the release of GABA, further supporting the direct action of DORs on the prefrontal cortex. The study identified that most DORs were expressed in parvalbumin-positive interneurons in the IL-PFC, offering new insights into the cell-specific expression of DOR in distinct brain regions. DOR signaling is mainly mediated by inhibitory G proteins (Gi and G0), which suppress cyclic AMP-dependent pathways (e.g. PKA) while enhancing calcium-dependent ones (PLC-DAG-PKC).
These calcium-related events are tighlty connected to ion channel regulation (voltage-dependent currents), neurotrasmitter release and cytoskeletal changes. Moreover, the PKC transduction module often crosstalks with ERK MAP-kinase signaling, which is implicated in the anxiolytic and memory-strenghtening effects on neurons. After all endorphins, the endogenous modulators of pain, pleasure and mood, act mainly through opioid receptors (mu, delta, kappa). According to the published data, it is very likely that positive mood and antidepressant effect mat rely on their interaction with DOR toward ERK and mTOR signaling.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Yoshioka T, Yamada D et al. Mol Psych. 2024 Dec; in press.
Jelen LA et al. Curr Top Behav Neurosci. 2024; 66:67-99.
Yoshioka T et al. Neuropharmacol. 2023; 232:109511.
