Background and Purpose Growing evidence demonstrates that the
delta opioid receptor (DOP) is an attractive candidate for novel
antidepressants with the potential to exhibit rapid action with few
adverse effects. However, the underlying detailed functional mechanism
remains elusive. Previously, we reported that the selective DOP agonist,
KNT-127, produced robust antidepressant-like effects in the mice forced
swimming test (FST). Thus, we attempted to identify the cellular
mechanism underlying this effect. Experimental Approach Male
ICR mice (4–6 weeks) were used in all experiments. The FST was
conducted as a screening model for antidepressants. The phosphorylation
level of proteins in specific brain regions was quantified using Western
blotting. Glutamate/gamma-aminobutyric acid-dependent postsynaptic
currents were detected using whole-cell voltage-clamp recordings.
Key Results The selective mTOR inhibitor, rapamycin, and the
PI3K inhibitor, LY294002, blocked the antidepressant-like effects of
KNT-127 in the FST. KNT-127 increased the phosphorylation level of mTOR
signal-related proteins, Akt and p70S6K, in the medial prefrontal
cortex. The bilateral microinfusion of KNT-127 in the infralimbic cortex
decreased immobility in the FST. The frequency of miniature excitatory
postsynaptic currents in the infralimbic cortex increased and that of
miniature inhibitory postsynaptic currents decreased with the perfusion
of KNT-127, which was blocked by pretreatment with rapamycin.
Conclusions and Implications KNT-127 displays
antidepressant-like actions through the direct facilitation of neuronal
excitability in the mice infralimbic cortex, which is implicated in the
PI3K-Akt-mTOR-p70S6K signaling pathway. These results could indicate the
first steps in elucidating the complete mechanical functions of DOPs as
a potential candidate for novel antidepressants.
Delta Opioid Receptor Agonist KNT-127 Facilitates Neuroexcitability in the Mouse Infralimbic Cortex via mTOR Pathway to Exert an Antidepressant Effect
