Activation of δ-opioid receptors in the infralimbic cortex and amygdala facilitates contextual fear extinction in mice.

Facilitation of fear extinction is expected to shorten the duration of treatment for fear-related disorders. Previously, we found that selective agonist of δ-opioid receptor (DOP), KNT-127, facilitates extinction learning of contextual fear. Here, we investigated the brain regions which mediate the action of KNT-127 on fear extinction in mice. On day 1, male C57BL/6J mice were contextually conditioned with 8 foot-shocks. On day 2, the mice were re-exposed to the conditioning chamber for 6 min as an extinction training (re-exposure 1). KNT-127 was microinjected into the amygdala (AMY), hippocampus (HPC), prelimbic (PL) and infralimbic (IL) sub-regions of the medial prefrontal cortex, 30 min before re-exposure 1. On day 3, mice were re-exposed to the chamber for 6 min as a memory testing (re-exposure 2). As a result, KNT-127 (50 ng/mouse) into the AMY and IL, but not HPC and PL, significantly reduced freezing behavior in re-exposures 1 and 2. These effects of KNT-127 in the AMY and IL were abolished by pretreatment with a selective DOP antagonist naltrindole (NTI). Further, MEK/ERK inhibitor, U-0126, blocked the effect of KNT-127 in the AMY. These results suggested that KNT-127 facilitated extinction learning via DOPs in the AMY and IL, and that MEK/ERK pathway in the AMY mediates the extinction-facilitating action of KNT-127.