Selective agonists of the δ-opioid receptor, KNT-127 and SNC80, act differentially on extinction learning of contextual fear memory in mice.

We reported previously that KNT-127 and SNC80, selective agonists of the δ-opioid receptor (DOP), had potent anxiolytic-like effects in rodents. In this study, we evaluated whether KNT-127 and SNC80 influence extinction learning of contextual fear memory in the mice fear conditioning test. On day 1, the mice were contextually conditioned with eight trials (footshock; 0.8 mA, 1-s, 30-s interval). On day 2, the mice were re-exposed to the conditioning chamber for 6 min as an extinction training (re-exposure 1), 30 min after drug administration. On day 3, the mice were re-exposed to the chamber for 6 min as a memory testing (re-exposure 2). In re-exposure 1, KNT-127 and SNC80 significantly reduced the freezing behavior. In re-exposure 2, KNT-127, but not SNC80, significantly reduced the freezing behavior. These effects of KNT-127 were antagonized by the DOP antagonist naltrindole. KNT-127 increased the phosphorylated ERK levels in the amygdala and hippocampus, but not in the medial prefrontal cortex 60 min after re-exposure 1. These results suggest that both KNT-127 and SNC80 produced anxiolytic-like effects in the re-exposure 1, however, in contrast to SNC80, KNT-127 facilitated extinction learning of contextual fear memory in the re-exposure 2. Further, we suggest that amygdaloid and hippocampal MAPK/ERK signaling serves as the key mediators of the enhancement of extinction learning of contextual fear memory via DOPs after KNT-127 treatment. We propose that, although the DOP agonists KNT-127 and SNC80 produce anxiolytic-like effects on contextually conditioned fear, these drugs have different mechanisms on extinction learning of contextual fear memory.