We previously found that acute treatment of SYK-623, a new inverse agonist of δ-opioid receptors, improved restraint stress-induced learning dysfunction. In the present study, we investigated the chronic effects of SYK-623 in the chronic stress model mice. ddY mice (6-week) were administered adrenocorticotrophic hormone (once a day) and exposed to chronic mild stress for 3 weeks (herein after referred to as ACMS). SYK-623 or imipramine was administered once a day before the ACMS exposure. Short-term memory was evaluated by Y-maze. Hippocampi, adrenal glands and thymus were isolated after the behavioral test. Astrocytes and immature neurons were detected by the immunofluorescent staining in the hippocampus. ACMS induced short-term memory impairment, adrenal hypertrophy, thymic atrophy, and decreases in the density of astrocytes and immature neurons of the hippocampus. SYK-623 reversed the short-term memory impairment and the density of immature neurons, but not the others. Imipramine treatment had no effects on these symptoms. Together, chronic SYK-623 treatment reversed chronic-stress induced short-term memory impairment in imipramine resistant mice, and the increased neurogenesis may be important in this effect.