Morphine administration induces change in anxiety-related behavior via Wnt/β-catenin signaling.

Chronic morphine administration is known to decrease anxiety-related behavior, which may lead to morphine-seeking and other social problems. Recent studies have revealed that Wnt/β-catenin signaling plays an important role in anxiety-related behavior. We used HT22 cells, which were derived from primary mouse hippocampal neuronal cultures, to explore the relationship between Wnt signaling and morphine exposure. Many techniques, such as western blot analysis, immunofluorescence and luciferase assays, were utilized. We also examined anxiety-related behaviors and dendritic spines in Male Sprague-Dawley (SD) rats after chronic morphine injection and stereotaxic injection of Dkk1. The cell cultures indicated that morphine treatment induced β-catenin expression. The rats that received morphine injection entered open pathways more often in elevated plus maze, spent a greater proportion of time in the interior zone of open field test, and showed less dendritic spine than their vehicle-injected counterparts. However, the injection with Dkk1 significantly prevented this change. Our study demonstrated that Wnt signaling is activated by morphine exposure. The use of Dkk1 before morphine treatment induced a decrease of β-catenin indicated that frizzled receptor(FZD) and LDL receptor-related protein 5/6(LRP5/6) may be crucial to the activity of wnt signaling after morphine exposure. Additional investigation involving animals suggested that the less anxiety observed in the SD rats after morphine treatment could be caused by the loss of dendritic spines and that this may be related to Wnt/β-catenin signaling.