Duloxetine improves hyperosmia in mice with pancreatic cancer by increasing dopamine levels in the olfactory bulb

The mechanism and therapeutic insights regarding hyperosmia to food odors in patients with cancer are poorly understood. We therefore evaluated the mechanism and effect of duloxetine in KPPC (LSL-Kras^G12D/+; Trp53^flox/flox; Pdx-1^cre/+) mice with pancreatic cancer. Six-week-old KPPC mice were orally administered 4 mg/kg/day duloxetine (n = 7) or vehicle water (n = 6) daily until the humane endpoint. In healthy mice (n = 6), the buried pellet test (BPT) time was stable during the observation period, whereas BPT time was shortened in vehicle-treated KPPC mice, and this effect was inhibited by administration of duloxetine. The number of degenerated glomerular/mitral cells in the ventral olfactory bulb increased in vehicle-treated KPPC mice compared with healthy mice, and this effect was inhibited by duloxetine. Electron microscopic analysis revealed enlarged mitochondria in the degenerated neural cells. High-performance liquid chromatography analysis revealed a decrease in dopamine levels in the olfactory bulb of KPPC mice compared with healthy mice. The shortened BPT time in vehicle-treated KPPC mice was extended by L-dopa injection and wheel activity (n = 6 each). These findings suggest that duloxetine improves hyperosmia to food odors in mice with pancreatic cancer by increasing dopamine levels in the olfactory bulb.