In this study, enhancement of transbuccal permeation of morphine sulfate was studied in the presence of sodium glycodeoxycholate (GDC). The permeability of the bovine buccal mucosa to morphine sulfate was determined in vitro in the absence and presence of GDC at 10 mM and 100 mM concentrations. Light and electron microscopy studies were performed to determine the histological and ultrastructural changes resulting from transepithelial permeation enhancement. In addition, infrared spectroscopy (IR) was used to investigate the interaction of GDC with the epithelial lipids of bovine buccal mucosa, The permeation of morphine sulfate across the bovine buccal epithelium was enhanced in the presence of 100 mM GDC by a factor of five whereas at lower concentrations, no significant enhancement was obtained. After 4 h treatment with 100 mM (5% w/v) GDC, significant changes were observed in the epithelium at histological and ultrastructural levels which can be defined as formation of vacuoles, swelling of the cells and a possible increase in intercellular space. Furthermore, by means of IR spectroscopy, it was possible to show the effect of GDC on bovine buccal epithelial lipid domains which was in good correlation with the permeation results. In the light of the results obtained by permeation, histological and IR spectroscopy studies, it is concluded that GDC at 100 mM concentration significantly enhances the permeation of MS across the buccal epithelium and the mechanism of this action appears to involve an interaction with the epithelial lipids.