Stevia Extract and MK-801 Attenuate Nalbuphine Tolerance and Dependence in Mice: Role of Glutamate, Nitric Oxide, and Oxidative stress

Abstract

This study aimed to investigate for the first time, the potential role of stevia aqueous extract alone and in combination with MK-801 on nalbuphine-induced tolerance and dependence in mice using biochemical and histological tools. In this study, Repeated administration of stevia extract (300 mg/kg, p.o) along with nalbuphine (10 mg/kg, s.c.) attenuated the development of tolerance, as measured by the hot plate test, and dependence, as assessed by naloxone (5 mg/kg, i.p.) -precipitated withdrawal manifestations. Concomitantly, increase in brain glutamate level, malondialdehyde level, and serum nitrite level-induced by repeated administration of nalbuphine to mice or by administration of naloxone to nalbuphine-dependent mice were inhibited by co-administration of stevia extract. Also, co-administration of the stevia extract inhibited the decrease in brain intracellular reduced glutathione level and glutathione peroxidase activity induced by both treatments. The inhibitory effect of the extract on nalbuphine-induced tolerance and dependence and on naloxone-induced biochemical alterations in nalbuphine-dependent mice was enhanced by concurrent i.p. administration of the NMDA receptor antagonist, MK-801 (0.25 mg/kg). histopathological results revealed that stevia extract coadministration produced decrease in nerve cell degeneration, vacuolation, apoptosis and enhance neuropil appearance. This histopathological improvement increased by concurrent administration of MK-801 with stevia extract. These results provide evidence that stevia extract appears to have a therapeutic potential in opioid tolerance and dependence, through inhibition of nalbuphine-induced elevation in glutamate level, NO overproduction and oxidative stress.