الفهرس 
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Abstract
4. Summary and conclusion
In this study, we investigate the potential role of stevia extract and steviosidein attenuation of nalbuphine tolerance and dependence. Additionally, the role of glutamate, NO, and oxidative stress on these effects were examined to clarify the possible mechanism.
Ten groups of mice, each group consist of 6 animals, were used in this study. group I: were given saline solution twice daily for 14 days. group II: Mice were given nalbuphine 10 mg/kg subcutaneously twice daily for 14 days. group III: Mice were received, 30 minutes before each nalbuphine injection for 14 days, stevia aqueous extract 300 mg/kg orally by stomach tube. group IV: Mice were received, 30 minutes before each nalbuphine injection for 14 days, stevioside 200 mg/kg intraperitoneally. group Vand group VI: Mice were pretreated 30 minutes before each nalbuphine injection for 14 days with stevia extract 300 mg/kg orally and stevioside 200 mg/kg intraperitoneally separately in combination with L-arginine 300 mg/kg intraperitoneally. group VIIandGroupVIII:Mice were pretreated 30 minutes before each nalbuphine injection for 14 days with stevia extract 300 mg/kg orally and stevioside 200 mg/kg intraperitoneally separately in combination with aminoguanidine 20 mg/kg intraperitoneally.group IX and group X: Mice were pretreated 30 minutes before each nalbuphine injection for 14 days with stevia extract 300 mg/kg orally and stevioside 200 mg/kg intraperitoneally separately in combination with MK-801 0.25 mg/kg intraperitoneally.
Treatment of mice with nalbuphine(10 mg/kg) subcutaneously produced an antinociceptive effect in hot plate test. Repeated administration of nalbuphine(10 mg/kg) subcutaneously to mice twice daily for 14 days produced tolerance to analgesic effect of nalbuphine.
Pretreatment of mice with stevia extract (300 mg/kg) orally or stevioside (200 mg/kg)intraperitoneally 30 minutes before each nalbuphine injection inhibited the development of nalbuphine tolerance to analgesia.
The inhibitory effect of stevia extract and stevioside on the development of nalbuphine tolerance to analgesia in mice was increased by concurrent intraperitoneal administration of MK-801 (0.25 mg/kg) and aminoguanidine(20 mg/kg) while decreased by concurrent intraperitoneal administration of L-arginine (300 mg/kg).
In nalbuphine-treated mice administration of naloxone (5 mg/kg)intraperitoneally on fifteenth day of treatment, 2 hours after nalbuphine injection induced withdrawal manifestations such as jumping, rearing, teeth chattering, and paw tremor. This indicated dependence development on nalbuphine.
Pretreatment of mice with stevia extract (300 mg/kg) orally or stevioside (200 mg/kg)intraperitoneally 30 minutes before each nalbuphine injection inhibited naloxone- induced withdrawal manifestations.
The inhibitory effect of stevia extract and stevioside on the development of nalbuphine withdrawal manifestations following naloxone challenge was enhanced by concurrent intraperitoneal administration of MK-801 (0.25 mg/kg) and aminoguanidine(20 mg/kg) while antagonized by concurrent intraperitoneal administration of L-arginine (300 mg/kg).
In mice treated with nalbuphine(10 mg/kg) twice daily for 14 days, intraperitoneal administration of naloxone (5 mg/kg) on fifteenth day, 2 hours after nalbuphine injection resulted in a significant increase in brain glutamate, malondialdehyde level and serum nitrite level. This treatment also produced a significant decrease in brain intracellular reduced glutathione level and glutathione peroxidase activity.
Pretreatment of mice with stevia extract (300 mg/kg) or stevioside(200 mg/kg) 30 minutes before each nalbuphine injection inhibited these biochemical changes induced by naloxone challenge.
The inhibitory effect of stevia extract (300 mg/kg) or stevioside(200 mg/kg) on naloxone-induced elevation of brain glutamate, malondialdehyde and serum nitrite level as well as inhibition of intracellular reduced glutathione level and glutathione peroxidase activity in nalbuphine- dependent mice was enhanced by concurrent administration of MK-801 (0.25 mg/kg) and aminoguanidine(20 mg/kg)intraperitoneally. While decreased by concurrent administration of L-arginine (300 mg/kg)intraperitoneally.This indicated that NMDA/NO pathway involved in nalbuphine tolerance and dependence.
Histopathologicalexaminations showed that repeated administration of nalbuphine to mice resulted in degenerative changes in nerve cells. However, when stevia and stevioside were used as pretreatment, improvements were observed in the appearance of nerve cells, as well as a decrease in nerve cell degeneration, nerve cell apoptosis, and neuropilvacuolation.
The results of this investigation led to the following conclusion:
• Stevia extract and stevioside can attenuate the development of nalbuphine tolerance and dependence.
• The stevia extract and stevioside may producethese effects through inhibition of nalbuphine induced an increase in glutamate release. nitric oxide overproduction and oxidative stress mitigation.
• Possibility of application of this study in humanas food supplement, need further investigation.