الفهرس 
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Abstract
The chronic use of tramadol as an analgesic can result in many psychological and physical manifestations such as CNS disturbances, headache, seizures, constipation, nausea, and vomiting.
Neurotoxicity of tramadol has been reported in patients administrated tramadol both at repeated prolonged recommended dosage and at the high dosage. The neurotoxic effect of prolonged tramadol usage is mediated by oxidative stress, inflammation, and apoptosis.
Melatonin effects as antioxidant and anti-apoptotic on the brain have been proved. Its rule as a free radical scavenger for oxidative injury of the brain was reported in several past studies.
This study was designed to assess the chronic toxic effects of tramadol on the brains of adult albino rats of both sexes (males & females) using physical, behavioral, biochemical, histopathological, and immuno-histochemical parameters, as well as to investigate the possible ameliorative effects of melatonin.
This study was carried out on 56 adult albino rats of both sexes (males & females), divided into seven groups as follows:
• group Ⅰ (negative control group): (n=8 rats “4 males & 4 females”): left without intervention to measure the basic parameters, free access to food and distilled water were allowed during the whole period of the study (6 months).
• group Ⅱ (solvent control group): (n=8 rats “4 males & 4 females”): received a single oral daily dose of 0.5 ml distilled water by gavage tube for the whole period of study (6 months).
• group III (Melatonin-treated male group): (n=8 rats “4 males & 4 females”): treated with melatonin (10mg/kg/day) dissolved in distilled water orally by gastric gavage for 6 months.
• group Ⅳ (Tramadol treated male group): (n= 8 rats): treated with a single daily dose (50 mg/kg body weight) of tramadol dissolved in distilled water orally by gavage tube for 6 months.
• group Ⅴ (Tramadol treated female group): (n= 8 rats): treated with a single daily dose (50 mg/kg body weight) of tramadol dissolved in distilled water orally by gavage tube for 6 months.
• group Ⅵ (Tramadol and melatonin treated male group): (n= 8 rats): treated with a single daily dose of melatonin (10 mg/kg/day), 30 minutes after treatment with a single daily dose of tramadol (50 mg/kg/day) via gastric gavage for 6 months.
• group VII (Tramadol and melatonin treated female group): (n= 8 rats): treated with a single daily dose of melatonin (10 mg/kg/day), 30 minutes after treatment with a single daily dose of tramadol (50 mg/kg/day) via gastric gavage for 6 months.
The results of all studied parameters on either adult male and female albino rats in the present study showed insignificant differences between the corresponding male and female studied groups.
Regarding body weight and relative brain weight (RBW%), this study, either in male or female studied groups, showed that there was a statistically highly significant decrease in the body weight and RBW% in tramadol treated groups compared to control groups. In the tramadol-melatonin treated groups, body weight & relative brain weight showed an insignificant increase compared to the tramadol treated groups.
As regard behavioral test parameters, either in male or female studied groups, there was a statistically highly significant decrease in behavioral test parameters in tramadol treated groups as compared to control groups with a significant increase of these tests in the tramadol-melatonin treated groups compared to tramadol treated groups.
The results of the present study, either in male or female studied groups, showed a statistically highly significant increase in serum UCH-L1 levels in tramadol treated groups compared to the control groups and showed a significant decrease in serum UCH-L1 levels in tramadol-melatonin treated groups compared to tramadol treated groups.
Regarding the neurotransmitter sassy, the present study either in male or female studied groups showed a statistically highly significant increase in brain tissue serotonin (5-HT) and noradrenaline (NA) levels in the tramadol treated groups compared to control groups and showed a significant decrease of brain tissue serotonin and noradrenaline levels in the tramadol-melatonin treated groups compared to tramadol treated groups.
The results of the present study either in male or female studied groups and as regard malondialdehyde (MDA) levels showed a statistically highly significant increase in tramadol treated groups compared to control groups and showed a significant decrease in tramadol-melatonin treated groups compared to tramadol treated groups.
As regard the antioxidant assay, the present study either in male or female studied groups as regard superoxide dismutase (SOD) and reduced glutathione (GSH) levels in the brain tissue showed a statistically highly significant decrease in tramadol treated groups compared to control groups and showed a significant increase in tramadol-melatonin treated groups compared to tramadol group.
The results of the present study either in male or female studied groups as regard brain histopathological findings in the tramadol treated groups showed loss of organization of all layers of cerebral cortex. The molecular layer showed pyknotic neurons surrounded by haloes with red neurons. The external granular layer showed pyknotic granular cells with deeply stained nuclei. In the external pyramidal layer, pyramidal cells appeared pyknotic with deeply stained nuclei and surrounded by haloes. Neuropil appears vacuolated. The internal granular layer showed granular cells with karyolytic nuclei. In the internal pyramidal layer, pyramidal cells were shrunken & showed deeply stained pyknotic nuclei. Some neurons are pyknotic and surrounded by haloes. Vascular congestion and dilation, apoptotic cells, and focal acidophilic neuropil were also found.
In the present study after treatment with melatonin either in male or female studied groups, the brain histopathological findings showed attenuated apoptosis, few acidophilic degenerated neurons, focal dark stained cellular and non-cellular deposits with foal area of neuropil vacuolations and focal gliosis.
The results of the present study either in male or female studied groups as regard caspase-3 immuno-histochemical reaction, the control groups showed diffuse negative (-) reaction with minimal positive reaction for caspase-3, while tramadol treated groups showed a severe positive reaction (+++) to moderate (++) reaction and in tramadol & melatonin treated groups there was a focal mild positive reaction (+) to negative (-) reaction for caspase- 3.