الفهرس 
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Abstract
The central role of liver and kidney in drug metabolism predisposes them to toxic injury. Hepatic metabolism is, first and foremost, a mechanism that converts drugs and other compounds into products that are more easily excreted. A metabolite may have higher activity and/or greater toxicity than the original drug. Metabolites of the drugs that are excreted from kidneys may also cause cellular damage leading to kidney dysfunction.
Opioids are the most potent and effective analgesics available and have become accepted as appropriate treatment for acute, cancer and non-cancer chronic pain. Tramadol, a widely used opioid in recent years, is an effective analgesic agent for the treatment of moderately severe acute or chronic pain. It is converted in the liver to an active and more potent substance than tramadol. Further, biotransformation results in inactive metabolites, which are excreted by kidneys
In this study, biochemical, histopathological and immunohistochemical changes in liver, kidneys and brain due to chronic usage of tramadol were assessed in rats.
This work included two groups; the first group served as control and was administered saline solution orally only along the study. The second group was administered oral doses of tramadol (tramadol HCl) suspended in saline solution equal to 60 mg/kg /daily for 90 days respectively. Then, after scarification biochemical evaluation of liver function (ALT, AST, LDH), kidney function (BUN, creatinine), oxidative stress markers (liver MDA, kidney MDA) and total antioxidant capacity was carried out. Also histopathological examination of liver, kidney and brain followed by immunohistochemical examination with anti BCL2 antibodies were done.
There was significant elevation in liver enzymes; serum ALT, AST and LDH levels in the tramadol group in comparison with the control group.
There was insignificant elevation in renal function; serum creatinine and blood urea nitrogen levels in the tramadol group in comparison with the control group.
There was highly significant elevation of tissue MDA (liver and kidney) in the tramadol group compared to the control. There was highly significant decrease of serum TAC in the tramadol group compared to the control.
Histopatholgical examination of the liver showed sinusoidal dilatation, congestion, hydropic degeneration (ballooning) in most of the rats in perivenular region (zone 3). Degeneration had proceeded to midzonal region (zone 2) in some rats. In addition to these findings perivenular necrosis and haemorrhge were found in some rats and focal portal tract infiltrate with inflammatory cells. No histopathological abnormality was found in control group.
Hydropic degeneration was found in 70%, haemorrhage in 30%, congestion in 70%, cytolysis in 50%, apoptotic bodies in 50%, granuloma formation in 20%, perivenular necrosis in 20% and focal microvesicular steatosis in 30%.
Histopathological examination of the kidney showed interstitial mononuclear cell infiltration in some rats with minimal vacuolization. No glomerular damage was found in all examined rats.
Tubular epithelial vacuolization was found in 10%, interstitial cellular infiltration in 30%, focal necrosis in 20%, glomerular haemorrhage in 20%and degenerated tubules in 20%.
Brain examination of Hx&E stained sections of tramadol treated group showed marked disorganization of the cortical layers and hypercellularity as well as increased apoptotic cells.
Almost all pyramidal cells appeared irregular in shape darkly stained with pyknotic nuclei and surrounded by haloes. Some pyramidal cells were shrunken and showed marked cytoplasmic vacuolization. Others appeared with faintly stained cytoplasm and nuclei. There were areas of haemorrhage and dilated blood vessels.
Hypercellularity was found in 64%, apoptotic cells are found in 70%, inflammatory cellular infiltration in 45%, congested blood vessels in 50%, haemorrhage in 55%, degenerated neurons in 55% and cytoplasmic vacuolization in 50%.
Immunohistochemical study of the expression of the Bcl-2 antigen in the rats’ livers, kidneys and brains showed decrease in the reactivity of the tramadol group compared to the control group. The control group is more positive than the tramadol treated group.
This decrease in the Bcl-2 antigen expression was more obvious in the brain than in the liver and the kidney.