Tramadol hydrochloride (TH) is an atypical opioid synthetic agent which is a centrally acting analgesic, used for treating moderate to severe pain with fewer side effects than traditional opioid medications. The present work aimed to study the dose-dependent possible deleterious effect of long-term administration of TH as well as a 4-weeks spontaneous recovery period to evaluate the reversibility of the toxic effects on the brain tissues of the rats. Forty adult male albino rats were divided into 4 groups. Group I (control), group II (low dose) was treated orally with TH (30 mg/kg/day) and group III (high dose) was treated orally with TH (60 mg/kg/day) for 4 weeks. Group IV (follow up) was treated as group III and then held for 4-weeks recovery period. At the end of experimental period, rats were sacrificed, histopathological and immunohistolochemical (IHC) examinations of the brains were carried out. The obtained results revealed that both low and high doses of TH produced remarkable histomorphological changes in rats’ brains (cerebral cortex {CC} and hippocampus {HC}) as compared to control and were more pronounced in high than low dose group and in both doses when compared to that of control. On the other hand, group IV showed remarkable regression of the total degenerative changes induced by TH with some residual effect. This was noted by nearly normal morphology of brain tissues and marked significant decrease of p53 and Bax along with significant increase of Bcl-2 protein expressions when compared to those of group II and III treated rates.
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