A study of the neurotoxic effects of tramadol and cannabis in adolescent male albino rats

Ola E. Nafea, Iman A. ElKhishin, Othman A. Awad, Dalia A. Mohamed


Background: Adolescence is a critical period for cerebral development. Exposure to addictive substances during this phase leads to various alterations in brain functions that persist into adulthood. The present study was designed to study the neurotoxic effects of tramadol and cannabis, alone and in combination, in adolescent male albino rats by studying their behavioral, biochemical, and histopathological neurotoxic effects and their long–term consequences after withdrawal.

Methods: For this purpose, 132 adolescent male albino rats were divided into 5 groups (22 rats/ group). Group I (negative control), received only regular diet and tap water to measure the basic parameters, Group II (positive control; IIA&IIB); IIA, gavaged with normal saline. IIB, gavaged with olive oil. Group III (tramadol), gavaged with tramadol (42, 84 and 168 mg/kg/day) in the first, second and third ten days of the study respectively. Group IV (cannabis), gavaged with hashish extract (92, 184 and 368 mg/kg/day) in the first, second and third ten days of the study respectively. Group V (tramadol+cannabis), gavaged with tramadol and hashish extract in the same doses as Group III&IV. By the end of the first month, the half number of rats was subjected to performing behavior tests. Specimens from the brain were taken for performing biochemical and histopathological studies. All remaining rats were held for another 4 weeks non–dosing spontaneous recovery period after withdrawal of the treatment and were evaluated again by the same previous parameters.

Results: Abuse of tramadol or cannabis, alone and in combination, caused antidepressant effect (sucrose preference test), impaired spatial memory (Morris water maze), elevated serotonin levels in the cerebral cortex and hippocampus, induced oxidative stress (significantly elevated malondialdehyde level and reduced catalase activity) as well as deleteriously altered brain histopathology and marked increase in brain Caspase–3 expression. However, abuse of both tramadol and cannabis conferred more antidepressant effect but more neurotoxic effect. After withdrawal, the antidepressant effect was reversed, no improvement of the spatial memory, marked depletion of 5–HT, more improvement in antioxidants and apoptotic markers and incomplete regression of brain histopathological alteration resulted.

Conclusions: Abuse of tramadol and cannabis, alone and in combination, induced neurotoxicity which proved behaviorally, biochemically and histopathologically.


Adolescence, Opioid, Cannabinoid, Neurotoxicity, Sucrose preference, Morris water maze

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