A study of the effects of repeated doses of tramadol and benzhexol on brain neurotransmitters in rabbits

Other Title(s)

دراسة تأثير الجرعات المتكررة لعقاري الترامادول و البنزهكسول على النواقل العصبية في دماغ الأرانب

Dissertant

Abd al-Qadir, Umar Salih

Thesis advisor

Ali, Nabil Abd al-Jalil

University

University of Basrah

Faculty

Medicine College

Department

Department of Pharmacology

University Country

Iraq

Degree

Master

Degree Date

2013

English Abstract

Background Drug dependence is defined as a cluster of cognitive, behavioral, and physiologic symptoms indicative of an individual continuing substance use despite its significant related problems.

The term dependence includes both psychic dependence, characterized by compulsive drug-seeking behavior, and physical dependence, characterized by the occurrence of withdrawal symptoms upon abrupt discontinuation of the drug, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Some recent studies suggest that multiple neurotransmitters, like dopamine, serotonin and GABA, may play a key role in the development and expression of drug dependence through the brain reward system.

The mechanism of dependence of two of the most commonly abused drugs in Iraq, benzhexol and tramadol is not well known.

Aim To study the effect of repeated administration of tramadol and benzhexol on brain transmitter’s levels including dopamine, serotonin and GABA and to study the effect of both drugs on brain oxidative state as measured by MDA and correlate any change in the neurotransmitters levels with the brain oxidative state.

Materials and methods The experiments were carried out on 32 locally bred, sexually mature male rabbits; they were divided into four groups (eight rabbits each) as follow: Group1 (Control): animals in this group received 2 ml/kg distilled water once daily orally.

Group 2: animals in this group received 15 mg/kg tramadol once daily orally.

Group 3: animals in this group received 15 mg/kg tramadol once daily by intramuscular injection.

Group 4: animals in this group received 10 mg/kg benzhexol once daily orally.

The treatments were administered daily for 2 weeks.

The rabbits were sacrificed at day 15.

The response to treatments was evaluated by measurement of brain tissue dopamine, serotonin and GABA by ELISA.

Evaluation of oxidative stress was made by measurement of malondialdehyde (MDA) in brain homogenate.

Results Tramadol by intramuscular injection produced a large and statistically significant increase in brain tissue MDA from the normal value of 6231± 1376(nmol/g) to 12925 ± 2144(nmol/g) (p˂ 0.001).

Tramadol oral, tramadol injection and benzhexol all lead to statistically significant increase in brain tissue dopamine from the normal value of 27.4 ± 2.6(pg/ml) to 40.1 ± 4.5(pg/ml) (p˂ 0.001), 42.0 ± 3.0(pg/ml) (p˂ 0.001) and 45.7 ± 10.4(pg/ml) (p˂ 0.001) respectively.

Tramadol orally and by intramuscular injection produced a large and statistically significant increase in brain tissue serotonin from the normal value of 1.526 ± 1.28(ng/ml) to 3.78 ± 2.33(ng/ml) (p˂0.002) and 4.41 ± 2.19(ng/ml) (p˂0.04) respectively.

Tramadol by intramuscular injection produced a large and statistically significant increase in brain tissue GABA from the normal value of 8.09 ± 3.36(ng/ml) to 12.78 ± 4.15(ng/ml) (p˂ 0.008).

Benzhexol given orally also lead to statistically significant increase in brain tissues GABA from the normal value of 8.09 ± 3.36(ng/ml) to 12.56 ± 3.44(ng/ml) (p˂0.003).

There was a statistically significant positive correlation between brain tissue dopamine and MDA (p˂ 0.05).

Also there was a statistically significant positive correlation between brain tissue serotonin and MDA (p˂ 0.02).

There was a statistically significant positive correlation between brain tissue GABA and MDA (p˂ 0.05).

Conclusions Tramadol and benzhexol caused a statistically significant increase in brain tissue dopamine following repeated administration to rabbits.

Tramadol but not benzhexol increased brain tissue serotonin.

Both injectable tramadol and oral benzhexol increased brain tissue GABA.

Only injectable tramadol significantly increased brain tissue MDA.

There was a significant correlation between neurotransmitter’s changes and oxidative stress.

Main Subjects

Pharmacology

No. of Pages

78

Table of Contents

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Language

English

Data Type

Arab Theses

Record ID

BIM-744765