Comparative Study of the Neurotoxic Effects of Pregabalin Versus Tramadol in Rats

Abstract

In Egypt, both pregabalin and tramadol misuse increased in the last decade. Although many studies have confirmed the neurotoxic effects of tramadol, those of pregabalin are understudied. The aim of the study is to evaluate the neurotoxic effects of pregabalin compared with tramadol. Thirty male albino rats were included in this experimental study, and they were randomly allocated into three equal groups: group I (normal saline), group II (tramadol misuse), and group III (pregabalin misuse). All rats received the commenced drugs for 1 month. Open field tests were performed on the day of scarification, and after that, cortical samples were taken for immunohistochemical analysis and quantification of dopamine receptors' gene expression. The drug misuse groups showed a significant decrease in weight gain at the end of the study. Open field testing showed the upper hand of controls regarding all of the tested parameters. Tramadol has a more negative impact on the locomotor parameters compared with pregabalin. Both drugs induced relatively low dopamine-1 receptor (D1Rs) expression to dopamine-2 receptors (D2Rs), mimicking the schizophrenia model. Both tramadol and pregabalin were associated with neurotoxic effects in male albino rats. These effects were less noticed with pregabalin. It is suggested that long-term abuse may end in psychosis.

Keywords: Dopamine; Misuse; Neurotoxicity; Pregabalin; Rats; Tramadol.

Fig. 1

a A photomicrograph of a paraffin section in a control rat cerebral cortex demonstrating pyramidal cells “Arrows” with rounded open face nuclei and long apical dendrites “Curved arrow”. Granular cells “Arrow heads” with round open face nuclei are demonstrated. Neuroglial cells “Wavy arrows” are also demonstrated (H&E × 400). b H&E × 1000. c, d A photomicrograph of a paraffin section in a rat cerebral cortex of tramadol group showing many apoptotic cells surrounded with empty spaces “Wavy arrows,” shrunken pyramidal cells surrounded by empty spaces “Arrows,” dilated and congested blood vessels are also seen “Crossed arrows,” and inflammatory cell infiltration (asterisks) is seen in the surrounding neuropil (H&E × 400). e, f A photomicrograph of a paraffin section in a rat cerebral cortex of pregabalin group showing shrunken pyramidal cells surrounded by empty spaces “Thick Arrows.” However, apparently, normal pyramidal cells “Arrows” with their apical dendrites “Curved arrows” are also seen. Granular cells “Arrow heads” and neuroglial cell “Wavy arrows” are also seen. Congested blood vessels are also seen “Crossed arrows” (H&E × 400)

Fig. 2

a A photomicrograph of a paraffin section in a control rat cerebral cortex with no amyloid deposits detected (Congo red × 400). b A photomicrograph of a paraffin section in a rat cerebral cortex of tramadol group showing numerous amyloid deposits “Arrows” (Congo red × 400). c A photomicrograph of a paraffin section in a rat cerebral cortex of pregabalin group showing few amyloid deposits “Arrows” (Congo red × 400). d A photomicrograph of a paraffin section in a control rat cerebral cortex demonstrating strong PAS reactions in the pyramidal and granular cells “Arrows” (PAS × 400). e A photomicrograph of a paraffin section in a rat cerebral cortex of tramadol group demonstrating a weak PAS reaction in the degenerated pyramidal and granular cells “Arrow heads” (PAS × 400). f A photomicrograph of a paraffin section in a rat cerebral cortex of pregabalin group demonstrating a weak PAS reaction in the pyramidal and granular cells, especially the degenerated ones “Arrow heads” and moderate PAS reaction in other pyramidal and granular cells “Arrows” (PAS × 400)

Fig. 3

a A photomicrograph of a paraffin section in a control rat cerebral cortex showing a negative P53 reaction (anti P53 immunostain × 400). b A photomicrograph of a paraffin section in a rat cerebral cortex of tramadol group showing numerous P53 positive cells “Arrows” (anti P53 immunostain × 400). c A photomicrograph of a paraffin section in a rat cerebral cortex of pregabalin group showing few P53 positive cells “Arrows” (anti P53 immunostain × 400)

Fig. 4

a A photomicrograph of a paraffin section in a control rat cerebral cortex showing some positive cells (anti Ki 67 immunostain × 400). b A photomicrograph of a paraffin section in a rat cerebral cortex of tramadol group showing more positive cells and increased staining intensity with mitotic figures (anti Ki 67 immunostain × 400). c A photomicrograph of a paraffin section in a rat cerebral cortex of pregabalin group showing more positive cells as compared to the control group (anti Ki 67 immunostain × 400)

Fig. 5

a A photomicrograph of a paraffin section in a control rat cerebral cortex showing some positive GFAP immunostaining in the star-shaped glial cells and their processes (anti GFAP immunostain × 400). b A photomicrograph of a paraffin section in a rat cerebral cortex of the tramadol group showing more positive GFAP immunostaining in star-shaped glial cells with increased branches of their cytoplasmic processes (anti GFAP immunostain × 400). c A photomicrograph of a paraffin section in a rat cerebral cortex of the pregabalin group showing more positive GFAP immunostaining in star-shaped glial cells as compared to the control group (anti GFAP immunostain × 400)