Evidence for the Involvement of the Dopaminergic System in Seizure and Oxidative Damage Induced by Tramadol

Abstract

Tramadol (TR) is a synthetic analgesic drug with central function that can induce seizures even at therapeutic doses. The exact mechanism of TR effect on seizure generation is not clear, but inhibition of the serotonin and nitric oxide pathways and inhibitory effects on GABA receptors are the most common hypotheses about the seizure-inducing mechanism of the TR. This study aimed to evaluate the role of dopaminergic system on the seizure and oxidative damage induced by TR using agonist and antagonist drugs of this system in the Albino mice. Clonic seizure induced by TR was evaluated as seizure threshold. Haloperidol (0.2 mg/kg, IP), a predominantly D receptor antagonist, and cabergolin (0.5 mg/kg, IP), a dopamine agonist specific for the D receptors, were injected 60 minutes before the seizure induction. The seizure threshold was significantly increased by dopaminergic antagonist, but it was decreased significantly by pretreatment with the selective agonist. Oxidative stress biomarkers (reactive oxygen species, lipid peroxidation, and protein carbonyl content) significantly increased and glutathione content significantly decreased in brain mitochondria by TR compared with the control group, whereas oxidative markers were decreased significantly after pretreatment with haloperidol compared with the TR group. This study revealed that the dopaminergic system is involved in TR-induced seizure, and meanwhile, inhibition of dopamine D receptors can increase the TR threshold seizure and decrease the oxidative damage in the brain mitochondria. Conversely, stimulation of dopamine D receptors by cabergolin can decrease the TR threshold seizure and glutathione content in the brain mitochondria.

Tramadol Promotes Oxidative Stress, Fibrosis, Apoptosis, Ultrastructural and Biochemical alterations in the Adrenal Cortex of Adult Male Rat with Possible Reversibility after Withdrawal

“…The mechanism underlying the increased generation of the reactive oxygen species (ROS) via tramadol consumption can be explained by the findings of Mohamed et al (2015), who reported a significant decrease in the activities of mitochondrial electron transport chain complexes I, III, and IV complexes, but not complex II, in rats exposed to tramadol abuse. Moreover, Bameri et al (2018) explained that the dopaminergic system is also involved in tramadol-induced oxidative damage.…”

The spinal NR2BR/ERK2 pathway as a target for the central sensitization of collagen-induced arthritis pain

“…Further investigation revealed that tramadol could reduce the synaptic phosphorylation state of NR2B at Tyr1472, which may be closely related to its effect on reduced spinal synaptic NR2BR expression. The analgesic mechanisms of tramadol are complicated, and in addition to the oxidative damage side effect of tramadol, which may also affect the pain perception process [ 34 , 35 ], further investigation will be required to elucidate the mechanisms in detail. The present study is the first to report that NR2BR might be a potential downstream target of tramadol.…”

Computational study on the molecular interactions of tramadol with selected antioxidant and detoxification enzymes in Drosophila melanogaster

“…Catalase (CAT) is a heme-containing enzyme that catalyses the dismutation of H2O2 to molecular oxygen and water, thereby lessening the risk of hydroxyl radical formation [37]. Several studies have pointed to the relationship between the chronic opioid administration and increased production of reactive oxygen species (ROS) [38,39,40]. Oxidative stress is an imbalance between ROS production of and the ability of antioxidant defenses to neutralize them.…”