1 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
2 Pharmacutical Science Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran.
Int J Toxicol. 2018 Mar/Apr;37(2):164-170. doi: 10.1177/1091581817753607. Epub 2018 Mar 19.
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.
曲马多（TR）是一种具有中枢作用的合成阿片类药物，即使在治疗剂量下也可能引发癫痫。TR 对癫痫发作的影响的确切机制尚不清楚，但抑制 5-羟色胺和一氧化氮途径以及对 GABA 受体的抑制作用是 TR 引发癫痫机制的最常见假设。本研究旨在使用该系统的激动剂和拮抗剂药物来评估多巴胺能系统在 TR 诱导的癫痫发作和氧化损伤中的作用，在白化小鼠中进行研究。TR 诱导的强直-阵挛性癫痫发作作为癫痫发作阈值进行评估。氟哌啶醇（0.2mg/kg，IP），一种主要的 D 受体拮抗剂，和卡麦角林（0.5mg/kg，IP），一种针对 D 受体的多巴胺激动剂，在癫痫发作诱导前 60 分钟注射。多巴胺能拮抗剂显著增加癫痫发作阈值，但选择性激动剂预处理可显著降低癫痫发作阈值。与对照组相比，TR 可使脑线粒体中的氧化应激生物标志物（活性氧、脂质过氧化和蛋白质羰基含量）显著增加，谷胱甘肽含量显著降低，而与 TR 组相比，氟哌啶醇预处理可使氧化标志物显著降低。本研究表明，多巴胺能系统参与了 TR 诱导的癫痫发作，同时，多巴胺 D 受体的抑制可增加 TR 致癫痫发作的阈值并减少脑线粒体中的氧化损伤。相反，卡麦角林刺激多巴胺 D 受体可降低 TR 致癫痫发作的阈值和脑线粒体中的谷胱甘肽含量。
