Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Eur J Pharmacol. 2013 Feb 28;702(1-3):62-70. doi: 10.1016/j.ejphar.2013.01.036. Epub 2013 Jan 30.
In this study, the effect of thymoquinone on morphine-induced tolerance and dependence in mice was investigated. Repeated administration of thymoquinone along with morphine attenuated the development of morphine tolerance, as measured by the hot plate test, and dependence, as assessed by naloxone-precipitated withdrawal manifestations. Concurrently, morphine-induced progressive increase in brain malondialdehyde (MDA) level and nitric oxide (NO) production as well as progressive decrease in brain intracellular reduced glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity were inhibited by co-administration of thymoquinone. Morphine-induced progressive increase in brain glutamate level was not inhibited by concomitant administration of thymoquinone. Similarly, co-administration of thymoquinone inhibited naloxone-induced increase in brain MDA level, NO overproduction and decrease in brain intracellular GSH level and GSH-Px activities but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The inhibitory effect of thymoquinone on morphine-induced tolerance and dependence on naloxone-induced biochemical alterations in morphine-dependent mice was enhanced by concurrent i.p. administration of the NMDA receptor antagonist, dizocilpine, the antioxidant, N-acetylcysteine or the NO synthase inhibitor, L-N (G)-nitroarginine methyl ester. On the other hand, this inhibitory effect of thymoquinone was antagonized by concurrent i.p. administration of NO precursor, L-arginine. In addition, concomitant administration of thymoquinone inhibited morphine tolerance and dependence-induced increase in inducible but not in neuronal NO synthase mRNA expression in mice brain. These results demonstrate that inhibition of morphine-induced oxidative stress, increase in the expression of brain inducible NO synthase and NO overproduction by thymoquinone can attenuate the development of morphine tolerance and dependence.
在这项研究中，研究了百里醌对吗啡诱导的小鼠耐受和依赖的影响。与吗啡一起重复给予百里醌可减轻吗啡耐受的发展，如热板试验所示，并且可减轻依赖，如纳洛酮诱发的戒断表现所评估。同时，百里醌抑制了吗啡诱导的脑丙二醛（MDA）水平和一氧化氮（NO）产生的进行性增加，以及脑内还原型谷胱甘肽（GSH）水平和谷胱甘肽过氧化物酶（GSH-Px）活性的进行性降低。同时给予百里醌不抑制吗啡诱导的脑谷氨酸水平的进行性增加。同样，百里醌抑制了纳洛酮诱导的脑 MDA 水平升高、NO 过产生以及脑内 GSH 水平和 GSH-Px 活性的降低，但不抑制吗啡依赖小鼠脑中脑谷氨酸水平的升高。同时给予 NMDA 受体拮抗剂地卓西平、抗氧化剂 N-乙酰半胱氨酸或一氧化氮合酶抑制剂 L-N（G）-硝基精氨酸甲酯可增强百里醌对吗啡诱导的耐受和依赖以及纳洛酮诱导的吗啡依赖小鼠生化改变的抑制作用。另一方面，这种百里醌的抑制作用被同时给予的 NO 前体 L-精氨酸所拮抗。此外，同时给予百里醌可抑制吗啡耐受和依赖诱导的诱导型但不是神经元型一氧化氮合酶 mRNA 表达的增加。这些结果表明，抑制吗啡诱导的氧化应激、脑诱导型一氧化氮合酶表达增加和 NO 过度产生，可减轻吗啡耐受和依赖的发展。
