Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Brain Res. 2013 May 13;1510:22-37. doi: 10.1016/j.brainres.2012.12.035. Epub 2013 Feb 8.
Peroxizome proliferator-activated receptor gamma (PPARγ) is highly expressed in the central nervous system where it modulates numerous gene transcriptions. Nitric oxide synthase (NOS) expression could be modified by simulation of PPARγ which in turn activates nitric oxide (NO)/soluble guanylyl-cyclase (sGC)/cyclic guanosine mono phosphate (cGMP) pathway. It is well known that NO/cGMP pathway possesses pivotal role in the development of opioid dependence and this study is aimed to investigate the effect of PPARγ stimulation on opioid dependence in mice as well as human glioblastoma cell line. Pioglitazone potentiated naloxone-induced withdrawal syndrome in morphine dependent mice in vivo. While selective inhibition of PPARγ, neuronal NOS or GC could reverse the pioglitazone-induced potentiation of morphine withdrawal signs; sildenafil, a phosphodiesterase-5 inhibitor amplified its effect. We also showed that nitrite levels in the hippocampus were significantly elevated in pioglitazone-treated morphine dependent mice. In the human glioblastoma (U87) cell line, rendered dependent to morphine, cAMP levels did not show any alteration after chronic pioglitazone administration while cGMP measurement revealed a significant rise. We were unable to show a significant alteration in neuronal NOS mRNA expressions by pioglitazone in mice hippocampus or U87 cells. Our results suggest that pioglitazone has the ability to enhance morphine-dependence and to augment morphine withdrawal signs. The possible pathway underlying this effect is through activation of NO/GC/cGMP pathway.
过氧化物酶体增殖物激活受体 γ (PPARγ) 在中枢神经系统中高度表达，调节众多基因转录。一氧化氮合酶 (NOS) 的表达可以通过模拟 PPARγ 来修饰，而 PPARγ 又可以激活一氧化氮 (NO)/可溶性鸟苷酸环化酶 (sGC)/环鸟苷酸 (cGMP) 途径。众所周知，NO/cGMP 途径在阿片类药物依赖的发展中起着关键作用，本研究旨在研究 PPARγ 刺激对小鼠和人神经胶质瘤细胞系中阿片类药物依赖的影响。吡格列酮增强了吗啡依赖小鼠体内纳洛酮诱导的戒断综合征。而选择性抑制 PPARγ、神经元 NOS 或 GC 可以逆转吡格列酮对吗啡戒断症状的增强作用；磷酸二酯酶-5 抑制剂西地那非增强了其作用。我们还表明，在吡格列酮处理的吗啡依赖小鼠的海马体中，亚硝酸盐水平显著升高。在人神经胶质瘤 (U87) 细胞系中，经过慢性吡格列酮处理后，cAMP 水平没有任何变化，而 cGMP 测量显示出显著升高。我们未能显示吡格列酮在小鼠海马体或 U87 细胞中对神经元 NOS mRNA 表达有显著改变。我们的结果表明，吡格列酮具有增强吗啡依赖和增强吗啡戒断症状的能力。这种作用的可能途径是通过激活 NO/GC/cGMP 途径。
