Alonso Elba, Garrido Elisa, Díez-Fernández Carmen, Pérez-García Carmen, Herradón Gonzalo, Ezquerra Laura, Deuel Thomas F, Alguacil Luis F
Lab. Pharmacology and Toxicology, Universidad San Pablo CEU, 28668 Boadilla del Monte, Madrid, Spain.
Neurosci Lett. 2007 Jan 29;412(2):163-7. doi: 10.1016/j.neulet.2006.11.002. Epub 2006 Nov 22.
The alpha(2)-adrenoceptor antagonist yohimbine is known to oppose to several pharmacological effects of opioid drugs, but the consequences and the mechanisms involved remain to be clearly established. In the present study we have checked the effects of yohimbine on morphine-induced alterations of the expression of key proteins (glial fibrillary acidic protein, GFAP) and genes (alpha(2)-adrenoceptors) in rat brain areas known to be relevant in opioid dependence, addiction and individual vulnerability to drug abuse. Rats were treated with morphine in the presence or absence of yohimbine. The effects of the treatments on GFAP expression were studied by immunohistochemical staining in Locus Coeruleus (LC) and Nucleus of the Solitary Tract (NST), two important noradrenergic nuclei. In addition, drug effects on alpha(2)-adrenoceptor gene expression were determined by real time RT-PCR in the hippocampus, a brain area that receives noradrenergic input from the brainstem. Morphine administration increased GFAP expression both in LC and NST as it was previously reported in other brain areas. Yohimbine was found to efficiently prevent morphine-induced GFAP upregulation. Chronic (but not acute) morphine downregulated mRNA levels of alpha(2A)- and alpha(2C)-adrenoceptors in the hippocampus, while simultaneously increased the expression of the alpha(2B)-adrenoceptor gene. Again, yohimbine was able to prevent morphine-induced changes in the levels of expression of the three alpha(2)-adrenoceptor genes. These results correlate the well-established reduction of opioid dependence and addiction by yohimbine and suggest that this drug could interfere with the neural plasticity induced by chronic morphine in central noradrenergic pathways.
α₂肾上腺素能受体拮抗剂育亨宾已知可对抗阿片类药物的多种药理作用，但其后果及相关机制仍有待明确。在本研究中，我们检测了育亨宾对吗啡诱导的大鼠脑区关键蛋白（胶质纤维酸性蛋白，GFAP）和基因（α₂肾上腺素能受体）表达改变的影响，这些脑区已知与阿片类药物依赖、成瘾及个体对药物滥用的易感性相关。在有或没有育亨宾存在的情况下，给大鼠注射吗啡。通过免疫组织化学染色研究了这些处理对蓝斑（LC）和孤束核（NST）中GFAP表达的影响，这两个是重要的去甲肾上腺素能核团。此外，通过实时逆转录聚合酶链反应（RT-PCR）测定了药物对海马体中α₂肾上腺素能受体基因表达的影响，海马体是一个接受来自脑干去甲肾上腺素能输入的脑区。如先前在其他脑区所报道的那样，注射吗啡会增加LC和NST中的GFAP表达。发现育亨宾可有效预防吗啡诱导的GFAP上调。慢性（而非急性）吗啡会下调海马体中α₂A -和α₂C -肾上腺素能受体的mRNA水平，同时增加α₂B -肾上腺素能受体基因的表达。同样，育亨宾能够预防吗啡诱导的三种α₂肾上腺素能受体基因表达水平的变化。这些结果将育亨宾对阿片类药物依赖和成瘾的显著降低作用联系起来，并表明该药物可能会干扰慢性吗啡在中枢去甲肾上腺素能途径中诱导的神经可塑性。
