Li Fei, Wu Ning, Su Rui-Bin, Liu Yin, Lu Xin-Qiang, Li Jin
Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.
Eur J Pharmacol. 2009 Jun 10;612(1-3):1-8. doi: 10.1016/j.ejphar.2009.03.077. Epub 2009 Apr 6.
Moxonidine and rilmenidine are classical imidazoline I(1) receptor agonists, and used as anti-hypertension drugs in clinical practice. Agmatine is an imidazoline I(1) receptor endogenous ligand as well as its agonist, but more and more evidences suggest it has no influence on blood pressure. In the present study we compared the effects of moxonidine, rilmenidine and agmatine in the development of morphine dependence, and investigated the role of imidazoline I(1) receptor in the effects of these agents. Chinese hamster ovary cells co-expressing mu opioid receptor and imidazoline receptor antisera-selected protein (IRAS), the strong candidate for imidazoline I(1) receptor, were used as the cell line. cAMP overshoot, which represents an opioid dependent state in vitro, was measured to study the effects on morphine dependence. siRNA against IRAS was carried out to investigate the role of imidazoline I(1) receptor. Moxonidine and rilmenidine (0.01-10 microM) were ineffective on cAMP level in the cells when given alone, and failed to inhibit chronic morphine exposure, naloxone-precipitated cAMP overshoot when co-pretreated with morphine. Agmatine (0.01-10 microM) by itself was ineffective but co-pretreated with morphine concentration-dependently inhibited chronic morphine exposure, naloxone-precipitated cAMP overshoot in the cells. Furthermore, we found that the inhibitory effect of agmatine (100 nM and 1 microM) on cAMP overshoot was significantly reduced by siRNA against IRAS. This study indicates that agmatine can inhibit the development of morphine dependence in vitro, whereas moxonidine and rilmenidine have no the effect. Imidazoline I(1) receptor plays an important role in agmatine inhibiting morphine dependence.
莫索尼定和利美尼定是经典的咪唑啉I(1)受体激动剂，在临床实践中用作抗高血压药物。胍丁胺是一种咪唑啉I(1)受体内源性配体及其激动剂，但越来越多的证据表明它对血压没有影响。在本研究中，我们比较了莫索尼定、利美尼定和胍丁胺在吗啡依赖形成中的作用，并研究了咪唑啉I(1)受体在这些药物作用中的作用。共表达μ阿片受体和咪唑啉受体抗血清选择蛋白（IRAS，咪唑啉I(1)受体的有力候选者）的中国仓鼠卵巢细胞被用作细胞系。通过测量代表体外阿片依赖状态的cAMP过冲来研究对吗啡依赖的影响。进行针对IRAS的小干扰RNA（siRNA）以研究咪唑啉I(1)受体的作用。单独给予时，莫索尼定和利美尼定（0.01 - 10微摩尔）对细胞内cAMP水平无效，并且在与吗啡共同预处理时不能抑制慢性吗啡暴露、纳洛酮诱发的cAMP过冲。胍丁胺（0.01 - 10微摩尔）本身无效，但与吗啡共同预处理时可浓度依赖性地抑制细胞内慢性吗啡暴露、纳洛酮诱发的cAMP过冲。此外，我们发现针对IRAS的siRNA可显著降低胍丁胺（100纳摩尔和1微摩尔）对cAMP过冲的抑制作用。本研究表明，胍丁胺可在体外抑制吗啡依赖的形成，而莫索尼定和利美尼定则无此作用。咪唑啉I(1)受体在胍丁胺抑制吗啡依赖中起重要作用。
