Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence.
Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence.
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胆囊收缩素受体1介导外源性胆囊收缩素八肽对细胞吗啡依赖的抑制作用
DOI：
10.1186/1471-2202-13-63
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发表时间：
2012-06-08
期刊：
影响因子：
2.4
通讯作者：
Cong B
中科院分区：
文献类型：
--
作者：
Wen D;Ma CL;Zhang YJ;Meng YX;Ni ZY;Li SJ;Cong B
胆囊收缩素八肽（CCK-8）是最有效的内源性抗阿片肽，已被证明可调节吗啡依赖过程。在我们之前的研究中，我们发现外源性CCK-8可以减轻纳洛酮引起的戒断症状。为了研究外源性CCK-8的确切作用以及CCK1和/或2受体在吗啡依赖中的作用，我们采用μ-阿片受体、CCK1/2受体和内源性CCK共表达的SH-SY5Y细胞模型。结果吗啡（10 μM）作用SH-SY5Y细胞48 h后，纳洛酮（10 μM）诱导细胞cAMP过调，提示细胞吗啡依赖。慢性吗啡暴露后，CCK受体和内源性CCK均上调。1-10 μM的CCK2受体拮抗剂（LY-288,513）抑制纳洛酮沉淀的cAMP过调，但CCK1受体拮抗剂（L-364,718）没有。有趣的是，CCK-8 （0.1-1 μM）是一种强CCK受体激动剂，当与吗啡共预处理时，CCK-8剂量依赖性地抑制了SH-SY5Y细胞中纳洛酮沉淀的cAMP过调。L-364,718显著阻断了外源CCK-8对1-10 μM cAMP过调的抑制作用，而LY-288,513则没有。因此，CCK2受体似乎是低浓度内源性CCK增强SH-SY5Y细胞吗啡依赖性所必需的。CCK-8在较高浓度下的另一个抑制作用似乎与CCK1受体有关。结论本研究揭示了外源性CCK-8与内源性CCK对吗啡依赖发展的影响差异，为CCK1受体参与外源性CCK-8对吗啡依赖的抑制作用提供了第一个证据。
BackgroundCholecystokinin octapeptide (CCK-8), the most potent endogenous anti-opioid peptide, has been shown to regulate the processes of morphine dependence. In our previous study, we found that exogenous CCK-8 attenuated naloxone induced withdrawal symptoms. To investigate the precise effect of exogenous CCK-8 and the role of cholecystokinin (CCK) 1 and/or 2 receptors in morphine dependence, a SH-SY5Y cell model was employed, in which the μ-opioid receptor, CCK1/2 receptors, and endogenous CCK are co-expressed.ResultsForty-eight hours after treating SH-SY5Y cells with morphine (10 μM), naloxone (10 μM) induced a cAMP overshoot, indicating that cellular morphine dependence had been induced. The CCK receptor and endogenous CCK were up-regulated after chronic morphine exposure. The CCK2 receptor antagonist (LY-288,513) at 1–10 μM inhibited the naloxone-precipitated cAMP overshoot, but the CCK1 receptor antagonist (L-364,718) did not. Interestingly, CCK-8 (0.1-1 μM), a strong CCK receptor agonist, dose-dependently inhibited the naloxone-precipitated cAMP overshoot in SH-SY5Y cells when co-pretreated with morphine. The L-364,718 significantly blocked the inhibitory effect of exogenous CCK-8 on the cAMP overshoot at 1–10 μM, while the LY-288,513 did not. Therefore, the CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence in SH-SY5Y cells. An additional inhibitory effect of CCK-8 at higher concentrations appears to involve the CCK1 receptor.ConclusionsThis study reveals the difference between exogenous CCK-8 and endogenous CCK effects on the development of morphine dependence, and provides the first evidence for the participation of the CCK1 receptor in the inhibitory effects of exogenous CCK-8 on morphine dependence.
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