Mechanism of morphine addiction by inhibiting the soluble Guanylate Cyclase-Nitric Oxide (sGC-NO) pathway
Mechanism of morphine addiction by inhibiting the soluble Guanylate Cyclase-Nitric Oxide (sGC-NO) pathway
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DOI：
10.1016/j.mbs.2015.06.004
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发表时间：
2015-08-01
影响因子：
4.3
通讯作者：
Kumar, Amitesh
中科院分区：
文献类型：
--
作者：
Bhatt, Karan;Kumar, Amitesh
大量证据表明，吗啡会影响学习和记忆，从而导致成瘾。各种研究表明，它降低了通过可溶性鸟苷酸环化酶（sGC）和一氧化氮（NO）途径的抑制性gaba能突触传递（LTPGABA）。但吗啡如何抑制sGC-NO通路尚不清楚。在本研究中，我们借助数学模型展示了吗啡抑制LTPGABA的机制。采用两步sGC激活模型，吗啡在第一步抑制NO，从而阻断sGC激活。在这里，吗啡与mu-阿片受体的结合阻断了逆行移动的NO与sGC的结合，从而阻止了sGC的激活。结果，LTPGABA不会产生，这增加了成瘾的机会。同时揭示了吗啡抑制对吗啡解离、吗啡浓度、NO去除率、抑制率等主要参数的依赖性及其对成瘾的影响。(C) 2015爱思唯尔公司版权所有。
Ample evidence has shown that morphine influences learning and memory and thereby causing addiction. Various studies have shown that it decreases the inhibitory GABAergic synaptic transmission (LTPGABA) via the soluble guanylate cyclase (sGC) and nitric oxide (NO) pathway. But still it is unclear on how does morphine inhibit the sGC-NO pathway. In this study, we show the mechanism of LTPGABA inhibition by morphine with the help of a mathematical model. A two step model of sGC activation is used, where morphine inhibits NO during the first step and consequently blocks sGC activation. Here, morphine binding on mu-opioid receptors blocks the binding of retrogradely travelling NO to sGC and hence its activation. As a result, LTPGABA is not produced which increases the chances of addiction manifold. Alongwith the mechanism, the dependence of morphine inhibition on major parameters such as morphine dissociation, morphine concentration, NO removal & rate of inhibition and its effect on addiction is also shown. (C) 2015 Elsevier Inc. All rights reserved.