Kielstein Anousheh, Tsikas Dimitrios, Galloway Gantt P, Mendelson John E
Addiction Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, St. Luke's Hospital, 3555 Cesar Chavez Street, San Francisco, CA 94110, USA.
Nitric Oxide. 2007 Sep;17(2):55-9. doi: 10.1016/j.niox.2007.05.005. Epub 2007 Jun 7.
Nitric oxide (NO) is generated from l-arginine by NO synthases, of which three forms have been identified: endothelial, inducible and neuronal (eNOS, iNOS and nNOS, respectively). The l-arginine metabolite asymmetric dimethylarginine (ADMA) is a potent, noncompetitive inhibitor of nNOS, while its congener N(G)-monomethyl-l-arginine (l-NMMA) is a less potent, competitive inhibitor. In rat neurons large amounts of ADMA are found, suggesting its importance in modulating neuronal activity. Humans generate approximately 300mumol ( approximately 60mg) ADMA per day. It is released from myelin basic proteins that are highly expressed in neuronal tissue. ADMA is mainly degraded by the action of the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which exists in two isoforms. DDAH1 is highly expressed in brain, suggesting specific function in this area. The presence of nNOS and DDAH1 in brain suggests that ADMA may have specific CNS activity and be more than an unregulated metabolite. Increased NO production-either prior to or concurrently with opioid administration-results in an enhanced rate and extent of development of tolerance to morphine in mice. NO produces an alteration in the mu-opioid receptor that increases constitutive receptor activity. It thereby reduces the ability of a selective mu-opioid agonist to activate the mu-opioid receptor; these in vitro molecular effects occur in a time course consistent with the in vivo development of antinociceptive tolerance in mice. Amongst many other synthetic NOS inhibitors of varying specificity, 7-nitroindazole (7-NI) has been shown to have a high affinity (IC(50) 0.71 microM) to nNOS. Selective blockade of nNOS by 7-NI attenuated morphine withdrawal in opiate dependent rats, suggesting nNOS as a viable target for development of pharmacotherapies. We hypothesize that, by inhibiting nNOS and reducing NO levels, ADMA may decrease mu-opiate receptor constitutive activity, resulting in alteration of the analgesic dose-response curve of morphine.
一氧化氮（NO）由一氧化氮合酶从L-精氨酸生成，已鉴定出三种形式：内皮型、诱导型和神经型（分别为eNOS、iNOS和nNOS）。L-精氨酸代谢产物不对称二甲基精氨酸（ADMA）是nNOS的一种强效非竞争性抑制剂，而其同类物N(G)-单甲基-L-精氨酸（L-NMMA）是一种效力较弱的竞争性抑制剂。在大鼠神经元中发现大量ADMA，表明其在调节神经元活动中具有重要作用。人类每天产生约300μmol（约60mg）ADMA。它从在神经组织中高度表达的髓鞘碱性蛋白中释放出来。ADMA主要通过二甲基精氨酸二甲胺水解酶（DDAH）的作用降解，DDAH存在两种同工型。DDAH1在大脑中高度表达，表明其在该区域具有特定功能。大脑中nNOS和DDAH1的存在表明ADMA可能具有特定的中枢神经系统活性，而不仅仅是一种不受调节的代谢产物。在给予阿片类药物之前或同时增加NO的产生，会导致小鼠对吗啡耐受性的发展速度和程度增强。NO会导致μ-阿片受体发生改变，从而增加受体的组成性活性。因此，它会降低选择性μ-阿片激动剂激活μ-阿片受体的能力；这些体外分子效应的时间进程与小鼠体内抗伤害感受耐受性的发展一致。在许多其他具有不同特异性的合成NOS抑制剂中，7-硝基吲唑（7-NI）已被证明对nNOS具有高亲和力（IC(50)为0.71μM）。7-NI对nNOS的选择性阻断减弱了阿片类药物依赖大鼠的吗啡戒断反应，表明nNOS是开发药物疗法的一个可行靶点。我们假设，通过抑制nNOS并降低NO水平，ADMA可能会降低μ-阿片受体的组成性活性，从而导致吗啡镇痛剂量反应曲线的改变。
