Targeting peroxynitrite driven nitroxidative stress with synzymes: A novel therapeutic approach in chronic pain management.
Targeting peroxynitrite driven nitroxidative stress with synzymes: A novel therapeutic approach in chronic pain management.
复制标题
用合酶靶向过氧亚硝酸盐驱动的硝基氧化应激：慢性疼痛管理的一种新治疗方法。
DOI：
10.1016/j.lfs.2009.06.011
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发表时间：
2010
期刊：
影响因子：
6.1
通讯作者：
Neumann,William
中科院分区：
文献类型：
--
作者：
Salvemini,Daniela;Neumann,William
硫酸吗啡和其他阿片类/麻醉性镇痛药是治疗急性和慢性严重疼痛的最有效方法。然而，它们的临床应用往往受到镇痛耐受性发展的阻碍。这种复杂的病理生理循环显著导致了由于过度镇静、体力活动减少、呼吸抑制、便秘、成瘾可能性和其他副作用而导致的慢性疼痛受试者人群的生活质量下降。因此，人们对在重复给药期间维持阿片剂功效而不产生耐受性或不可接受的副作用的新方法越来越感兴趣。相当多的证据表明，氮氧化应激与多种病因的疼痛发展有关，重要的是与阿片类抗伤害耐受有关，这是由超氧化物O2−、（SO）一氧化氮NO（NO）和最近的过氧亚硝酸盐ONOO−或其共轭酸ONOOH（PN）的存在引起的，ONOO−或ONOOH（PN）是它们相互作用的产物。为此，已经开发了几种抗氧化剂合成酶（合成酶）以有效地防止PN的形成（超氧化物歧化酶模拟物，SODms）或一旦PN形成就将其分解（PN分解催化剂）。这篇关于PN和吗啡抗伤害性耐受的小型综述的目的是：1）总结新的合成酶作为治疗药物的最新进展，2）讨论氮氧化应激在阿片类药物抗伤害性耐受中的重要性，3）认为PN是疼痛管理中治疗干预的合理靶点。这些概念为开发PN生物合成抑制剂作为新型非麻醉性镇痛药提供了药理学基础，从而解决了目前尚未满足的大量医疗需求，并产生了重大的社会经济后果。
Morphine sulfate and other opiate/narcotic analgesics are the most effective treatments for acute and chronic severe pain. However, their clinical utility is often hampered by the development of analgesic tolerance. This complex pathophysiological cycle contributes significantly to decreased quality of life in the growing population of subjects with chronic pain due to oversedation, reduced physical activity, respiratory depression, constipation, potential for addiction, and other side-effects. Accordingly, there is growing interest in new approaches that would maintain opiate efficacy during repetitive dosing without engendering tolerance or unacceptable side-effects. Considerable evidence implicates nitroxidative stress in the development of pain of several etiologies and importantly in opiate antinociceptive tolerance, caused by the presence of superoxide, O2−, (SO) nitric oxide, NO (NO) and more recently peroxynitrite, ONOO−or its conjugate acid ONOOH, (PN) that is the product of their interaction. To this end, several antioxidant synthetic enzymes (synzymes) have been developed to effectively prevent the formation of PN (superoxide dismutase mimetics, SODms) or to decompose PN once it is formed (PN decomposition catalysts). The objectives of this mini-review written on PN and morphine antinociceptive tolerance are to 1) summarize recent advances made in the development of novel synzymes as therapeutics, 2) discuss the importance of nitroxidative stress in opiate anatinociceptive tolerance and 3) argue that PN is a rational target for therapeutic intervention in pain management. These concepts provide a pharmacological basis for developing inhibitors of PN biosynthesis as novel non-narcotic analgesics, thus addressing a large and currently unmet medical need with major socioeconomic consequences.