Peroxynitrite and opiate antinociceptive tolerance: a painful reality.
Peroxynitrite and opiate antinociceptive tolerance: a painful reality.
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DOI：
10.1016/j.abb.2008.11.005
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发表时间：
2009-04-15
影响因子：
3.9
通讯作者：
Salvemini, Daniela
中科院分区：
文献类型：
--
作者：
Salvemini, Daniela
慢性疼痛是一个严重的全球性健康问题[1]。仅在美国，三分之一的美国人患有某种形式的慢性疼痛，在这些人中，超过30%的报告疼痛对镇痛治疗有抵抗力[1]。疼痛的经济影响同样巨大，每年约为1000亿美元[1]。虽然选择性环氧合酶-2（考克斯-2）抑制剂对几种形式的慢性疼痛有效，但它们偶尔的副作用包括增加心脏病发作和中风的风险[2]促使其中一些药物（即万络）在2004年从市场上突然撤出。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药物。然而，其临床应用通常受到镇痛耐受性的发展以及对无害和有害刺激的从头疼痛超敏反应的阻碍，在动物和人体研究中均观察到此类现象[3; 4; 5]。特别是对于吗啡，耐受性的发展需要逐步增加剂量以达到等效的疼痛缓解[6]，即使吗啡诱导的超敏反应的发作破坏了这种剂量增加的治疗效果[3; 4; 5]。这种复杂的病理生理循环显著降低了因过度镇静、体力活动减少、呼吸抑制、便秘、潜在成瘾和其他副作用而导致的慢性疼痛受试者人群的生活质量[6]。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，氮氧化应激与几种病因的疼痛发展有关，重要的是与阿片类镇痛耐受有关，这是由超氧化物、O2·-、一氧化氮、· NO和最近的过氧亚硝酸盐（ONOO-或其质子化对应物ONOOH）的存在引起的，后者是它们相互作用的产物（图1）。除了图1中描述的3种降低ONOO毒性的途径外，还有第四种途径：清除ONOOH中的自由基（尿酸盐、甲硫氨酸和酪氨酸肽是这一类的例子）[7]。
Chronic severe pain is a significant global health problem [1]. In the US alone, one third of Americans suffer some form of chronic pain, and in these individuals over 30% of reported pain is resistant to analgesic therapy [1]. The economic impact of pain is equally large at approximately $100 billion annually [1]. While selective cyclooxygenase-2 (COX-2) inhibitors are effective for several forms of chronic pain, their occasional side-effects including increased risks of heart attack and stroke [2] prompted the precipitous withdrawal of some of them (ie Vioxx) from the market in 2004.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 as well as by de novo painful hypersensitivity to innocuous and noxious stimuli with such phenomena observed in both animal and human studies [3; 4; 5]. For morphine in particular, development of tolerance necessitates escalating doses to achieve equivalent pain relief [6], even as the onset of morphine-induced hypersensitivity subverts the therapeutic impact of such dose increases [3; 4; 5]. 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 [6]. 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·-, nitric oxide,· NO and more recently peroxynitrite (ONOO-or its protonated counterpart ONOOH) that is the product of their interaction (Figure 1). In addition to the 3 routes of reducing ONOO-toxicity depicted in Figure 1, there is a fourth: scavenging of the radicals from ONOOH (urate, methionine and tyrosine peptides are examples in this category)[7].
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