Costa-Malaquias Allan, Almeida Mauro B, Souza Monteiro José R, Macchi Barbarella de Matos, do Nascimento José Luiz M, Crespo-Lopez María Elena
Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará (UFPA), Belém, Brasil.
Laboratório de Neuroquímica Molecular e Celular, Instituto de Ciências Biológicas, Universidade Federal do Pará (UFPA), Belém, Brasil.
PLoS One. 2014 Oct 17;9(10):e110815. doi: 10.1371/journal.pone.0110815. eCollection 2014.
Mercury is an extremely dangerous environmental contaminant responsible for episodes of human intoxication throughout the world. Methylmercury, the most toxic compound of this metal, mainly targets the central nervous system, accumulating preferentially in cells of glial origin and causing oxidative stress. Despite studies demonstrating the current exposure of human populations, the consequences of mercury intoxication and concomitant use of drugs targeting the central nervous system (especially drugs used in long-term treatments, such as analgesics) are completely unknown. Morphine is a major option for pain management; its global consumption more than quadrupled in the last decade. Controversially, morphine has been proposed to function in oxidative stress independent of the activation of the opioid receptors. In this work, a therapeutic concentration of morphine partially protected the cellular viability of cells from a C6 glioma cell line exposed to methylmercury. Morphine treatment also reduced lipid peroxidation and totally prevented increases in nitrite levels in those cells. A mechanistic study revealed no alteration in sulfhydryl groups or direct scavenging at this opioid concentration. Interestingly, the opioid antagonist naloxone completely eliminated the protective effect of morphine against methylmercury intoxication, pointing to opioid receptors as the major contributor to this action. Taken together, the experiments in the current study provide the first demonstration that a therapeutic concentration of morphine is able to reduce methylmercury-induced oxidative damage and cell death by activating the opioid receptors. Thus, these receptors may be a promising pharmacological target for modulating the deleterious effects of mercury intoxication. Although additional studies are necessary, our results support the clinical safety of using this opioid in methylmercury-intoxicated patients, suggesting that normal analgesic doses could confer an additional degree of protection against the cytotoxicity of this xenobiotic.
汞是一种极其危险的环境污染物，在全球范围内导致多起人类中毒事件。甲基汞是这种金属毒性最强的化合物，主要靶向中枢神经系统，优先在神经胶质起源的细胞中蓄积并引起氧化应激。尽管有研究表明当前人群存在汞暴露情况，但汞中毒的后果以及同时使用靶向中枢神经系统的药物（尤其是长期治疗中使用的药物，如镇痛药）的影响却完全未知。吗啡是疼痛管理的主要选择；在过去十年中其全球消费量增长了四倍多。有争议的是，有人提出吗啡在氧化应激中的作用独立于阿片受体的激活。在这项研究中，治疗浓度的吗啡部分保护了暴露于甲基汞的C6胶质瘤细胞系细胞的活力。吗啡处理还减少了脂质过氧化，并完全阻止了这些细胞中亚硝酸盐水平的升高。一项机制研究表明，在此阿片类药物浓度下，巯基没有改变，也没有直接清除作用。有趣的是，阿片拮抗剂纳洛酮完全消除了吗啡对甲基汞中毒的保护作用，表明阿片受体是这一作用的主要贡献者。综上所述，本研究中的实验首次证明，治疗浓度的吗啡能够通过激活阿片受体来减少甲基汞诱导的氧化损伤和细胞死亡。因此，这些受体可能是调节汞中毒有害影响的一个有前景的药理学靶点。尽管还需要进一步研究，但我们的结果支持在甲基汞中毒患者中使用这种阿片类药物的临床安全性，表明正常镇痛剂量可能会对这种外源性物质的细胞毒性提供额外程度的保护。
