title: Morphine protects against methylmercury intoxication: a role for opioid receptors in oxidative stress?
abstract: 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.
authors.affiliation: Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará (UFPA), Belém, Brasil.
authors.forename: Allan
authors.initials: A
authors.lastname: Costa-Malaquias
authors.affiliation: Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará (UFPA), Belém, Brasil.
authors.forename: Mauro B
authors.initials: MB
authors.lastname: Almeida
authors.affiliation: Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará (UFPA), Belém, Brasil.
authors.forename: José R
authors.initials: JR
authors.lastname: Souza Monteiro
authors.affiliation: Laboratório de Neuroquímica Molecular e Celular, Instituto de Ciências Biológicas, Universidade Federal do Pará (UFPA), Belém, Brasil.
authors.forename: Barbarella de Matos
authors.initials: Bde M
authors.lastname: Macchi
authors.affiliation: Laboratório de Neuroquímica Molecular e Celular, Instituto de Ciências Biológicas, Universidade Federal do Pará (UFPA), Belém, Brasil.
authors.forename: José Luiz M
authors.initials: JL
authors.lastname: do Nascimento
authors.affiliation: Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará (UFPA), Belém, Brasil.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Crespo-Lopez
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008767:Methylmercury Compounds / Q000633:toxicity*; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000008:administration & dosage; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011957:Receptors, Opioid / Q000378:metabolism*
chemical_list: D008767:Methylmercury Compounds; D011957:Receptors, Opioid; D009270:Naloxone; D009020:Morphine; C004925:methylmercuric chloride