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.

Is Low Non-Lethal Concentration of Methylmercury Really Safe? A Report on Genotoxicity with Delayed Cell Proliferation

“…This study demonstrated that exposure to a low, sublethal and non-apoptotic concentration of methylmercury causes significant genotoxicity and disturbances of the cell cycle and proliferation in cells of glial origin. Exposure of C6 cells to MeHg for 24 h showed an LC 50 (the lethal concentration allowing 50% cellular viability) of 6.08 μM ( Fig 2 ), a similar value to those previously described in other cell lines or primary cultures of CNS [ 8 , 11 , 21 , 22 ]. Our results seem to be closer to those of primary cultures of human astrocytes exposed to this metal, compared to data using other glioma models in similar conditions [ 21 , 23 ].…”

Antioxidants Protect against Arsenic Induced Mitochondrial Cardio-Toxicity

“…Using morphine in clinical settings is controversial, particularly for chronic or non-cancer pain, based on concerns about addiction, safety, and efficacy [ 108 ]. Amini-Kohei et al (2016) is the only report we are aware of using morphine to prevent arsenic induced cardiovascular toxicity, but it is worth noting that the antioxidant properties of morphine have been reported to protect against methyl-mercury intoxication in rat glioma cells [ 109 ] and reverse oxidative damage in neuroblastomas [ 110 ], astrocytes [ 111 ], and microglial cells [ 107 ]. Proposed mechanisms for the antioxidant properties of morphine include direct scavenger activity [ 107 ] recovery of GSH levels [ 110 ], and/or inhibition of NADPH oxidase activity [ 112 ].…”

“…It is worth noting, however, that several recent double blind, placebo-controlled studies support the role of antioxidant amelioration of oxidative stress in humans. For example, 12-week supplementation with 100 mg resveratrol significantly ameliorated arterial stiffness and decreased serum diacron-reactive oxygen metabolites (d-ROMS)-a measure of oxidative stress- in type 2 diabetics [ 107 ], supplementation with 500 mg/day resveratrol significantly decreased oxidative stress (measured as serum MDA) in subjects with ulcerative colitis [ 108 ], and supplementation with α-lipoic acid in type-2 diabetics significantly increased SOD and GPx, and decreased MDA in subjects compared to baseline measures and compared to the placebo-control group [ 109 ]. Thus, recent clinical trials provide evidence that antioxidant’s ability to ameliorate oxidative stress translates to human subjects.…”

Towards Therapeutic Alternatives for Mercury Neurotoxicity in the Amazon: Unraveling the Pre-Clinical Effects of the Superfruit Açaí (Euterpe oleracea, Mart.) as Juice for Human Consumption

“…The MeHg-induced neurotoxicity is closely linked to oxidative stress and its subcellular consequences such as lipid peroxidation or genotoxicity [17,18,23,57,58]. A significant increase in lipid peroxidation was detected in the brains of exposed animals, including when no spontaneous neurobehavioral abnormalities were shown in the open field test (Figure 2 and Figure 5).…”