Morphine protects against methylmercury intoxication: a role for opioid receptors in oxidative stress?

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.

Molecular chaperones: toward new therapeutic tools.

Molecular chaperones (or heat shock proteins) are evolutionarily conserved and essential proteins that play a key role in cell survival through cytoprotective mechanisms. Despite their possible clinical applications, the understanding of these structures is still quite limited. The aim of the present study is to review the literature to understand the physiological importance, implication in various diseases (especially in cancer and neurodegenerative diseases), possible applicability, and future prospects of heat shock proteins. The cytoprotective mechanisms of molecular chaperones can be co-opted by oncogenic processes favoring tumor growth, invasion, evasion of apoptosis, and metastasis, thus making inhibitors to these molecules possible therapeutic options for cancer patients. However, there is also evidence showing that upregulation of heat shock proteins can have an antineoplastic effect through immunomodulatory activity. This is why chaperones have already been investigated for conventional chemotherapy under specific conditions, yielding interesting results. The induction of heat shock protein activity is also of potential benefit in many other diseases where structural and functional preservation of proteins may enhance cell survival, including neurodegeneration, trauma, stroke, and cardiovascular disease. In addition, the immune properties of chaperones can potentially be exploited for such diseases as diabetes, atherosclerosis, and other chronic inflammatory conditions. Thus, continuing efforts to clarify the role of chaperones may guide the development of new therapeutic modalities capable of minimizing the impact of diseases such as cancer, heart disease, and diabetes as well as obtaining better results in neurological conditions currently lacking alternative treatments.