# These authors contributed equally to this work. AbstractPurpose-In this study we evaluated the analgesic potential of demethylating drugs on oral cancer pain. While demethylating drugs could affect expression many genes, we focused on the mu-opioid receptor (OPRM1) gene pathway, because of its role in pain processing. We determined the antinociceptive effect of OPRM1 re-expression in a mouse oral cancer model.Experimental Design-Using a mouse oral cancer model we determined whether demethylating drugs produced antinociception through re-expression of OPRM1. We then reexpressed OPRM1 with adenoviral transduction and determined if, and by what mechanism, OPRM1 re-expression produced antinociception. To determine the clinical significance of OPRM1 on cancer pain, we quantified OPRM1 methylation in painful cancer tissues and non-painful contralateral normal tissues of oral cancer patients, and non-painful dysplastic tissues of oral dysplasia patients.Results-We demonstrated that OPRM1 was methylated in cancer tissue, but not normal tissue, of oral cancer patients, and not in dysplastic tissues from oral dysplasia patients. Treatment with demethylating drugs resulted in mechanical and thermal antinociception in the mouse cancer model. This behavioral change correlated with OPRM1 re-expression in the cancer and associated neurons. Similarly, adenoviral-mediated OPRM1 re-expression on cancer cells resulted in naloxone-reversible antinociception. OPRM1 re-expression on oral cancer cells in vitro increased beta-endorphin secretion from the cancer, and decreased activation of neurons that were treated with cancer supernatant.Conclusion-Our study establishes the regulatory role of methylation in cancer pain. OPRM1 re-expression in cancer cells produces antinociception through cancer-mediated endogenous opioid secretion. Demethylating drugs have an analgesic effect that involves OPRM1.
Background-Previous studies have already substantiated alcohol's causal role in injuries. Yet the role that alcoholic beverage preferences and the drinking context play in the risk for injury is still under-investigated. In this study a cross-national comparison of the association between alcohol and injury focusing on beverage type preference and the drinking context is reported.Methods-Emergency department injured patients were interviewed in eight countries from the Latin American and Caribbean (LAC) region. Data on the type of alcoholic beverage, total alcohol volume, and the place where the injury occurred were obtained from patients who reported any alcohol consumption within 6 hours prior to being injured. Patients who did not drink prior to injury were also asked about their typical drinking pattern and the injury place. Differences within-and between-groups were evaluated regarding patients' typical drinking and drinking before injury.Results-Beer was the most prevalent beverage type usually consumed among injured patients across countries, however, patients who drank before injury had a higher typical consumption of spirits than those not drinking prior to injury. The total alcohol volume typically consumed and drinking in public settings were also found to be positively associated with alcohol-related injury.Conclusions-A similar beverage-specific association with alcohol-related injury was found across LAC countries, mainly attributed to beer consumption, and spirits drinkers seem to have a greater chance of becoming involved in injury events. Future prevention strategies should inform the public about harms from drinking associated with the context in which drinking takes place.
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