Backgrounds: Nalmefene, an opioid receptor modulator, is one of the reducing alcohol consumption drugs for patients with alcohol dependence. Opioid receptors have been reported to involve in peripheral inflammatory diseases such as colitis and arthritis in animal models. The uptake of oxidized low-density lipoprotein (oxLDL) in macrophages in atherosclerotic plaques develops atherosclerosis, one of the inflammatory diseases. In this study, we determined if nalmefene increases risk of atherosclerosis formation using apolipoprotein E knockout (ApoE KO) mice and peritoneal macrophages.
Methods and results: ApoE KO mice (8-week-old) were fed a high-fat diet and intraperitoneally administrated with vehicle (saline) or nalmefene (1 mg and 3 mg kg^-1 day^-1) for 21 days. Atherosclerotic lesions were histologically analyzed by oil red O-staining and immunohistochemistry using anti-MOMA2 (monocytes / macrophages) antibody. The atherosclerotic plaque formation in ApoE KO mice was dose-dependently progressed by nalmefene treatment. In addition, nalmefene significantly increased the MOMA2-positive area in aorta in ApoE KO mice. Next, to examine the effects of nalmefene on oxLDL uptake in peritoneal macrophage, peritoneal macrophages were treated with nalmefene (300 μg / mL) for 24 h and then DiI-labeled oxLDL (DiI-oxLDL) was added to the cells for 4 h. Nalmefene significantly increased DiI-oxLDL uptake in cells compared with vehicle (P<0.01).
Conclusion: Nalmefene may progress the atherosclerotic plaque formation via enhancing oxLDL uptake in macrophages.