A Novel Inhibitory Effect of Naloxone on Macrophage Activation and Atherosclerosis Formation in Mice

Objectives: We investigated whether naloxone could reduce macrophage activation and influence atherosclerotic lesion formation in mice. Background: Macrophages play an important role in the inflammatory process in atherosclerosis. Naloxone could inhibit activation of microglia, the resident macrophage in the nervous system. Methods: The anti-inflammatory effect of naloxone was evaluated by stimulating the macrophage cell culture and FVB mice with lipopolysaccharide or oxidized low-density lipoprotein with and without naloxone pretreatment. Apolipoprotein-E (apoE)-deficient mice received naloxone injection for 10 weeks, and the severity of aortic atherosclerosis was measured. The left common carotid arteries of C57BL/6 mice were ligated near the carotid bifurcation. The mice then received naloxone injection for 4 weeks after ligation, and the severity of neointima formation was evaluated. Results: Naloxone pretreatment significantly suppressed the production of tumor necrosis factor-α (TNF-α), interleukin-6, monocyte chemoattractant protein-1, and superoxide in macrophages after stimulation. In FVB mice, naloxone reduced the TNF-α level in circulation, inflammatory cell infiltration in lungs, and superoxide production in aorta. Naloxone injection significantly decreased the severity of aortic atherosclerosis in the apoE-deficient mice and carotid neointima formation in the C57BL/6 mice after ligation. Conclusions: Naloxone, with its novel anti-inflammatory effect, significantly reduces atherosclerosis and neointima formation in mice.