Role of endogenous opioids in stress induced aberrations of cholesterol transport and disposition

Henry Uhlman Bryant, Purdue University

Abstract

Recent studies have indicated that stress induced activation of endogenous opioid systems leads to the development of gallstones and changes in hepatic cholesterol levels. Since gallstone disease and atherosclerosis have been linked etiologically, these studies were aimed at assessing the role of endogenous opioids in stress induced atherogenesis. Initial studies in mice demonstrated that chronic restraint stress or morphine administration led to increases in plasma, aortic and hepatic cholesterol levels. Pre-treatment with an opiate receptor antagonist, naltrexone (1.0 mg/kg) reversed these effects. Chronic loperamide administration had no effect on plasma or tissue cholesterol levels. In male rats, immobilization stress or morphine pellet implants (75 mg) led to naltrexone reversible elevations in circulating and aortic cholesterol levels. A second stressor, high intensity noise, raised the plasma cholesterol concentration but naltrexone did not reverse this effect. A third stressor, electric footshock, had no effect on plasma or tissue cholesterol. The latter stressors were not associated with a naltrexone reducible analgesia, while immobilization was. In female rats, plasma cholesterol levels were also elevated following immobilization or noise stress. However, the magnitude of the response tended to be smaller than that observed in male rats following immobilization and larger after noise stress. When compared to chronic (28 day) regimens, shorter treatment periods (i.e. 5 day or 2 hr) were associated with smaller elevations of plasma and aortic cholesterol following immobilization or morphine treatment. Liver cholesterol levels were not elevated after the shorter regimens, thereby, dissociating plasma cholesterol changes from hepatic cholesterol changes. Morphine and immobilization stress elevated low and very low density lipoprotein transported cholesterol and reduced high density lipoprotein cholesterol. Such changes have been positively associated with the development of coronary heart disease. These effects were reversed by naltrexone. In summary, endogenous opioid involvement in stress induced pre-atherogenic changes has been demonstrated by reversal of these effects by an opiate antagonist and duplication by morphine. These findings suggest that opiate antagonists may offer a novel prophylactic approach to the treatment of stress related heart disease.

Degree

Ph.D.

Advisors

Yim, Purdue University.

Subject Area

Pharmacology

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