STUDIES ON CHRONIC OPIATE ACTIVATION, GALLSTONE FORMATION, AND CHOLESTEROL TRANSPORT IN MICE

CELESTE CONSOLATA KUTA, Purdue University

Abstract

Objectives of this study were to determine if chronic opiate activation increases gallstone formation, if endogenous opioids mediate the increased gallstone risk of stress and diabetes, and if changes in cholesterol transport mediate opiate-induced lithogenicity. Female mice fed a lithogenic diet for four weeks were used in all experiments. Chronic morphine administration in drinking water increased the incidence and severity of gallstones, and reduced bile acid and phospholipid concentrations of gallbladder bile. These effects were reversed by naltrexone (1.0 mg/kg, 3 times weekly). Loperamide produced similar effects to morphine, suggesting that these effects were peripherally-mediated. Chronic immobilization stress increased the incidence and severity of gallstones, reduced bile acid and phospholipid concentrations without changing cholesterol levels of gallbladder bile, thereby increasing the lithogenic index. Naltrexone reversed all these effects except the increased lithogenic index. Adrenalectomy prevented the increased gallstone incidence implicating adrenal enkephalins. Chronic morphine and stress increased low-density lipoprotein (LDL) relative abundance, and increased cholesterol levels of serum, liver, and aorta. These findings, and the stress-induced increase in lithogenic index, are consistent with the putative role of LDL as a source of biliary and tissue cholesterol. These effects were reversed by naltrexone, but not by adrenalectomy. Loperamide did not affect lipoprotein or tissue cholesterol levels. Therefore, central opiate-induced increased LDL levels may explain the epidemiological finding of increased gallstone incidence in atherosclerosis. Streptozotocin-induced diabetes increased gallstone severity but not incidence, reduced bile acid and phospholipid levels of gallbladder bile, and did not increase the lithogenic index. Naltrexone partially reversed the bile composition changes and increased the lithogenic index. Streptozotocin treatment increased very low-density lipoprotein (VLDL) and decreased high-density lipoprotein (HDL) relative abundance. Cholesterol levels of serum, liver, and aorta were increased, consistent with findings that HDL inhibits tissue cholesterol uptake. Naltrexone did not reverse these effects emphasizing the difference between stress and streptozotocin. The reversal by naltrexone of stress-induced changes in cholesterol handling, bile composition, and gallstone formation suggests that endogenous opioids mediate these effects, and that opiate antagonists may be beneficial in treatment of gallstone disease.

Degree

Ph.D.

Subject Area

Pharmacology

COinS