Dietary History Affects the Potency of Chronic Opioid Receptor Subtype Antagonist Effects upon Body Weight in Rats

Body weight of rats placed acutely on a palatable diet is significantly reduced following chronic administration of μ (9%), κ₁ (3%) or δ₂ (6%) opioid antagonists. Whereas weight loss is comparable in lean Zucker rats (8–11%) following these antagonists, greater weight loss occurs in genetically-obese Zucker rats following chronic μ (10%) and δ₂ (7%), relative to κ₁ (2%) antagonism. The present study examined whether rats exposed to high-energy diets (6 weeks) that were either high-carbohydrate or high-fat displayed differential weight and intake reductions following chronic (7 days) daily central administration of equimolar doses (5,20,40 nmol) of selective μ(β-funaltrexamine), κ₁ (nor-binaltorphamine) or δ₂ (naltrindole isothiocyanate) opioid antagonists. The high-fat diet stimulated significantly greater weight gain (165 g) than the high-carbohydrate diet. Greater magnitudes and potencies of weight loss were noted for the high-fat diet following μ (11.5%, 3.0 nmol), δ₂ (8.4%, 0.01 nmol) and κ₁ (6.2%, 17.8 nmol) antagonists relative to the high-carbohydrate diet μ: 5.8%, 27.5 nmol; δ₂: 1.3%, >1000 nmol; κ₁: 2.4%, >1000 nmol). Antagonist-induced weight losses in either dietary group could not be predicted by corresponding intake alterations. These data underscore the importance of dietary history in mediating opioid antagonist effects upon weight, and establishes the μ receptor as the most consistent opioid mediator of weight control.