Opposite effects of opiate agonists on metabolic weight loss in mice

Morphine (M) produced a dose-related decrease in metabolic weight loss (MWL) over a three-hour period, despite the fact that it significantly enhanced locomotor activity in male mice. This conservation of energy was specific to opioid receptors because naltrexone HCl (N) blocked it. These receptors were localized mainly to the periphery because a form of N that does not enter the brain, MR2663 BR (QN) eliminated the conservation response and instead increased MWL. The increase in MWL induced by M plus QN was blocked by MR2266 (MR), a specific kappa receptor antagonist. We suggest that this increase is due to the unmasking of a kappa opioid system located in the brain that acts to enhance energy expenditure. In support of this idea, administration of the kappa receptor agonist U-50, 488H (U) produced a dose-related increase in MWL to levels nearly twice that of saline controls, while markedly reducing locomotor activity. These actions were blocked by MR but not by N. They were not blocked by QN and this suggests they originate mainly in the brain. Increasing amounts of M caused increasing inhibition of metabolic weight loss induced by a constant amount of U. This supports the idea of an antagonistic relationship between the two opioid systems.