chlornaltrexamine and Body-Weight

The effects of an irreversible long term opioid antagonism on circadian rhythms in body temperature (Tb), locomotor activity (Act) and feeding under normal conditions and following lipopolysaccharide administration (LPS; 2.5 mg/kg) have been investigated in unrestrained mice housed at their thermoneutral zone (30 degrees C). beta-chlornaltrexamine (beta-CNA; 5 mg/kg) given intraperitoneally decreased Tb on the day of injection, depressed Act, and reduced food and water intake for several days. The drug destroyed circadian rhythm in Tb for 4 consecutive days after administration due to prevention of the night time increases in temperature, whereas mean day time Tb of mice treated with beta-CNA remained similar to controls. Between days 5-8 the day-time Tb of beta-CNA-injected mice decreased, and the mice started displaying regular daily variations albeit with smaller amplitude and at lower level than controls. The depressive effect of beta-CNA on circadian variation in activity was more prolonged than its effect on Tb suggesting that these two variables are independently regulated. beta-CNA prevented the febrile response of the mice to LPS and enhanced the hypophagic effect of LPS. We conclude that normal circadian rhythms in Tb and Act, as well as certain symptoms of sickness behavior, have an opioid component.

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Circadian Rhythm; Drinking; Eating; Escherichia coli; Lipopolysaccharides; Male; Mice; Motor Activity; Naltrexone; Narcotic Antagonists; Telemetry

beta-Chlornaltrexamine (beta-CNA) is a non-equilibrium opioid receptor antagonist which alkylates and inactivates opioid receptors. Because opioid peptides are thought to contribute to the regulation of food intake, we examined the effects of intracerebroventricular (icv) injections of beta-CNA on the food intake and body weight of male rats. We also tested the ability of beta-CNA to block food intake stimulated by selective agonists of kappa, mu and delta opioid receptors: dynorphin A2 (DYN), Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAGO), and [(D-Ser2,Leu5]-enkephalin-Thr6 (DSLET). Treatment with beta-CNA caused a long-term (2-4 days) reduction in daily food intake and a concomitant reduction in body weight. An additional experiment indicated that the weight loss after beta-CNA treatment could be completely accounted for by the reduction in intake. beta-CNA treatment also abolished or greatly attenuated the feeding effects of DAGO, DSLET and DYN, even when these peptides were tested 26 hours after beta-CNA administration. The long duration of the effects of beta-CNA suggests that this compound will be a useful pharmacological tool in further study of the opioid feeding system.

Topics: Animals; Body Weight; Dynorphins; Eating; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; Male; Naltrexone; Oligopeptides; Rats; Rats, Inbred Strains; Receptors, Opioid