u-50488 and Anorexia

We have proposed that endogenous opioids play a critical role in the etiology of anorexia nervosa, mediating an auto-addiction, and that atypical opioid systems in mice may be representative of those in anorexia nervosa patients, in contrast to normal humans and rats. A biological predisposition to eating disorders may result from these atypical opioid systems. Definition of these systems as atypical is based on their responses to morphine, which are preferential for the mu receptor subtype. Three patterns have been described in four strains of mice: anorexia with hyperactivity (BALB/C and C57BL/J), anorexia without hyperactivity (DBA/J), and a biphasic curve (CF-1). The latter showed anorexia and hyperactivity at high doses but increased food intake without a change in motor activity at low doses. These patterns contrast to the increase in food intake and sedation in typical species, including rats and normal humans. In the present study, U50,488, a selective kappa agonist, increases food intake in all four mouse strains, as previously reported in rats. Thus, these two agonists have opposite effects on the atypical mouse systems, but similar effects on the typical rat system. The typical and atypical opioid systems respond oppositely to morphine but similarly to U50,488.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Anorexia; Eating; Endorphins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Morphine; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

To evaluate the possibility that tolerance to the anorectic effects of cathinone (CATH), an amphetamine-like compound, involves the sensitization of endogenous kappa opioid mechanisms, the influence of chronic treatment with CATH on the effects of the selective kappa opioid agonist U50488H (U50) on food and water intake was evaluated in rats. Since kappa agonists specifically increase urine output, the interaction between CATH and U50 on this physiological function was also evaluated. Acutely, CATH produced anorexia and diuresis, whereas water intake was not affected. U50 resulted in an increase in both food and water intake as well as urine output. After 9 days of daily CATH, tolerance to its anorectic effects had developed. In addition, water intake, which was not affected acutely by CATH, was significantly enhanced with respect to controls treated daily with water. In a group treated chronically with U50, its diuretic effect was unchanged, but water intake was no longer increased after 9 days of treatment. Food intake in this group remained higher than control intake for at least 19 days, but this hyperphagic effect was not detectable on day 34. On days 10 and 20 of the chronic regimen, the administration of U50 to the chronic CATH group resulted in a doubling of the hyperphagic response to U50, and this effect was naloxone-reversible. Water intake was also increased but to a lesser extent. The diuretic effect of U50 did not appear to be influenced by chronic CATH administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Alkaloids; Animals; Anorexia; Drinking; Drug Tolerance; Eating; Feeding and Eating Disorders; Male; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

To study the role played by opiate mechanisms in the tolerance to the anorectic effects of amphetamines, the influence of chronic treatment with d,1-amphetamine (AMPH) on the effects of the selective kappa opiate agonist U50488H (U50), of morphine (MORPH) and of diazepam (DZP) on food and water intake was evaluated in rats. Since diuresis is selectively enhanced by kappa agonists, its sensitivity to chronic AMPH was also evaluated. On the first day of AMPH treatment the feeding response to U50 was depressed. On day 9, when tolerance to the anorectic effects of AMPH had developed, this response was enhanced and prolonged. U50-mediated diuresis was not increased in the AMPH group. AMPH however produced diuresis by itself and this effect may be responsible for the increased water intake that developed during chronic treatment. The administration of MORPH (on day 17), but not of DZP (on day 13), produced a similar pattern of response. Interruption of AMPH treatment brought about a slow normalization of response to U50, that appeared to be completed after 17 days. An increase in feeding response to U50 was also obtained after 14 days of cathinone administration, confirming the amphetamine-like properties of this drug. In order to evaluate the possibility that preventing sensitization of opiate mechanisms could also prevent tolerance to anorectic effects of AMPH, we chronically administered MORPH in combination with AMPH, obtaining a further reduction of feeding and an apparent slowing in tolerance development. However, such a reduction was also obtained acutely, although MORPH alone produced feeding stimulation. We suggest that opiates may both activate and inhibit feeding and that AMPH inhibits the activatory branch and works synergically with the inhibitory branch. The prolonged inhibition of the activatory branch causes its compensatory hypertrophy resulting in hypersensitivity to exogenous opiates.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amphetamines; Animals; Anorexia; Diazepam; Drinking Behavior; Drug Tolerance; Feeding and Eating Disorders; Feeding Behavior; Male; Morphine; Pyrrolidines; Rats; Rats, Inbred Strains; Reference Values