SENSITIZATION TO KAPPA OPIOID MECHANISMS ASSOCIATED WITH TOLERANCE TO THE ANORECTIC EFFECTS OF CATHINONE

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. Despite sensitization to the hyperphagic effects of U50 in the chronic CATH group, 3H-bremazocine binding to crude synaptosomal membranes of whole brain did not differ between chronically water-, CATH-, or U50-treated animals. These results suggest that tolerance to the anorectic effects of an amphetamine-like agent is associated with a sensitization to kappa-opiate mediated activation of feeding.