The role of opiate mechanisms in the development of tolerance to the anorectic effects of amphetamines.

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.