Effect of Chronic Treatment with Morphine on the Binding of 3H-N-n-Propylnorapomorphine to Striatal Membranes of Rats: Influence of Prolyl-Leucyl-Glycinamide

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Abstract
The effect of chronic administration of morphine to Sprague-Dawley rats on the binding of dopamine receptor agonist, 3H-N-n-propylnorapomorphine (3H-NPA) to striatal membranes was determined. For chronic administration of morphine, rats were implanted subcutaneously with four morphine pellets (each containing 75 mg of morphine free base) during a 3-day period. Placebo pellet-implanted rats served as controls. Two experimental protocols were followed. In one, the rats were sacrificed 70 h after the implantation of first pellet and in the other, the pellets were removed and the animals were sacrificed 24 h later, and the binding of 3H-NPA was determined. Rats receiving morphine showed no difference in the total number of binding sites (Bmax value) but there was a decrease in the apparent dissociation constant (Kd value) compared with placebo controls. Moreover, such a decrease in Kd in morphine-treated rats persisted even 24 h after removal of morphine pellets. The effect of prolyl-leucyl-glycinamide (MIF; 2 mg/kg), which has been shown to inhibit the development of tolerance to and dependence on morphine, on the changes in the binding of 3H-NPA induced by the implantation of morphine pellets was also determined. MIF antagonized the decreases in Kd values induced by the administration of morphine. However, when administered chronically by itself, MIF had no effect on either the Bmax or Kd values of 3H-NPA. It is concluded that the chronic administration of morphine is associated with enhanced activity of dopamine receptors in the central nervous system as revealed by lowering of the Kd value of the agonist, NPA. This effect was reversed by MIF, an agent known to inhibit the development of tolerance to and dependence on morphine.