CHARACTERISTICS OF MU-OPIOID AND DELTA-OPIOID BINDING-SITES IN STRIATAL SLICES OF MORPHINE-TOLERANT AND MORPHINE-DEPENDENT MICE

Previously, we demonstrated the enhanced affinity of opioid receptors for naloxone in striatal slices from morphine-dependent mice. In our present study, binding characteristics of the mu-opioid receptor agonists, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) and dihydromorphine, the 8 opioid receptor agonist, (D-Ala2,D-Leu5]enkephalin (DADLE), and the opioid antagonist, naloxone, were examined in striatal slices from morphine-tolerant and -dependent mice. Striatal slices from mice that were implanted with a morphine pellet for 3,7 and 21 days displayed significant decreases in K(d) values (5.1, 4.6 and 5.5 nM, respectively) of [H-3]DAMGO when compared to those in slices from control animals that were not implanted or implanted with placebo pellets (9.6 and 9.3 nM, respectively). Also, a significant increase in the binding affinity of naloxone, but not that of dihydromorphine, was observed in striatal slices of mice that were implanted with a morphine pellet for 3 days. Significant increases in the B(max) of delta-binding sites in striatal slices of mice that were implanted with a morphine pellet for 3, 7 and 21 days (20.7, 18.1 and 17.7 pmol/mg tissue, respectively) were observed when compared to that in slices from control mice that were implanted with placebo pellets (11.4 pmol/mg tissue). The enhancement in the binding affinity of DAMGO and naloxone and the increased density of DADLE binding sites paralleled the development of morphine tolerance and dependence and [D-Pen2,D-Pen5] enkephalin cross-tolerance in whole animals. An antinociceptive potentiation between morphine and DAMGO was observed in morphine-tolerant and -dependent mice whereas in naive animals the effects of the two drugs were additive. The data support our previous findings and demonstrate the involvement of delta as well as mu-opioid binding sites in the development of morphine tolerance and dependence.