Characteristics of μ and δ opioid binding sites in striatal slices of morphine-tolerant and -dependent mice

Abstract

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 (i opioid receptor agoiusts, [D-Ala 2MePhe 4Gly-ol 5]enkephalin (DAMGO) and dihydromorphine, the δ opioid receptor agonist, [D-Ala 2D-Leu 5enkephalin (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 [ 3H]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 δ 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-Pen 2D-Pen 5]enkephaun 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 δ as well as μ opioid binding sites in the development of morphine tolerance and dependence.