Differential antagonism of opioid delta antinociception by [D-Ala²,Leu⁵, Cys⁶]enkephalin and naltrindole 5'-isothiocyanate: Evidence for delta receptor subtypes

The present study has investigated the direct opioid delta receptor-mediated antinociception produced by i.c.v. administration of the highly selective delta agonists, [D-Pen²,D-Pen⁵]enkephalin (DPDPE) and [D-Ala²]deltorphin II, as well as that of the less delta-selective [D-Ser²,Leu⁵,Thr⁶]enkephalin (DSLET), by using two novel nonequilibrium opioid antagonists, [D-Ala²,Leu⁵,Cys⁶] enkephalin (DALCE) and naltrindole 5'-isothiocyanate (5'-NTII). At times ranging from 8 to 48 hr after a single i.c.v. pretreatment of mice with 5'-NTII, the antinociceptive effects of [D-Ala²] deltorphin II were significantly antagonized. In contrast, 5'-NTII pretreatment at times between 10 min and 24 hr failed to antagonize the antinociceptive effects of DPDPE. Previous studies have shown that pretreatment with i.c.v. DALCE produces a dose- and time-related antagonism of DPDPE, but not morphine, antinociception. However, pretreatment with i.c.v. DALCE failed to antagonize the antinociceptive effects of [D-Ala²]deltorphin II. Similarly, i.c.v. administration of DSLET produced time- and dose-related antinociception which was partially antagonized by either β-funaltrexamine (β-FNA) or by ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH), suggesting mixed activity at mu and delta receptors. ICI 174,864 produced essentially complete antagonism of DSLET antinociception in β-FNA-pretreated mice. Pretreatment with 5'-NTII (at -8 to -48 hr), blocked the antinociception produced by DSLET in control or in β-FNA-pretreated mice. In contrast, pretreatment with DALCE failed to antagonize the antinociception produced by i.c.v. DSLET in either control or in β-FNA-pretreated mice. These data show that the antinociceptive actions of [D-Ala²]deltorphin II and of DSLET are sensitive to the novel delta antagonist, 5'-NTII but not to DALCE. In contrast, the antinociception of DPDPE is sensitive to DALCE, but not to 5'-NTII. The differential antagonism of antinociception produced by these selective delta agonists suggests the existence of delta receptor subtypes.