Interaction of [d-Pen², d-Pen⁵]enkephalin and [d-Ala², Glu⁴]deltorphin with δ-opioid receptor subtypes in vivo

The interaction of [d-Pen², d-Pen⁵]enkephalin (DPDPE) and [d-Ala², Glu⁴]deltorphin with δ-opioid receptor subtypes was investigated. Pretreatment of mice with the δ₁-opioid receptor antagonists, [d-Ala², Leu⁵, Cys⁶]enkephalin (DALCE), produced a virtually complete antagonism of the antinociceptive actions of DPDPE, but had no effect on those of [d-Ala², Glu⁴]deltorphin. In DALCE pretreated mice (i.e., δ₁-opioid receptors blocked), DPDPE was able to significantly antagonize the antinociceptive effects of [d-Ala², Glu⁴]deltorphin. Pretreatment of mice with the δ₂-opioid receptor antagonist, na naltrindole-5′-isothiocynate (5′-NTII) produced a virtually complete antagonism of the antinociceptive effects of [d-Ala², Glu⁴]deltorphin, but had no effect on the antinociception produced by DPDPE. In 5′-NTII pretreated mice (i.e., δ₂-opioid receptors blocked), [d-Ala², Glu⁴]deltorphin had no effect on the antinociception produced by DPDPE. These data suggest that [d-Ala², Glu⁴]deltorphin is highly selective for the δ₂-opioid receptor in vivo, and that neither agonist nor antagonist actions can be demonstrated at δ₁-opioid receptors for this peptide. In contrast, under appropriate conditions, DPDPE can be shown to interact with both δ₁- and δ₂-opioid receptor subtypes; DPDPE may have limited efficacy (i.e., is a partial agonist) at the δ₂-opioid receptor.