Modulation of Mu-mediated antinociception in the mouse involves opioid delta-2 receptors

Recently, subtypes of the opioid δ receptor have been identified. It is not known, however, if a subtype of opioid δ receptor can be associated with the known modulatory action of δ agonists on μ-mediated antinociception. Thus, the present study has used the δ subtype-selective antagonists, [D- Ala²,Leu⁵,Cys⁶]enkephalin (DALCE) (δ₁ antagonist) and naltrindole-5'- isothiocyanate (5'-NTII) (δ₂ antagonist) in an effort to determine whether the positive and negative modulation of morphine antinociception produced by opioid δ agonists was the result of activity at specific subtypes of opioid δ receptors. Intracerebroventricular morphine produced a dose-related antinociceptive effect which was not antagonized by coadministration of the δ antagonist, ICI 174,864, or by pretreatment 24 hr before testing with the DALCE or 5'-NTII. Coadministration with morphine of a nonantinociceptive dose of DPDPE or [D-Ala²,Glu⁴]deltorphin resulted in a leftward displacement of the morphine dose-effect curve (i.e., positive modulation), whereas coadministration of a nonantinociceptive dose of [Met⁵]enkephalin with morphine resulted in a rightward displacement of the morphine dose-effect curve (i.e., negative modulation). Both the positive and the negative modulatory actions were antagonized when the experiment was conducted in the presence of the δ antagonist, ICI 174,864, or when the mice were pretreated with the δ₂ antagonist, 5'-NTII. In contrast, pretreatment with the δ₁- antagonist, DALCE, failed to affect either the positive or the negative modulatory actions of these δ agonists on morphine antinociception. The data suggest the involvement of an opioid δ₂ receptor in the modulation of morphine antinociception.