Recently, subtypes of the opioid delta receptor have been identified. It is not known, however, if a subtype of opioid delta receptor can be associated with the known modulatory action of delta agonists on mu-mediated antinociception. Thus, the present study has used the delta subtype-selective antagonists, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) (delta 1 antagonist) and naltrindole-5'-isothiocyanate (5'-NTII) (delta 2 antagonist) in an effort to determine whether the positive and negative modulation of morphine antinociception produced by opioid delta agonists was the result of activity at specific subtypes of opioid delta receptors. Intracerebroventricular morphine produced a dose-related antinociceptive effect which was not antagonized by coadministration of the delta 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 delta antagonist, ICI 174,864, or when the mice were pretreated with the delta 2 antagonist, 5'-NTII. In contrast, pretreatment with the delta 1 antagonist, DALCE, failed to affect either the positive or the negative modulatory actions of these delta agonists on morphine antinociception. The data suggest the involvement of an opioid delta 2 receptor in the modulation of morphine antinociception.