Previous work has suggested the existence of subtypes of the delta opioid receptor (DOR) which have been termed delta1 and delta2. [D-Ala2, Glu4]deltorphin has been suggested to selectively elicit antinociception via the delta2 receptor while [D-Pen2, D-Pen5]enkephalin (DPDPE) is thought to act via the delta1 receptor. Treatment with an antisense oligodeoxynucleotide (oligo) directed towards the N-terminal portion of the cloned DOR has been demonstrated to selectively inhibit the antinociceptive actions of [D-Ala2, Glu4]deltorphin, but not of DPDPE, suggesting that the cloned DOR corresponds to that pharmacologically defined as delta2. Here, an antisense oligo (or a mismatch sequence) was designed to target a conserved region of the cloned mu, delta and kappa opioid receptor. These oligos were employed in order to determine whether the antinociceptive effects of [D-Ala2, Glu4]deltorphin, as well as DPDPE, could be inhibited. The data indicate that the antinociceptive actions of both ligands were inhibited by treatment with this antisense, but not with the mismatch oligo. Taken together, the results of the treatments with oligos directed towards the N-terminal portion of the cloned DOR and with that directed to the conserved region of the opioid receptors suggest that (a) DPDPE effects are mediated by a subtype of the DOR which shares a domain common to the cloned opioid receptors, and (b) the N-terminal region differs between these putative DOR subtypes.