Treatment with antisense oligodeoxynucleotide to the opioid δ receptor selectively inhibits δ₂-agonist antinociception

Using approaches emphasizing differential antagonism of receptor selective agonists and cross-tolerance paradigms, evidence in vivo has suggested the existence of subtypes of opioid δ receptors, which have been termed δ₁ and δ₂. Recent work has elucidated the structure of an opioid δ receptor. The present investigation attempted to continue to test the hypothesis of subtypes of 5 receptors and to correlate the cloned δ receptor with the existing pharmacological classification. Synthetic oligodeoxynucleotides (oligos) complementary to the 5' end of the cloned δ receptor coding region (antisense) or its corresponding sequence (sense) were given by intracerebroventricular (i.c.v.) administration to mice, twice-daily for 3 days and antinociceptive responses to selective agonists at putative δ₁ and δ₂ receptors were subsequently determined. Treatment with antisense, but not sense, oligo significantly inhibited the response to [D-Ala², GIu⁴]deItorphin (δ₂ agonist), but not to [D-Pen², D-Pen⁵]enkephalin (DPDPE, δ₁ agonist). Further, subsequent administration of DPDPE elicited a full antinociceptive response in the same anti-sense oligo treated mice which did not show a significant response to [D-Ala², Glu⁴]deltorphin while antisense oligo treated mice which responded to DPDPE did not show antinociception when tested subsequently with [D-Ala², Glu⁴]deItorphin. The data suggest that the cloned δ receptor corresponds to that pharmacologically classified as δ₂ and continue to support the concept of subtypes of opioid δ receptors.