Abstract

To analyze the selectivity of delta receptor subtypes to regulate different classes of G proteins, the expression of the α-subunits of Gi2, Gi3, Go1, Go2, Gq and G11 transducer proteins was reduced by administration of oligodeoxynucleotides (ODNs) complementary to sequences in their respective mRNAs. Mice receiving antisense ODNs to G_i2α, G_i3α, G_o2α and G₁₁α subunits showed an impaired antinociceptive response to all the delta agonists evaluated. An ODN to G_o1α specifically blocked the antinociceptive effect of the agonist of delta-1 receptors, [d-Pen^2,5]enkephalin (DPDPE), without altering the activity of [d-Ala²]deltorphin II or [d-Ser²]-Leu-enkephalin-Thr (DSLET). In mice treated with an ODN to G_qα, the effects of the agonists of delta-2-opioid receptors were reduced, but not those of DPDPE. Thus, Go1 proteins are selectively linked todelta-1-mediated analgesia, and Gq proteins are related to delta-2-evoked antinociception. After impairing the synthesis of G_o1α subunits, DPDPE exhibited an antagonistic activity on the antinociception produced by [d-Ala²]deltorphin II. After treatment with ODNs complementary to sequences in G_qα or PLC-β1 mRNAs, the analgesic capacity of [d-Ala²]deltorphin II was diminished. However, the delta-2-agonist did not alter the antinociceptive activity of DPDPE. An ODN complementary to nucleotides 7 to 26 of the murine delta receptor reduced the analgesic potency of [d-Ala²]deltorphin II, but not that observed for DPDPE. In these mice, [d-Ala²]deltorphin II did not antagonize the effect of DPDPE. These results suggest the existence of different molecular forms of the delta opioid receptor, and the involvement of inositol-signaling pathways in the supraspinal antinociceptive effects of delta agonists.