Delta opioid receptor subtypes activate inositol-signaling pathways in the production of antinociception

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(i2)α, G(i3)α, G(o2)α and G11α subunits showed an impaired antinociceptive response to all the delta agonists evaluated. An ODN to G(o1)α specifically blocked the antinociceptive effect of the agonist of delta-1 receptors, [D- Pen2.5]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(q)α, the effects of the agonists of delta-2-opioid receptors were reduced, but not those of DPDPE. Thus, Go1 proteins are selectively linked to delta-1-mediated analgesia, and Gq proteins are related to delta-2 evoked antinociception. After impairing the synthesis of G(o1)α subunits, DPDPE exhibited an antagonistic activity on the antinociception produced by [D-Ala2]deltorphin II. After treatment with ODNs complementary to sequences in G(q)α 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.