Vol. 285, Issue 2, 820-827, May 1998

Delta Opioid Receptor Subtypes Activate Inositol-Signaling Pathways in the Production of Antinociception¹

Pilar Sánchez-Blázquez and Javier Garzón

Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce 37, E-28002 Madrid, Spain

To analyze the selectivity of delta receptor subtypes to regulate different classes of G proteins, the expression of the -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, G_i3, G_o2 and G₁₁ subunits showed an impaired antinociceptive response to all the delta agonists evaluated. An ODN to G_o1 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_q, 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 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 or PLC-1 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.