DELTA-OPIOID RECEPTOR SUBTYPES ACTIVATE INOSITOL-SIGNALING PATHWAYS IN THE PRODUCTION OF ANTINOCICEPTION

To analyze the selectivity of delta receptor subtypes to regulate diff erent classes of G proteins, the expression of the alpha-subunits of G i2, Gi3, Go1, Go2, Gq and G11 transducer proteins was reduced by admin istration of oligodeoxynucleotides (ODNs) complementary to sequences i n their respective mRNAs. Mice receiving antisense ODNs to G(i2)alpha, G(i3)alpha, G(o1)alpha and G(11)alpha subunits showed an impaired ant inociceptive response to all the delta agonists evaluated. An ODN to G (o1)alpha specifically blocked the antinociceptive effect of the agoni st of delta-1 receptors, [D-Pen(2,5)]enkephalin (DPDPE), without alter ing the activity of [o-Ala(2)]deltorphin II or [D-Ser(2)]-Leu-enkephal in-Thr (DSLET). In mice treated with an ODN to G(q) alpha, the effects of the agonists of delta-2-opioid receptors were reduced, but not tho se of DPDPE. Thus, Go1 proteins are selectively linked to delta-1-medi ated analgesia, and Gq proteins are related to delta-2-evoked antinoci ception. After impairing the synthesis of G(o1)alpha subunits, DPDPE e xhibited an antagonistic activity on the antinociception produced by [ D-Ala(2)]deltorphin II. After treatment with ODNs complementary to seq uences in G(q) alpha or PLC-beta 1 mRNAs, the analgesic capacity of [D -Ala(2)]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 analg esic potency of [D-Ala(2)]deltorphin II, but not that observed for DPD PE. In these mice, [D-Ala(2)]deltorphin II did not antagonize the effe ct of DPDPE. These results suggest the existence of different molecula r forms of the delta opioid receptor, and the involvement of inositol- signaling pathways in the supraspinal antinociceptive effects of delta agonists.