Antisense Oligodeoxynucleotides Targeting Distinct Exons of the Cloned mu-Opioid Receptor Distinguish Between Endomorphin-1 and Morphine Supraspinal Antinociception in Mice

Antisense oligodeoxynucleotides (ODN) were used to investigate the supraspinal antinociceptive effects of endomorphin-1, an endogenous peptide whose analgesic profile suggests that it is a ligand at the mu-opioid receptor. To selectively restrict the expression of this receptor, five ODN targeting distinct exons of the gene sequence were injected subchronically by the intracerebroventricular route (i.c.v.) into mice. The antinociception induced by endomorphin-1 was greatly reduced in animals receiving the ODN directed to nucleotides 677′697, which code for a sequence located on the second extracellular loop of the mu receptor. ODN-μ_un, one of the two antisense ODN directed to exon 1, also impaired endomorphin-1 antinociception. ODN targeting exons 2 and 4 were totally inactive. In contrast, all five ODN blocked the antinociception induced by morphine and β-casomorphin. The analgesic potency of endomorphin-1, morphine, and β-casomorphin remained unaltered by administration of an ODN to nucleotides 29′46 of the murine delta-opioid receptor gene sequence of a random-sequence ODN. This suggest the existence of diverse molecular forms for the mu-opioid receptor that mediate the antinociceptive effects of endomorphin-1 and morphine/β-casomorphin.