Effects of antisense oligonucleotides on brain delta‐opioid receptor density and on SNC80‐induced locomotor stimulation and colonic transit inhibition in rats

To reduce the density of δ‐opioid receptor protein, five antisense phosphorothioate oligodeoxynucleotides (aODN), targeting the three exons of rat δ‐opioid receptor mRNA (DOR), were injected twice daily for 4 days or continuously infused for 7 days into brain lateral ventricles (i.c.v.) of Sprague‐Dawley rats. Rats acting as controls were infused or injected with a mismatch sequence (mODN) of each aODN. The density of opioid receptors in rat brain membranes was measured by saturation binding experiments using selective ligands for δ, μ and κ opioid receptors. aODNs injected twice a day for 4 days left rat brain δ‐opioid receptor density unchanged. The ODN targeting the DOR nucleotide sequence 280–299 (aODN 280–299 , exon 2), decreased brain δ‐opioid receptor density significantly more than aODNs targeting exon 1 (aODN 239–258 ), exon 2 (aODN 361–380 ), or exon 3 (aODN 741–760 ) (to 52% vs 79, 72, and 68%). None of the aODNs to the DOR changed the brain density of μ‐ or k‐opioid receptors. When in a novel environment (but not when kept in their home cages), the locomotor activity of aODN 280–299 treated rats was significantly lower than that of saline or mODN treated rats. The δ‐opioid agonist SNC80 (5 mg kg −1 , s.c.) significantly and potently stimulated locomotion and delayed colonic propulsion in saline‐ and mODN‐infused rats, but left motor behaviour and colonic transit of δ‐knockdown rats unchanged. The baseline nociceptive threshold and the antinociceptive response to morphine were unchanged in δ‐knockdown rats.British Journal of Pharmacology (1999) 128 , 1554–1560; doi: 10.1038/sj.bjp.0702931