An antisense oligodeoxynucleotide to μ-opioid receptors inhibits μ-opioid receptor agonist-induced analgesia in rats

We examined effects of an antisense oligodeoxynucleotide against the μ-opioid receptor on μ-opioid receptor agonist-induced antinociception in the cold water (−3°C) tail-flick test in rats. Rats were injected intracerebroventricularly (i.c.v.) with an antisense, sense or missense oligodeoxynucleotide or artificial cerebrospinal fluid on days 1, 3 and 5. On day 6, antinociceptive effects of opioid agonists were tested. Compared to the artificial cerebrospinal fluid treatment, the cumulative does-effect curve for subcutaneous (s.c.) morphine was shifted to the right by the antisense oligodeoxynucleotide, but not by the missense oligodeoxynucleotide or the sense oligodeoxynucleotide treatment. Antisense oligodeoxynucleotide treatment reduced the analgesic effect of the μ-opioid receptor agonist PL017 ([ N-MePhe 3, d-Pro 4]morphiceptin), but not the δ-opioid receptor agonist BW373U86 ((±)-4-(( a-R∗)- a-((2 S∗,5 R∗)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)- N,N-diethyl-benzamide) or the κ receptor agonist spiradoline ((±)-(5 a,7 a,8 b)-3,4-dichloro- N-methyl- N-[7-(1-pyrrolidinyl)-1-(oxaspiro-[4.5]dec-8-yl]benzeneacetamide monohydrochloride). The drugs were given by i.c.v. injection. These findings indicate that i.c.v. administration of a μ antisense oligodeoxynucleotide specifically blocks μ-, but not δ- or κ-opioid receptor-mediated analgesia in the rat cold water tail-flick test.