AN ANTISENSE OLIGODEOXYNUCLEOTIDE TO MU-OPIOID RECEPTORS INHIBITS MU-OPIOID RECEPTOR AGONIST-INDUCED ANALGESIA IN RATS

We examined effects of an antisense oligodeoxynucleotide against the m u-opioid receptor on mu-opioid receptor agonist-induced antinociceptio n in the cold water (-3 degrees C) tail-flick test in rats. Rats were injected intracerebroventricularly (i.c.v.) with an antisense, sense o r missense oligodeoxynucleotide or artificial cerebrospinal fluid on d ays 1, 3 and 5. On day 6, antinociceptive effects of opioid agonists w ere tested. Compared to the artificial cerebrospinal fluid treatment, the cumulative dose-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 t reatment. Antisense oligodeoxynucleotide treatment reduced the analges ic effect of the mu-opioid receptor agonist PL017([N-MePhe(3),D-Pro(4) ]morphiceptin), but not the delta-opioid receptor agonist perazinyl)-3 -hydroxybenzyl)-N,N-diethyl-benzamide) or the kappa-opioid receptor ag onist spiradoline dinyl)-1-(oxaspiro-[4,5]dec-8-yl]ben-zeneacetamide m onohydrochloride). The drugs were given by i.c.v. injection. These fin dings indicate that i.c.v. administration of a mu antisense oligodeoxy nucleotide specifically blocks mu-, but not delta- or kappa-opioid rec eptor-mediated analgesia in the rat cold water tail-flick test.