USE OF A MU-ANTISENSE OLIGODEOXYNUCLEOTIDE AS A MU-OPIOID RECEPTOR NONCOMPETITIVE ANTAGONIST IN-VIVO

We examined whether mu-antisense (AS) oligodeoxynucleotide (oligo) tre atment can be used in a manner similar to the mu-selective irreversibl e antagonist beta-funaltrexamine (beta-FNA) for in vivo pharmacology. Rats were injected intracerebroventricularly (icv) with a mu-AS or a m issense (MS) oligo on days 1, 3, 5, 7, and 9 and were tested for the a ntinociceptive effect of sc injection of morphine on days 2, 4, 6, 8, and 10 in the cold water tail-flick (CWT) test. In another set of expe riments, rats were also tested for the antinociceptive action of morph ine twenty-four hours after icv injection of beta-FNA. Both beta-FNA a nd mu-AS produced rightward shifts in the dose-effect curves of morphi ne. In addition, pretreatment with 2.5 mu g or more of beta-FNA or the mu-AS oligo for 5-9 days (but not for 1-3 days) reduced the maximal a nalgesic effect of morphine. The approximate fraction of functional re ceptor remaining for morphine was determined with the method of Furchg ott to be 49.5% following 2.5 mu g of beta-FNA; that after 5 days of t he mu-AS oligo treatment was 50.8%. The results suggest that the mu-AS oligo can be used in the same manner as highly selective, irreversibl e mu opioid receptor ligands. Thus, properly designed AS oligos agains t receptors are of particular benefit when irreversible antagonists ar e not available. AS oligos represent a new class of selective and powe rful pharmacological antagonists.