Use of a mu-antisense oligodeoxynucleotide as a mu opioid receptor noncompetitive antagonist in vivo.
We examined whether mu-antisense (AS) oligodeoxynucleotide (oligo) treatment can be used in a manner similar to the mu-selective irreversible antagonist beta-funaltrexamine (beta-FNA) for in vivo pharmacology. Rats were injected intracerebroventricularly (icv) with a mu-AS or a missense (MS) oligo on days 1, 3, 5, 7, and 9 and were tested for the antinociceptive 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 experiments, rats were also tested for the antinociceptive action of morphine twenty-four hours after icv injection of beta-FNA. Both beta-FNA and mu-AS produced rightward shifts in the dose-effect curves of morphine. In addition, pretreatment with 2.5 micrograms or more of beta-FNA or the mu-AS oligo for 5-9 days (but not for 1-3 days) reduced the maximal analgesic effect of morphine. The approximate fraction of functional receptor remaining for morphine was determined with the method of Furchgott to be 49.5% following 2.5 micrograms of beta-FNA; that after 5 days of the 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, irreversible mu opioid receptor ligands. Thus, properly designed AS oligos against receptors are of particular benefit when irreversible antagonists are not available. AS oligos represent a new class of selective and powerful pharmacological antagonists.
Chen
X H
XH
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Liu-Chen
L Y
LY
Tallarida
R J
RJ
Geller
E B
EB
de Riel
J K
JK
Adler
M W
MW
D000818:Animals; D001483:Base Sequence; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D008969:Molecular Sequence Data; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology
D009292:Narcotic Antagonists; D016376:Oligonucleotides, Antisense; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine