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 mu-opioid receptor on mu-opioid receptor agonist-induced antinociception in the cold water (-3 degrees 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 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 treatment. Antisense oligodeoxynucleotide treatment reduced the analgesic effect of the mu-opioid receptor agonist PL017 ([N-MePhe3,D-Pro4]morphiceptin), but not the delta-opioid receptor agonist BW373U86 ((+/-)-4-((a-R*)-a-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethyl-benzamide) or the kappa-opioid receptor agonist spiradoline ((+/-)-(5a,7a,8b)-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 mu antisense oligodeoxynucleotide specifically blocks mu-, but not delta- or kappa-opioid receptor-mediated analgesia in the rat cold water tail-flick test.
Chen
X H
XH
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Adams
J U
JU
Geller
E B
EB
DeRiel
J K
JK
Adler
M W
MW
Liu-Chen
L Y
LY
D000698:Analgesia; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D002555:Cerebrospinal Fluid / Q000378:metabolism; D004723:Endorphins / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D008969:Molecular Sequence Data; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists*
D000700:Analgesics; D001549:Benzamides; D004723:Endorphins; D016376:Oligonucleotides, Antisense; D010879:Piperazines; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C083877:BW 373U86; D009020:Morphine; C044708:morphiceptin, N-Me-Phe(3)-; C051272:spiradoline