Pharmacologically selective block of mu opioid antinociception by peptide nucleic acid antisense in absence of detectable ex vivo knockdown.
The goal of this study was to determine the neuroanatomical extent of mu opioid receptor knockdown in central nervous system (CNS) following intracerebroventricular (i.c.v.) administration of peptide nucleic acid antisense. Rats received subchronic i.c.v. injections of anti-mu opioid receptor antisense, mismatch or vehicle, and were tested for paw pressure latency following i.c.v. mu opioid receptor agonist ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin; DAMGO) or delta opioid receptor agonist ((+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide; SNC80). The anti-mu opioid receptor antisense (but not mismatch) sequence abolished DAMGO-induced antinociception with no reduction in the delta opioid receptor-mediated response. In contrast, postmortem receptor autoradiographic analysis of CNS areas revealed no change in mu opioid receptor functional response ([35S]GTPgammaS assay) or receptor labelling ([125I]FK-33824 and mu opioid receptor immunoautoradiography). These results provide further evidence for antisense-induced knockdown at the behavioural level in the absence of clear changes at the tissue level.
Pradhan
Amynah A A
AA
Department of Pharmacology and Therapeutics, McGill University, 3655 Prom. Sir William Osler Room 1325 Montreal, Quebec, Canada, H3G 1Y6.
Clarke
Paul B S
PB
D000700:Analgesics / Q000037:antagonists & inhibitors / Q000378:metabolism; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D020135:Peptide Nucleic Acids / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000700:Analgesics; D000701:Analgesics, Opioid; D020319:Oligodeoxyribonucleotides, Antisense; D020135:Peptide Nucleic Acids; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-