An antisense oligonucleotide on the mouse Shaker-like potassium channel Kv1.1 gene prevents antinociception induced by morphine and baclofen.
Inactivation of the Kv1.1 gene, which codes for a member of the Shaker-like potassium channels by an antisense oligodeoxyribonucleotide (aODN), was carried out in mice. The effect of this inactivation on analgesia induced by morphine (5-9 mg kg-1 s.c.) and baclofen (2-5 mg kg-1 s.c.) was investigated in the mouse hot-plate test. Mice received a single intracerebroventricular injection of mKv1.1 aODN (0.5, 1.0, 2.0 or 3.0 nmol per injection), degenerated ODN or vehicle on days 1, 4 and 7. A dose-dependent inhibiton of morphine and baclofen antinociception was observed 72 h after the last intracerebroventricular aODN injection, whereas degenerated ODN and vehicle, used as controls, did not affect morphine- and baclofen-induced antinociception. Sensitivity to both analgesic drugs returned to the normal range 7 days after the end of the aODN treatment, which indicated the absence of any irreversible damage or toxicity caused by aODN. Quantitative reverse transcription-polymerase chain reaction analysis demonstrated that a decrease in mKv1.1 mRNA levels occurred only in the aODN-treated group, being absent in all control groups. Furthermore, neither aODN, degenerated ODN nor vehicle produced any behavioral impairment of mice. These results indicate that the mKv1.1 potassium channel, whose gene expression we specifically modulated by means of the antisense ODN strategy, plays an important role in central analgesia induced by morphine and baclofen.
Galeotti
N
N
Department of Pharmacology, University of Florence, Italy.
Ghelardini
C
C
Papucci
L
L
Capaccioli
S
S
Quattrone
A
A
Bartolini
A
A
D000700:Analgesics / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015195:Drug Design; D005786:Gene Expression Regulation / Q000187:drug effects; D051662:Kv1.1 Potassium Channel; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000494:pharmacology*; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated
D000700:Analgesics; C496947:Kcna1 protein, mouse; D016376:Oligonucleotides, Antisense; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051662:Kv1.1 Potassium Channel; D009020:Morphine; D001418:Baclofen