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 (aOD N), was carried out in mice. The effect of this inactivation on analge sia 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 inhibition of morphine and baclofen antinocice ption was observed 72 h after the last intracerebroventricular aODN in jection, whereas degenerated ODN and vehicle, used as controls, did no t affect morphine- and baclofen-induced antinociception. Sensitivity t o both analgesic drugs returned to the normal range 7 days after the e nd of the aODN treatment, which indicated the absence of any irreversi ble damage or toxicity caused by aODN. Quantitative reverse transcript ion-polymerase chain reaction analysis demonstrated that a decrease in mKv1.1 mRNA levels occurred only in the aODN-treated group, being abs ent 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 s pecifically modulated by means of the antisense ODN strategy, plays an important role in central analgesia induced by morphine and baclofen.