Blockade of clomipramine and amitriptyline analgesia by an antisense oligonucleotide to mKv1.1, a mouse Shaker-like K + channel

Abstract

The effect of an antisense oligonucleotide to the K + channel coding mKv1.1 mRNA on antinociception induced by the tricyclic antidepressants, clomipramine (20–35 mg kg −1 s.c.) and amitriptyline (10–25 mg kg −1 s.c.), was investigated in the mouse hot-plate test. Antisense oligonucleotide (0.5-1.0-2.0-3.0 nmol per i.c.v. injection) produced a dose-dependent inhibition of clomipramine and amitriptyline antinociception 72 h after the last i.c.v. injection. The sensitivity to both analgesic drugs returned 7 days after antisense oligonucleotide injection, indicating the absence of irreversible damage or toxicity. Treatment with a degenerated oligonucleotide did not modify the clomipramine- and amitriptyline-induced antinociception in comparison with that in naive (unpretreated controls), vector and saline i.c.v.-injected mice. A quantitative reverse transcription-polymerase chain reaction (RT-PCR) study demonstrated a reduction in mRNA levels only in the antisense oligonucleotide treated group. Antisense oligonucleotide, degenerated oligonucleotide or vector pretreatment, in the range of doses used, did not produce any behavioural impairment as revealed by the mouse rotarod and hole-board tests. The present results indicate that modulation of the mKv1.1 K + channel plays an important role in the central analgesia induced by the tricyclic antidepressants, clomipramine and amitriptyline.