Loss of muscarinic antinociception by antisense inhibition of M(1) receptors.

ABSTRACT: The effect on cholinergic analgesia of inactivation of the M(1) gene by an antisense oligodeoxyribonucleotide (aODN) was investigated in the mouse hot plate test. Mice received a single intracerebroventricular (i.c.v.) injection of anti-M(1) aODN (0.3, 1. 0 or 2.0 nmol per injection), degenerate ODN (dODN) or vehicle on days 1, 4 and 7. A dose-dependent inhibition of the antinociception induced by the muscarinic agonists oxotremorine (0.1 mg kg(-1) s.c.) and McN-A-343 (30 microg per mouse i.c.v.) and the cholinesterase inhibitor physostigmine (0.2 mg kg(-1) s.c.) was observed 24 h after the last i.c.v. injection of aODN. Time-course experiments revealed that, after the end of the aODN treatment, sensitivity to analgesic drugs progressively appeared reaching the normal range at 96 h. The anti-M(1) aODN was selective against muscarinic antinociception since the enhancement of pain threshold produced by morphine and baclofen were not affected by the above-mentioned treatment. dODN, used as control, did not affect muscarinic antinociception. Binding studies evidenced a selective reduction of M(1) receptor levels in the hippocampus of aODN-treated mice. Neither aODN, dODN nor vehicle produced any behavioural impairment of mice as revealed by the rota-rod and Animex experiments. These results indicate that activation of M(1) muscarinic receptor subtype is fundamental to induce central cholinergic analgesia in mice.

SUBMITTER: Ghelardini C 

PROVIDER: S-EPMC1572021 | biostudies-literature | 2000 Apr

REPOSITORIES: biostudies-literature