Loss of muscarinic antinociception by antisense inhibition of M1 receptors.

1 The e ect on cholinergic analgesia of inactivation of the M1 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-M1 aODN (0.3, 1.0 or 2.0 nmol per injection), degenerate ODN (dODN) or vehicle on days 1, 4 and 7. 2 A dose-dependent inhibition of the antinociception induced by the muscarinic agonists oxotremorine (0.1 mg kg71 s.c.) and McN-A-343 (30 mg per mouse i.c.v.) and the cholinesterase inhibitor physostigmine (0.2 mg kg71 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. 3 The anti-M1 aODN was selective against muscarinic antinociception since the enhancement of pain threshold produced by morphine and baclofen were not a ected by the above-mentioned treatment. dODN, used as control, did not a ect muscarinic antinociception. 4 Binding studies evidenced a selective reduction of M1 receptor levels in the hippocampus of aODN-treated mice. 5 Neither aODN, dODN nor vehicle produced any behavioural impairment of mice as revealed by the rota-rod and Animex experiments. 6 These results indicate that activation of M1 muscarinic receptor subtype is fundamental to induce central cholinergic analgesia in mice.