1 The effect on cholinergic analgesia of inactivation of the M-1 gene by an
antisense oligodeoxyribonucleotide (aODN) was investigated in the mouse ho
t plate test. Mice received a single intracerebroventricular (i.c.v.) injec
tion 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.
2 A dose-dependent inhibition of the antinociception induced by the muscari
nic agonists ortotremorine (0.1 mg kg(-1) s.c.) and McN-A-343 (30 mu g 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-cour
se experiments revealed that, after the end of the aODN treatment, sensitiv
ity to analgesic drugs progressively appeared reaching the normal range at
96 h.
3 The anti-M-1 aODN was selective against muscarinic antinociception since
the enhancement of pain threshold produced by morphine and baclofen were no
t affected by the above-mentioned treatment. dODN, used as control, did not
affect muscarinic antinociception.
4 Binding studies evidenced a selective reduction of M-1 receptor levels in
the hippocampus of aODN-treated mice.
5 Neither aODN, dODN nor vehicle produced any behavioural impairment of mic
e as revealed by the rota-rod and Animex experiments.
6 These results indicate that activation of M-1 muscarinic receptor subtype
is fundamental to induce central cholinergic analgesia in mice.