title: 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.
authors.affiliation: Department of Pharmacology, Viale G. Pieraccini 6, University of Florence, I-50139 Florence, Italy. ghelard@server1.pharm.unifi.it
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
authors.forename: N
authors.initials: N
authors.lastname: Galeotti
authors.forename: A
authors.initials: A
authors.lastname: Bartolini
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D018727:Muscarinic Antagonists; D016376:Oligonucleotides, Antisense; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic