Central cholinergic antinociception induced by 5HT4 agonists: BIMU 1 and BIMU 8.
The antinociceptive effect of two 5-HT4 agonists, BIMU 1 and BIMU 8, were examined in mice and rats by using the hot-plate, abdominal constriction and paw-pressure tests. In both species, BIMU 1 (10-20 mg kg-1 s.c. and 40-60 mg kg-1 p.o. in mice; 20 mg kg-1 i.p. in rats) and BIMU 8 (20-30 mg kg-1 s.c. and 60 mg kg-1 p.o. in mice; 20 mg kg-1 i.p. in rats), produced significant antinociception which was prevented by atropine (5 mg kg-1 i.p.), hemicholinium-3 (1 microgram per mouse i.c.v.), SDZ 205-557 (10 mg kg-1 i.p.), GR 125487 (20 mg kg-1 i.p.) but not by naloxone (1 mg kg-1 i.p.), CGP 35348 (100 mg kg-1 i.p.) and reserpine (2 mg kg-1 i.p.). Moreover, BIMU 1 and BIMU 8 increase of pain threshold, is abolished by nucleus basalis magnocellularis (NBM) lesions in rats. SDZ 205-557 and GR 125487 which totally antagonized BIMU 1 and BIMU 8 antinociception did not modify morphine (7 mg kg-1 s.c.) or baclofen (4 mg kg-1 s.c.) antinociception. Intracerebroventricular injection in mice of BIMU 1 (3 micrograms per mouse) and BIMU 8 (10 micrograms per mouse), doses which were largely ineffective by parenteral routes, induces an antinociception whose intensity equaled that obtainable s.c., i.p. or p.o. In the antinociceptive dose-range, neither 5HT4 agonist impaired mice motor coordination evaluated by rota-rod test. On the basis of the above data, it can be postulated that BIMU 1 and BIMU 8 exerted an antinociceptive effect mediated by a central amplification of cholinergic transmission.
Ghelardini
C
C
Galeotti
N
N
Casamenti
F
F
Malmberg-Aiello
P
P
Pepeu
G
G
Gualtieri
F
F
Bartolini
A
A
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011950:Receptors, Cholinergic / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D062366:para-Aminobenzoates
D000700:Analgesics; D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D009943:Organophosphorus Compounds; D011950:Receptors, Cholinergic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D062366:para-Aminobenzoates; C070187:(endo-N-8-methyl-8-azabicyclo(3.2.1)oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; D044422:Receptors, Serotonin, 5-HT4; C066430:CGP 35348; D010129:4-Aminobenzoic Acid; C082871:GR 113808