Central cholinergic antinociception induced by 5HT(4) 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 mu g 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 mu g per mouse) and BIMU 8 (10 mu g 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 5HT(4) 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.