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 pawpressure tests. In both species, BIMU 1 (lo-20 mg kg-’ s.c.and 40-60 mg kg-’ p.o. in mice; 20 mg kg-t i.p. in rats) and BIMU 8 (20-30 mg kg-’ S.C. and 60 mg kg-’ p.o. in mice; 20 mg kg-’ i.p. in rats), produced significant antinociception which was prevented by atropine (5 mg kg-’ i.p.), hemicholinium-3 (1 pg per mouse i.c.v.), SDZ 205-557 (10 mg kg-’ i.p.), GR 125487 (20 mg kg-’ i.p.) but not by naloxone (1 mg kg“ i.p.). CGP 35348 (100 mg kg-’ i.p.) and reserpine (2 mg kg-’ 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-’ s.c.) or baclofen (4 mg kg-’ s.c.) antinociception. Intracerebroventricular injection in mice of BIMU 1 (3 pg per mouse) and BIMU 8 (10 pg 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.