ANTINOCICEPTIVE AND ANTIAMNESIC PROPERTIES OF THE PRESYNAPTIC CHOLINERGIC AMPLIFIER PG-9

The antinociceptive effect of 3 alpha-tropyl 2-(p-bromophenyl)propiona te [(+/-)-PG-9] (10-40 mg kg(-1) s.c.; 30-60 mg kg(-1) p.o.; 10-30 mg kg(-1) i.v.; 10-30 mu g/mouse i.c.v.) was examined in mice, rats and g uinea pigs by use of the hot-plate, abdominal-constriction, tail-flick and paw-pressure tests. (+/-)-PG-9 antinociception peaked 15 min afte r injection and then slowly diminished. The antinociception produced b y (+/-)-PG-9 was prevented by the unselective muscarinic antagonist at ropine, the M-1-selective antagonists pirenzepine and dicyclomine and the acetylcholine depletor hemicholinium-3, but not by the opioid anta gonist naloxone, the gamma-aminobutyric acid, antagonist 3-aminopropyl -diethoxy-methyl-phosphinic acid, the H-3 agonist R-(alpha)-methylhist amine, the D-2 antagonist quinpirole, the 5-hydroxytryptamine antagoni st 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, the 5-hydroxytryptamine(1A) antagonist ethoxyphenyl)-4- [4-(2-phthalimido)butyl]piperazine hydrobromide and the polyamines dep letor reserpine. Based on these data, it can be postulated that (+/-)- PG-9 exerted an antinociceptive effect mediated by a central potentiat ion of cholinergic transmission, (+/-)-PG-9 (10-40 mg kg(-1) i.p.) was able to prevent amnesia induced by scopolamine (1 mg kg(-1) i.p.) and dicyclomine (2 mg kg(-1) i.p.) in the mouse passive-avoidance test. A ffinity profiles of (+/-)-PG-9 for muscarinic receptor subtypes, deter mined by functional studies (rabbit vas deferens for M-1, guinea pig a trium for M-2, guinea pig ileum for M-3 and immature guinea pig uterus for putative M-4), have shown an M-4/M-1 selectivity ratio of 10.2 th at might be responsible for the antinociception and the antiamnesic ef fect induced by (+/-)-PG-9 through an increase in acetylcholine extrac ellular levels. In the antinociceptive and antiamnesic dose range, (+/ -)-PG-9 did not impair mouse performance evaluated by the rota-rod tes t and Animex apparatus.