Vol. 284, Issue 3, 806-816, March 1998

Antinociceptive and Antiamnesic Properties of the Presynaptic Cholinergic Amplifier PG-9¹

Carla Ghelardini, Nicoletta Galeotti, Fulvio Gualtieri, Vittorio Marchese, Cristina Bellucci and Alessandro Bartolini

Department of Pharmacology (C.G., N.G., V.M., A.B.), University of Florence, Viale G.B. Morgagni 65, I-50134 and Department of Pharmaceutical Sciences (F.G., C. B.), University of Florence, Via G. Capponi 9, I-50121 Florence, Italy

The antinociceptive effect of 3-tropyl 2-(p-bromophenyl)propionate [(±)-PG-9] (10-40 mg kg¹ s.c.; 30-60 mg kg¹ p.o.; 10-30 mg kg¹ i.v.; 10-30 µg/mouse i.c.v.) was examined in mice, rats and guinea pigs by use of the hot-plate, abdominal-constriction, tail-flick and paw-pressure tests. (±)-PG-9 antinociception peaked 15 min after injection and then slowly diminished. The antinociception produced by (±)-PG-9 was prevented by the unselective muscarinic antagonist atropine, the M₁-selective antagonists pirenzepine and dicyclomine and the acetylcholine depletor hemicholinium-3, but not by the opioid antagonist naloxone, the -aminobutyric acid_B antagonist 3-aminopropyl-diethoxy-methyl-phosphinic acid, the H₃ agonist R-()-methylhistamine, the D₂ antagonist quinpirole, the 5-hydroxytryptamine₄ antagonist 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, the 5-hydroxytryptamine_1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide and the polyamines depletor reserpine. Based on these data, it can be postulated that (±)-PG-9 exerted an antinociceptive effect mediated by a central potentiation of cholinergic transmission. (±)-PG-9 (10-40 mg kg¹ i.p.) was able to prevent amnesia induced by scopolamine (1 mg kg¹ i.p.) and dicyclomine (2 mg kg¹ i.p.) in the mouse passive-avoidance test. Affinity profiles of (±)-PG-9 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M₁, guinea pig atrium for M₂, guinea pig ileum for M₃ and immature guinea pig uterus for putative M₄), have shown an M₄/M₁ selectivity ratio of 10.2 that might be responsible for the antinociception and the antiamnesic effect induced by (±)-PG-9 through an increase in acetylcholine extracellular levels. In the antinociceptive and antiamnesic dose range, (±)-PG-9 did not impair mouse performance evaluated by the rota-rod test and Animex apparatus.