THE CENTRAL CHOLINERGIC SYSTEM HAS A ROLE IN THE ANTINOCICEPTION INDUCED IN RODENTS AND GUINEA-PIGS BY THE ANTIMIGRAINE DRUG SUMATRIPTAN

The antinociceptive effect of the antimigraine drug sumatriptan was as sessed in mice and rats (hot-plate, abdominal constriction and paw-pre ssure tests) and in guinea pigs (paw-pressure test). The ACh extracell ular concentration also was detected in the hippocampus of freely movi ng rats by microdialysis experiments. Antinociception was induced by s umatriptan administered both parenterally (5-10 mg . kg i.v.; 10-30 mg . kg(-1) i.p.) and i.c.v. (50-100 mu g per mouse). Sumatriptan antino ciception was potentiated by physostigmine (0.05 mg . kg(-1) i.p.) and was prevented by the muscarinic antagonist atropine (5 mg . kg(-1) i. p.), the ACh depletor HC-3 (1 mu g per mouse i.c.v.) and the 5-hydroxy tryptamine(1A) antagonist 1-(2-methoxyphenyl)4-[4-(2 phthalimido)butyl ] piperazine (0.5 mg . kg(-1) i.p.). Naloxone, 3-aminopropyl-diethoxy- methyl-phosphinc acid, 2-methoxy-4-amino-5-chlorobenzoic acid 2-(dieth ylamino) ethyl ester and reserpine, administered in doses suitable for blocking analgesia induced by morphine, baclofen, 5-hydroxydryptamine (4) agonists and clomipramine, respectively, did not modify sumatripta n antinociception. Sumatriptan, administered in the range of antinocic eptive doses, was able to increase the level of ACh present in extrace llular hippocampal space. On the basis of these findings, we can deduc e that sumatriptan was able to induce antinociception by increasing ch ollinergic activation in the CNS. Such activation, as indicated by the antagonism exerted by 1-(2-methoxy-phenyl)-4-[4-(2 pethalimido)butyl] piperazine, may depend on stimulation of 5-hydroxytryptamine(1A) autor eceptors. it remains to be clarified whether the antimigraine activity of sumatriptan in humans is totally dependent on cranial vessel vasoc onstriction or whether its central cholinergic antinociception also pl ays a role.