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 sumatnptan was assessed in mice and rats (hot-plate, abdominal constnction and paw-pressure tests) and in guinea pigs (paw-pressure test). The ACh extracellular concentration also was detected in the hippocampus of freely moving rats by microdialysis experiments. Antinociception was induced by sumatriptan administered both parenterally (5-1 0 mg - kg1 i.V.; 1 0-30 mg - kg1 i.p.) and i.c.v. (50-100 .tg per mouse). Sumatriptan antinociception was potentiated by physostigmine (0.05 mg - kg1 i.p.) and was prevented by the muscarinic antagonist atropine (5 mg - kg1 i.p.), the ACh depletor HC-3 (1 ıtg per mouse i.c.v.) and the 5-hydroxytryptamine1ı antagonist 1 -(2-methoxyphenyl)- 4-[4-(2 phthalimido)butyl] piperazine (0.5 mg - kg1 i.p.). Naloxone, 3-aminopropyl-diethoxy-methyl-phosphinc acid, 2-methoxy- 4-amino-5-chlorobenzoic acid 2-(diethylamino) ethyl ester and reserpine, administered in doses suitable for blocking analgesia induced by morphine, baclofen, 5-hydroxytryptamine4 agonists and clomipramine, respectively, did not modify sumatriptan antinociception. Sumatnptan, administered in the range of antinociceptive doses, was able to increase the level of ACh present in extracellular hippocampal space. On the basis of these findings, we can deduce that sumatnptan was able to induce antinociception by increasing cholinergic activation in the CNS. Such activation, as indicated by the antagonism exerted by 1 -(2-methoxyphenyl)- 4-[4-(2 pethalimido)butyflpiperazine, may depend on stimulation of 5-hydroxytryptamine1ı autoreceptors. It remains to be clarified whether the antimigraine activity of sumatnptan in humans is totally dependent on cranial vessel vasoconstnction or whether its central cholinergic antinociception also plays a role.