Evidences of cannabinoids-induced modulation of paroxysmal events in an experimental model of partial epilepsy in the rat.
The anticonvulsant effect of cannabinoids (CB) has been shown to be mediated by the activation of the CB(1) receptor. This study evaluates the anticonvulsant activity of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN55,212-2, CB agonist) alone or preceded by the administration of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, selective CB(1) antagonist) in an experimental in vivo model of complex partial seizures (maximal dentate gyrus activation - MDA) in the rat. WIN55,212-2 (21mgkg(-1)) exerted an anticonvulsant effect, significantly reduced by the pre-treatment with AM251 (1mgkg(-1), 30 min interval). Surprisingly, AM251, administered alone at the same dose, failed to induce any modification in MDA responses. Our data suggest the involvement of the CB system in the inhibitory control of hyperexcitability phenomena in a model of acute partial epilepsy. Although the MDA model per se does not induce a basal activation of CB(1) receptors, as suggested by the lack of efficacy of AM251 when administered alone, the partial suppression of WIN55,212-2-induced effects in rats pre-treated with AM251 allows to hypothesise that the WIN55,212-2-induced antiepileptic effect is strictly linked to an increased CB(1) receptor activation or to the involvement of further receptor subtypes.
Rizzo
Valerio
V
Dipartimento di Medicina sperimentale, Sezione di Fisiologia umana G. Pagano, Università degli Studi di Palermo, Corso Tukory, 129 - 90134 Palermo, Italy.
Ferraro
Giuseppe
G
Carletti
Fabio
F
Lonobile
Gioacchino
G
Cannizzaro
Carla
C
Sardo
Pierangelo
P
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004828:Epilepsies, Partial / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone