Different studies have been shown a clear anticonvulsant activity exerted by cannabinoids (CB) through the CB1 receptor activation. The purpose of this study was to evaluate, in an in vivo experimental model of temporal lobe epilepsy (maximal dentate gyrus activation - MDA) in the rat, the protective effect of (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN 55,212-2, CB agonist) alone or in combination with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, selective CB1 antagonist). Pre-treatment with AM251 (1 mg kg-1, 30 min interval) dramatically reduced the significant anticonvulsant effect of WIN 55,212-2 (21 mg kg-1). However, in this experimental model, AM251 administration alone at the same dose, did not alter the number of DG responses to the AB stimulation nor the severity of MDA. Our data demonstrate the involvement of the CB system in the inhibitory control of hyperexcitability phenomena in a model of temporal lobe epilepsy. Moreover, the partial suppression of WIN 55,212-2-induced effects in rats pre-treated with AM251 allows to hypothesise an antiepileptic effect exerted by WIN 55,212-2 strictly linked to an increased CB1 receptor activation or to the functional involvement of an alternative receptor subtype.