This study aimed at providing an insight on the possible role of cannabinoid (CB) type 2 receptors (CB2R) and cGMP pathway in the antiepileptic activity of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone, a non-selective CB agonist, in the maximal dentate activation (MDA) model of partial epilepsy in adult male rats. We evaluated the activity of a CB2 antagonist/inverse agonist AM630, [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone or 6-iodopravadoline, alone or in co-administration with WIN 55,212-2. Also, in the MDA model it was investigated the co-treatment of WIN 55,212-2 and 1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the nitric oxide (NO)-activated soluble guanylyl cyclase (sGC), the cGMP producing enzyme. The WIN 55,212-2-dependent (21mg/kg) antiepileptic effects were significantly increased by the co-administration with AM630 and by the co-treatment with ODQ (10mg/kg). Whereas, the administration of AM630 (2mg/kg), alone exerts no effects on hippocampal hyperexcitability. Our data show that pharmacological blockade of CB2 receptors and of sGC seems to cooperate with WIN in its antiepileptic action. These findings shed light on CB signaling mechanisms, hinting that the modulation of the effects of CB agonist in the hyperexcitability phenomena may be exerted both by targeting CB receptors and their possible downstream effectors, such as nitrergic-dependent cGMP pathway.
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