Childhood absence epilepsy (CAE) occupies a prominent position in the genetic generalized epilepsies because CAE is a quite common, accounting for 10—17% of all cases of epilepsy diagnosed in children. Orexin, a neuropeptide neurotransmitter that mainly regulates sleep/wake cycle, has been shown to be involved in epilepsy. Limited data is available about the possible role of orexinergic system in the pathophysiology of absence seizures. Orexin receptors are strongly expressed in cortical neurons in the rodent brain, and some of these neurons have extensive intracortical and thalamic projections. Intracerebral administration of selective OX2R agonist, YNT-185 suppressed the cumulative duration of spontaneous absence seizures in genetic absence epilepsy rats (GAERS) which is the most validated animal model of genetic absence epilepsy. Our study revealed a suppressive effect of OX2R agonist on absence seizures for the first time suggesting that orexin signaling may have a modulating effect on absence seizures in GAERS and might be targeted by therapeutic intervention for absence epilepsy. The challenge is now to determine whether this effect is mediated on cortical or subcortical level. Further studies will elucidate the structures underlying absence seizure modulatory effect of orexin signaling.