The in vivo effects of nociceptin (N/OFQ(1-13)NH(2) ) and its structural analogues ([Dab(9) ]N/OFQ(1-13)NH(2) , [Dap(9) ]N/OFQ(1-13)NH(2) and [Cav(9) ]N/OFQ(1-13)NH(2) ) on the levels of lipid peroxidation and cell antioxidants (enzyme and non-enzyme) in brain of control and kainic acid (KA)-treated rats were studied. In control animals, [Dab(9) ]N/OFQ(1-13)NH(2) and [Dap(9) ]N/OFQ(1-13)NH(2) , unlike N/OFQ(1-13)NH(2) and [Cav(9) ]N/OFQ(1-13)NH(2) , slightly increased the brain lipid peroxidation; the rest of the parameters were unchanged by all neuropeptides tested. KA (0.25 µg in 0.5 µl, i.c.v) increased the lipid peroxidation (4 and 24 h after KA-injection) and decreased the glutathione level (1 h after KA-administration). One hour after KA-administration, the neuropeptides (2 µg in 0.5 µl, injected 30 min before KA) showed the following effects: a slight decrease in the KA-induced lipid peroxidation by all nociceptin analogues and an enhancement of the KA-decreased GSH level, but by [Cav(9) ]N/OFQ(1-13)NH(2) only. The brain antioxidant enzyme activities were unchanged in all used experimental groups. In addition, the nociceptin analogues, especially [Can(9) ]N/OFQ(1-13)NH(2) , showed a good antioxidant capacity in chemical systems, generating reactive oxygen species. In conclusion, the substitution of lysin (Lys) in N/OFQ(1-13)NH(2) molecule with other amino acids might contribute to changes in its antioxidant properties. Copyright © 2011 John Wiley & Sons, Ltd.