<p>We investigated the involvement of NOP receptors in the response of the primary fibroblast culture to oxidative stress (OS) and in the mechanisms of the cytoprotective effect of the NALE peptide. OS led to a decrease in the number of cells in monolayers and the absence of mitotic figures, increased the proportion of p53⁺ cells and the area of the nucleus, and reduced the number of nucleoli. Preliminary incubation with a NOP receptor blocker J-113397 before OS showed its cytoprotective effect: the number of p53⁺ cells decreased, though still was significantly higher than in the control, the area of the cell nuclei corresponded to the control parameter, and the density of the cell culture increased. Preincubation with the NALE peptide also attenuated the effects of OS in the cell culture. The combined application of the NOP receptor blocker and NALE peptide had a protective effect. Changes in the nucleo-nucleolar apparatus of cells were similar to those observed after incubations with the NALE peptide: a significant increase in the area of nuclei, a decrease in the number of nucleoli, an increase in the total area of nucleoli, and a significant increase in the number of cells in monolayers were recorded. An increase in mitotic activity was found in comparison with the effects of NOP receptor blocker and OS. NOP receptor blocker exhibited a weak anabolic effect: the number of nucleoli and their total area increased. The study demonstrated preservation of the cytoprotective effect of the non-opiate analogue of leu-enkephalin against the background of NOP receptor blockade. Moreover, according to some indicators, there is a synergistic effect of the NALE peptide and the NOP receptor antagonist J-113397.</p>