Hippocampus is a brain structure responsible for memory, learning, spatial navigation and emotional processing. Hippocampus also plays an important role in several brain diseases, such as Alzheimer, temporal lobe epilepsy, depression, and schizophrenia. Neuronal activity of the hippocampus is regulated by endogenous opiates, such as β-endorphin. Two types of opioid receptors are expressed in the hippocampus: δ-opioid receptors in a high concentration and μ-opioid receptors in a low concentration [1]. It is known that δ-opioid receptors inhibit neuronal excitability. Activation of δ-opioid receptors can affect hippocampal excitability either directly by attenuation of adenylyl cyclase-cyclic adenosine monoposphate-protein kinase A signaling pathway [2] or indirectly by inhibition of GABAergic interneurons [3]. In the present study, we investigated the effect of δ-opioid receptors on the firing of action potentials in rat hippocampal neurons in primary culture. For our experiment we used the antagonist δ-opioid receptors naltrindole, which was applied in concentrations of 100 nM, 1 μM, 10 μM and 100 μM. Two modes of hippocampal excitability were analyzed: evoked action potential series and a spontaneous activity. Number of action potential in series decreased significantly after administration of 1 μM, 10 μM or 100 μM naltrindole from approximately 7 APs in control to 5 (1 and 100 μM) or 3 (10 μM) APs in series. Application of 100 nM naltrindole did not alter this parameter. Spontaneous activity was measured for 5 minutes under the control conditions and in the presence of naltrindole. Concentration dependence of spontaneous activity suppression was similar to that observed in evoked action potential series. Number of spikes significantly decreased after administration of 1 μM, 10 μM or 100 μM naltrindole. The lowest concentration (100 nM) seems to be a threshold concentration for this effect. Our results demonstrate involvement of δ-opioid receptors in control of excitability in hippocampal pyramidal neurons from newborn rat. Antagonist of these receptors naltrindole significantly suppressed firing of evoked AP series and spontaneous activity in micromolar concentrations. Because of their ability to regulate the generation of action potentials are δ-opioid receptors a potential target for the treatment of disorders of the central nervous system.