Spontaneous transient outward currents have been found in peripheral neurons and smooth muscle cells, but rarely in central neurons. Using a nystatin-perforated patch clamp technique, we succeeded in recording spontaneous transient outward currents in mouse dentate gyrus granule cells. Nociceptin/orphanin FQ increased the amplitude and frequency of transient outward currents. We consider modulation of spontaneous transient outward currents to be a new means to regulate cell activity in central neurons, and studied their characteristics and mechanism of augmentation. The whole-cell current–voltage relationship showed outward rectification and the reversal potential was close to the equilibrium potential for K⁺. The frequency of spontaneous transient outward currents increased at depolarized potentials. Tetraethylammonium, iberiotoxin and a Ca²⁺ chelator BAPTA-AM inhibited spontaneous transient outward currents. These results suggest the involvement of large-conductance Ca²⁺-activated K⁺ channels. Single-channel recordings in the inside-out configuration revealed Ca²⁺-activated K⁺ channels with a conductance ranging from 82 to 352 pS. The augmenting effect of nociceptin/orphanin FQ was cancelled by [Phe¹ψ(CH₂-NH)Gly²]Nociceptin(1–13)NH₂. Cd²⁺ did not affect the transient outward currents or augmentation by nociceptin/orphanin FQ. Whereas nociceptin/orphanin FQ, theophylline and cyclic ADP ribose induced transient outward currents with short duration observed under control conditions, inositol 1,4,5-trisphosphate induced transient outward currents with long duration, in addition to those with short duration. Ryanodine inhibited nociceptin/orphanin FQ from augmenting spontaneous transient outward currents. Our data suggest that Ca²⁺ sparks transiently activate large-conductance Ca²⁺-activated K⁺ channels to induce transient outward currents. Nociceptin/orphanin FQ probably sensitizes ryanodine receptors and increases transient outward currents to reduce cell excitability.