Roles of K + and cation channels in ORL-1 receptor-mediated depression of neuronal excitability and epileptic activities in the medial entorhinal cortex.

Nociceptin (NOP) is an endogenous opioid-like peptide that selectively activates the opioid receptor-like (ORL-1) receptors. The entorhinal cortex (EC) is closely related to temporal lobe epilepsy and expresses high densities of ORL-1 receptors. However, the functions of NOP in the EC, especially in modulating the epileptiform activity in the EC, have not been determined. We demonstrated that activation of ORL-1 receptors remarkably inhibited the epileptiform activity in entorhinal slices induced by application of picrotoxin or by deprivation of extracellular Mg2+. NOP-mediated depression of epileptiform activity was independent of synaptic transmission in the EC, but mediated by inhibition of neuronal excitability in the EC. NOP hyperpolarized entorhinal neurons via activation of K+ channels and inhibition of cation channels. Whereas application of Ba2+ at 300 μM which is effective for the inward rectifier K+ (Kir) channels slightly inhibited NOP-induced hyperpolarization, the current-voltage (I-V) curve of the net currents induced by NOP was linear without showing inward rectification. However, a role of NOP-induced inhibition of cation channels was revealed after inhibition of Kir channels by Ba2+. Furthermore, NOP-mediated augmentation of membrane currents was differently affected by application of the blockers selective for distinct subfamilies of Kir channels. Whereas SCH23390 or ML133 blocked NOP-induced augmentation of membrane currents at negative potentials, application of tertiapin-Q exerted no actions on NOP-induced alteration of membrane currents. Our results demonstrated a novel cellular and molecular mechanism whereby activation of ORL-1 receptors depresses epilepsy.