This study was undertaken to determine the effect of U50488, a kappa-opioid receptor agonist, on outwardly rectifying potassium channel (Ik) in undifferentiated PC12 cells. Using whole-cell and on-cell patch-clamp techniques, we found that U50488 decreased Ik amplitude in a time-dependent manner and Ik activation was delayed. Single-channel kinetic analysis provided a two-stage model for us to illuminate the blockage effect induced by U50488. To identify whether U50488 mediates the effect through opioid receptor and G-protein, several specific blockers and activators were used. Not only naloxone but also PTX and GDP beta S abolished U50488-induced suppression; however, such effect was not observed when cAMP or other adenylyl cyclase activators were used. It is postulated that K-opioid receptor and G(i/o) protein, but not cAMP, are involved in U50488-induced suppression of Ik. (c) 2005 Elsevier Inc. All rights reserved.