The Journal of Neurophysiology Vol. 82 No. 4 October 1999, pp. 1776-1785
Copyright ©1999 by the American Physiological Society

Nociceptin Augments K⁺ Currents in Hippocampal CA1 Neurons by Both ORL-1 and Opiate Receptor Mechanisms

The Scripps Research Institute, Department of Neuropharmacology, La Jolla, California 92037

Madamba, Samuel G., Paul Schweitzer, and George Robert Siggins. Nociceptin Augments K⁺ Currents in Hippocampal CA1 Neurons by Both ORL-1 and Opiate Receptor Mechanisms. J. Neurophysiol. 82: 1776-1785, 1999. We previously reported (see also the accompanying paper) that dynorphin A significantly enhanced the voltage-dependent K⁺ M-current (I_M) in CA3 and CA1 hippocampal pyramidal neurons (HPNs). Because the opioid-receptor-like-1 (ORL-1) receptor shares a high sequence homology with opioid receptors and is expressed in rat hippocampus, we examined the effects of orphanin FQ or nociceptin, the endogenous ligand for the ORL-1 receptor, using the rat hippocampal slice preparation and intracellular voltage-clamp recording. Current-voltage (I-V) relationships from CA1 HPNs revealed that nociceptin superfusion induced an outward current reversing near the equilibrium potential for K⁺ ions. Ba²⁺ (2 mM) blocked this effect. The nociceptin-induced current was largest at depolarized membrane potentials, where I_M is largely activated. Nociceptin concentrations of 0.5-1 µM (but not 0.1 µM) significantly increased I_M relaxation amplitudes with recovery on washout. Interestingly, both the general opiate antagonist naloxone and the  receptor antagonist nor-binaltorphimine (nBNI) inhibited the nociceptin-induced I_M increases and outward currents in the depolarized range but not the inward current induced at hyperpolarized potentials. The putative ORL-1 receptor antagonist, [Phe¹(CH₂-NH)Gly²]NC(1-13)NH₂ (hereafter ORLAn), blocked most of the nociceptin current near rest but not the I_M increase. However, ORLAn alone had direct effects similar to those of nociceptin, indicating that ORLAn might be a partial agonist. Our results suggest that nociceptin postsynaptically modulates the excitability of HPNs through ORL-1 and -like opiate receptors linked to different K⁺ channels.