Vol. 283, Issue 3, 1342-1349, 1997

GR89,696 Is a Kappa-2 Opioid Receptor Agonist and a Kappa-1 Opioid Receptor Antagonist in the Guinea Pig Hippocampus

Robert M. Caudle, Andrew J. Mannes and Michael J. Iadarola

Pain and Neurosensory Mechanisms Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland (R.M.C., M.J.I.) and Department of Anesthesia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (A. J. M.)

Receptor binding studies and electrophysiological studies demonstrated the existence of at least two kappa opioid receptors, which have been designated kappa-1 and kappa-2. Several agonists and antagonists are selective for the kappa-1 receptor whereas no known ligands are selective for the kappa-2 receptor. In this study, the kappa opioid GR89,696 was tested in the guinea pig hippocampal slice preparation for kappa-1 versus kappa-2 activity. The perforant path-evoked population spike in the dentate was use to evaluate activity at the kappa-1 receptor, and the Schaffer collateral-evoked N-methyl-D-aspartate (NMDA) receptor-mediated synaptic current in CA3 pyramidal cells was used to measure kappa-2 receptor activation. GR89,696 had no effect on the perforant path-evoked dentate population spike; however, it did reverse the effects of the selective kappa-1 agonist U69,593 when co-perfused over the slices. In the CA3, GR89,696 inhibited the NMDA receptor-mediated synaptic current. The inhibition was antagonized by naloxone. The EC₅₀ for GR89,696 on the NMDA current was 41.7 nM (95% CL, 7.0-248 nM). These findings indicate that GR89,696 is an agonist for kappa-2 opioid receptors and an antagonist at kappa-1 receptors in the guinea pig hippocampus.