GR89,696 IS A KAPPA-2 OPIOID RECEPTOR AGONIST AND A KAPPA-1 OPIOID RECEPTOR ANTAGONIST IN THE GUINEA-PIG HIPPOCAMPUS

Receptor binding studies and electrophysiological studies demonstrated the existence of at least two kappa opioid receptors, which have been designated ka,apa-l and kappa-2, Several agonists and antagonists are selective for the kappa-1 receptor whereas no known ligands are selec tive for the kappa-2 receptor. In this study, the kappa opioid GR89,69 6 was tested in the guinea pig hippocampal slice preparation for kappa -l versus kappa-2 activity, The perforant path-evoked population spike in the dentate was use to evaluate activity at the kappa-l receptor, and the Schaffer collateral-evoked N-methyl-D-aspartate (NMDA) recepto r-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 effe cts of the selective kappa-l agonist U69,593 when co-perfused over the slices. In the CA3, GR89,696 inhibited the NMDA receptor-mediated syn aptic current. The inhibition was antagonized by naloxone. The EC50 fo r 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 rece ptors and an antagonist at kappa-l receptors in the guinea pig hippoca mpus.