title: GR89,696 is a kappa-2 opioid receptor agonist and a kappa-1 opioid receptor antagonist in the guinea pig hippocampus.
abstract: 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.
authors.affiliation: Pain and Neurosensory Mechanisms Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892-4410, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Caudle
authors.forename: A J
authors.initials: AJ
authors.lastname: Mannes
authors.forename: M J
authors.initials: MJ
authors.lastname: Iadarola
mesh_terms: D000818:Animals; D044482:Benzeneacetamides; D001575:Benzomorphans / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000187:drug effects*
chemical_list: D044482:Benzeneacetamides; D001575:Benzomorphans; D010879:Piperazines; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate; D017473:Receptors, Opioid, kappa; C071609:GR 89696; C027248:bremazocine; C045444:U 69593