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Journal of Pharmacology and Experimental Therapeutics

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OtherANALGESIA AND DRUGS OF ABUSE

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
Journal of Pharmacology and Experimental Therapeutics December 1997, 283 (3) 1342-1349;
Robert M. Caudle
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Andrew J. Mannes
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Michael J. Iadarola
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Abstract

Receptor binding studies and electrophysiological studies demonstrated the existence of at least two kappa opioid receptors, which have been designated kappa-1 andkappa-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, thekappa opioid GR89,696 was tested in the guinea pig hippocampal slice preparation for kappa-1versuskappa-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.

Footnotes

  • Send reprint requests to: Robert M. Caudle, PNMB/NIDR/NIH, Building 49, Room 1W26, 49 Convent Drive, MSC 4410, Bethesda, MD 20892-4410.

  • Abbreviations:
    CNQX
    10 μM 6-cyano-7-nitroquinoxaline-2,3-dione
    DAMGO
    [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin
    DPDPE
    [d-Pen2,5]enkephalin
    NMDA
    N-methyl-d-aspartate
    U69
    593, N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide
    GR89
    696, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate
    EGTA
    ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    GABA
    γ-aminobutyric acid
    CL
    confidence limit
    • Received April 18, 1997.
    • Accepted August 28, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 3
1 Dec 1997
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OtherANALGESIA AND DRUGS OF ABUSE

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
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1342-1349;

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OtherANALGESIA AND DRUGS OF ABUSE

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
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1342-1349;
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