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
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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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