Abstract
Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two neuropeptides derived from the same precursor protein that exhibit opposing effects on spinal neurotransmission and nociception. Here, we have used whole-cell, patch-clamp recordings from visually identified neurons in spinal cord dorsal horn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and γ-aminobutyric acid (GABA)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppressed excitatory transmission in a concentration-dependent manner but left inhibitory synaptic transmission unaffected. In contrast, NST reduced only inhibitory but not α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synaptic transmission. N/OFQ-mediated inhibition of excitatory transmission was completely absent in N/OFQ-R receptor-deficient (N/OFQ-R−/−) mice and significantly reduced in heterozygous (N/OFQ-R+/−) mice, whereas the action of NST on inhibitory neurotransmission was completely retained. To test for the relevance of these results for spinal nociception, we investigated the effects of intrathecally injected N/OFQ in the mouse formalin test, an animal model of tonic pain. N/OFQ (3 nmol/mouse) induced significant antinociception in wild-type mice, but had no antinociceptive effects in N/OFQ-R−/− mice. These results indicate that the inhibitory action of N/OFQ on excitatory glutamatergic synaptic transmission and its spinal antinociceptive action are mediated via the N/OFQ receptor, whereas the action of NST is independent of this receptor.
Footnotes
- Received August 9, 2000.
- Accepted December 1, 2000.
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Send reprint requests to: Dr. H.U. Zeilhofer, Institut für Pharmakologie und Toxikologie, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail: zeilhofe{at}pharma.unizh.ch
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This work was supported by a grant from the Deutsche Forschungsgemeinschaft to H.U.Z. and A.P. (SFB 353/A8).
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This work was supported by a grant from the Deutsche Forschungsgemeinschaft to H.U.Z. and A.P. (SFB 353/A8).
- The American Society for Pharmacology and Experimental Therapeutics
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