Modulation of Synaptic Transmission by Nociceptin/Orphanin FQ and Nocistatin in the Spinal Cord Dorsal Horn of Mutant Mice Lacking the Nociceptin/Orphanin FQ Receptor

  1. Seifollah Ahmadi1,
  2. Carolin Kotalla1,
  3. Hans Gühring1,
  4. Hiroshi Takeshima2,
  5. Andreas Pahl1 and
  6. Hanns Ulrich Zeilhofer1
  1. 1Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Erlangen, Germany (S.A., C.K., H.G., A.P., H.U.Z.); and 2Division of Cell Biology, Institute of Life Science, Kurume University, Fukuoka, Japan (H.T.)

    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

    • 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

    • This work was supported by a grant from the Deutsche Forschungsgemeinschaft to H.U.Z. and A.P. (SFB 353/A8).

    • This work was supported by a grant from the Deutsche Forschungsgemeinschaft to H.U.Z. and A.P. (SFB 353/A8).

    • Abbreviations:
      NOFQ
      nociceptin/orphanin FQ
      NST
      nocistatin
      ppN/OFQ
      prepronociceptin/orphanin FQ
      GABA
      γ-aminobutyric acid
      CNS
      central nervous system
      EPSC
      excitatory postsynaptic current
      IPSC
      inhibitory postsynaptic current
      ACSF
      artificial cerebrospinal fluid
      met-enk
      methionine-enkephalin
      ANOVA
      analysis of variance
      CNQX
      6-cyano-7-nitroquinoxaline-2,3-dione
      APV
      2-amino-5-phosphonovaleric acid
      N/OFQ-R
      N/OFQ receptor
      • Received August 9, 2000.
      • Accepted December 1, 2000.
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    1. Molecular Pharmacology March 1, 2001 vol. 59 no. 3 612-618
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