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PGE2 selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons

Nature Neuroscience volume 5, pages 34–40 (2002)Cite this article

Abstract

Despite the crucial role that prostaglandins (PGs) have in the sensitization of the central nervous system to pain, their cellular and molecular targets leading to increased pain perception have remained elusive. Here we investigated the effects of PGE2 on fast synaptic transmission onto neurons in the rat spinal cord dorsal horn, the first site of synaptic integration in the pain pathway. We identified the inhibitory (strychnine-sensitive) glycine receptor as a specific target of PGE2. PGE2, but not PGF2α, PGD2 or PGI2, reduced inhibitory glycinergic synaptic transmission in low nanomolar concentrations, whereas GABAA, AMPA and NMDA receptor-mediated transmission remained unaffected. Inhibition of glycine receptors occurred via a postsynaptic mechanism involving the activation of EP2 receptors, cholera-toxin-sensitive G-proteins and cAMP-dependent protein kinase. Via this mechanism, PGE2 may facilitate the transmission of nociceptive input through the spinal cord dorsal horn to higher brain areas where pain becomes conscious.

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Figure 1: Effects of PGE2 on PSCs mediated by glycine, GABAA, AMPA and NMDA receptors.
Figure 2: Localization of prostaglandin (PG)-sensitive and -insensitive neurons in the rat spinal cord dorsal horn.
Figure 3: Effects of different PGs on glycinergic neurotransmission.
Figure 4: Effects of several synthetic EP receptor agonists with preferential activity at EP1–4 receptor subtypes on glycinergic neurotransmission.
Figure 5: PGE2 reduced glycinergic mIPSCs in amplitude, but not in frequency.
Figure 6: Inhibition by PGE2 of whole-cell currents evoked by exogenous application of glycine and GABA.
Figure 7: Inhibition of glycinergic IPSCs by PGE2 required the activation of a ChTX-sensitive G-protein.
Figure 8: Involvement of protein kinase A, but not of protein kinase C.

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Acknowledgements

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (SFB 353/A8 to H.U.Z. and SFB/B15 to W.L.N.) and a stipend from the Graduiertenkolleg GRK 22 to S.L. The authors thank C.-M. Becker, K. Brune and P.W. Reeh for critically reading the manuscript and S. Gabriel, K. Löschner and H. Symowski for technical assistance.

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  1. Seifollah Ahmadi and Sebastian Lippross: The first two authors contributed equally to this work

Authors and Affiliations

  1. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Emil-Fischer-Zentrum, Fahrstrasse 17, Erlangen, D-91054, Germany

    Seifollah Ahmadi, Sebastian Lippross & Hanns Ulrich Zeilhofer

  2. Institut für Anatomie, Krankenhausstrasse 9, Universität Erlangen-Nürnberg, Erlangen, D-91054, Germany

    Winfried L. Neuhuber

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Correspondence to Hanns Ulrich Zeilhofer.

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Ahmadi, S., Lippross, S., Neuhuber, W. et al. PGE2 selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat Neurosci 5, 34–40 (2002). https://doi.org/10.1038/nn778

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