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Science 304 (5672): 884-887

Copyright © 2004 by the American Association for the Advancement of Science

GlyR {alpha}3: An Essential Target for Spinal PGE2-Mediated Inflammatory Pain Sensitization

Robert J. Harvey,1,8* Ulrike B. Depner,2* Heinz Wässle,3 Seifollah Ahmadi,2 Cornelia Heindl,2 Heiko Reinold,2 Trevor G. Smart,4 Kirsten Harvey,1 Burkhard Schütz,5 Osama M. Abo-Salem,5 Andreas Zimmer,5 Pierrick Poisbeau,6 Hans Welzl,7 David P. Wolfer,7 Heinrich Betz,8{dagger} Hanns Ulrich Zeilhofer,2 Ulrike Müller8{dagger}

Abstract: Prostaglandin E2 (PGE2) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR {alpha}3) by PGE2-induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR {alpha}3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR {alpha}3 not only lack the inhibition of glycinergic neurotransmission by PGE2 seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE2 injection or peripheral inflammation. Thus, GlyR {alpha}3 may provide a previously unrecognized molecular target in pain therapy.

1 Department of Pharmacology, The School of Pharmacy, London WC1N 1AX, UK.
2 Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
3 Abteilung Neuroanatomie, Max-Planck-Institut für Hirnforschung, D-60528 Frankfurt, Germany.
4 Department of Pharmacology, University College London, London WC1E 6BT, UK.
5 Institut für Molekulare Neurobiologie, Universitätsklinikum Bonn, D-53105 Bonn, Germany.
6 Laboratoire de Neurophysiologie Cellulaire et Intégrée, Université Louis Pasteur/CNRS UMR 7519, 67084 Strasbourg, France.
7 Abteilung für Neuroanatomie und Verhalten, Institut für Anatomie, Universität Zürich–Irchel, CH-8057 Zürich, Switzerland.
8 Abteilung Neurochemie, Max-Planck-Institut für Hirnforschung, D-60528 Frankfurt, Germany.

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* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: umueller{at} (U.M.); neurochemie{at} (H.B.)

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   Abstract »    Full Text »    PDF »
Inhibition of the Ethanol-induced Potentiation of {alpha}1 Glycine Receptor by a Small Peptide That Interferes with G{beta}{gamma} Binding.
L. San Martin, F. Cerda, V. Jimenez, J. Fuentealba, B. Munoz, L. G. Aguayo, and L. Guzman (2012)
J. Biol. Chem. 287, 40713-40721
   Abstract »    Full Text »    PDF »
Inhibitory Glycine Receptors: An Update.
S. Dutertre, C.-M. Becker, and H. Betz (2012)
J. Biol. Chem. 287, 40216-40223
   Abstract »    Full Text »    PDF »
Subunit-Specific Inhibition of Glycine Receptors by Curcumol.
L. Wang, W.-G. Li, C. Huang, M. X. Zhu, T.-L. Xu, D.-Z. Wu, and Y. Li (2012)
J. Pharmacol. Exp. Ther. 343, 371-379
   Abstract »    Full Text »    PDF »
Stoichiometry of the Human Glycine Receptor Revealed by Direct Subunit Counting.
N. Durisic, A. G. Godin, C. M. Wever, C. D. Heyes, M. Lakadamyali, and J. A. Dent (2012)
J. Neurosci. 32, 12915-12920
   Abstract »    Full Text »    PDF »
A Novel Dominant Hyperekplexia Mutation Y705C Alters Trafficking and Biochemical Properties of the Presynaptic Glycine Transporter GlyT2.
C. Gimenez, G. Perez-Siles, J. Martinez-Villarreal, E. Arribas-Gonzalez, E. Jimenez, E. Nunez, J. de Juan-Sanz, E. Fernandez-Sanchez, N. Garcia-Tardon, I. Ibanez, et al. (2012)
J. Biol. Chem. 287, 28986-29002
   Abstract »    Full Text »    PDF »
Prostaglandin E2 induces immediate migraine-like attack in migraine patients without aura.
M. Antonova, T. Wienecke, J. Olesen, and M. Ashina (2012)
Cephalalgia 32, 822-833
   Abstract »    Full Text »    PDF »
Cannabinoids suppress inflammatory and neuropathic pain by targeting {alpha}3 glycine receptors.
W. Xiong, T. Cui, K. Cheng, F. Yang, S.-R. Chen, D. Willenbring, Y. Guan, H.-L. Pan, K. Ren, Y. Xu, et al. (2012)
J. Exp. Med. 209, 1121-1134
   Abstract »    Full Text »    PDF »
A Common Molecular Basis for Exogenous and Endogenous Cannabinoid Potentiation of Glycine Receptors.
W. Xiong, X. Wu, D. M. Lovinger, and L. Zhang (2012)
J. Neurosci. 32, 5200-5208
   Abstract »    Full Text »    PDF »
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M. H. Yamada, K. Nishikawa, K. Kubo, Y. Yanagawa, and S. Saito (2012)
Mol. Pharmacol. 81, 610-619
   Abstract »    Full Text »    PDF »
Selective Glycine Receptor {alpha}2 Subunit Control of Crossover Inhibition between the On and Off Retinal Pathways.
R. D. Nobles, C. Zhang, U. Muller, H. Betz, and M. A. McCall (2012)
J. Neurosci. 32, 3321-3332
   Abstract »    Full Text »    PDF »
Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control.
H. U. Zeilhofer, H. Wildner, and G. E. Yevenes (2012)
Physiol Rev 92, 193-235
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress.
D. F. Woodward, R. L. Jones, and S. Narumiya (2011)
Pharmacol. Rev. 63, 471-538
   Abstract »    Full Text »    PDF »
Probing glycine receptor stoichiometry in superficial dorsal horn neurones using the spasmodic mouse.
B. A. Graham, M. A. Tadros, P. R. Schofield, and R. J. Callister (2011)
J. Physiol. 589, 2459-2474
   Abstract »    Full Text »    PDF »
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A. N. Shrivastava, A. Triller, W. Sieghart, and I. Sarto-Jackson (2011)
J. Biol. Chem. 286, 14455-14468
   Abstract »    Full Text »    PDF »
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S. A. Pless, A. P. Hanek, K. L. Price, J. W. Lynch, H. A. Lester, D. A. Dougherty, and S. C. R. Lummis (2011)
Mol. Pharmacol. 79, 742-748
   Abstract »    Full Text »    PDF »
Molecular Requirements for Ethanol Differential Allosteric Modulation of Glycine Receptors Based on Selective G{beta}{gamma} Modulation.
G. E. Yevenes, G. Moraga-Cid, A. Avila, L. Guzman, M. Figueroa, R. W. Peoples, and L. G. Aguayo (2010)
J. Biol. Chem. 285, 30203-30213
   Abstract »    Full Text »    PDF »
Glycinergic and GABAergic tonic inhibition fine tune inhibitory control in regionally distinct subpopulations of dorsal horn neurons.
T. Takazawa and A. B. MacDermott (2010)
J. Physiol. 588, 2571-2587
   Abstract »    Full Text »    PDF »
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H.-G. Breitinger, C. Villmann, N. Melzer, J. Rennert, U. Breitinger, S. Schwarzinger, and C.-M. Becker (2009)
J. Biol. Chem. 284, 28624-28633
   Abstract »    Full Text »    PDF »
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J. Li, S. M. Walker, M. Fitzgerald, and M. L. Baccei (2009)
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   Abstract »    Full Text »    PDF »
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K. Kubo, K. Nishikawa, J. Ishizeki, M. Hardy-Yamada, Y. Yanagawa, and S. Saito (2009)
J. Pharmacol. Exp. Ther. 331, 162-169
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. Majumdar, J. Weiss, and H. Wassle (2009)
J. Physiol. 587, 3831-3849
   Abstract »    Full Text »    PDF »
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T Wienecke, J Olesen, P. Oturai, and M Ashina (2009)
Cephalalgia 29, 509-519
   Abstract »    Full Text »    PDF »
Models and Mechanisms of Hyperalgesia and Allodynia.
J. Sandkuhler (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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C. Villmann, J. Oertel, Z.-L. Ma-Hogemeier, M. Hollmann, R. Sprengel, K. Becker, H.-G. Breitinger, and C.-M. Becker (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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X.-B. Zhang, G.-C. Sun, L.-Y. Liu, F. Yu, and T.-L. Xu (2008)
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   Abstract »    Full Text »    PDF »
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E. A. Mitchell, L. J. Gentet, J. Dempster, and D. Belelli (2007)
J. Physiol. 583, 1021-1040
   Abstract »    Full Text »    PDF »
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T. Papadopoulos, M. Korte, V. Eulenburg, H. Kubota, M. Retiounskaia, R. J. Harvey, K. Harvey, G. A. O'Sullivan, B. Laube, S. Hulsmann, et al. (2007)
EMBO J. 26, 3888-3899
   Abstract »    Full Text »    PDF »
Moving From an Averaged to Specific View of Spinal Cord Pain Processing Circuits.
B. A. Graham, A. M. Brichta, and R. J. Callister (2007)
J Neurophysiol 98, 1057-1063
   Abstract »    Full Text »    PDF »
Cell-type-specific excitatory and inhibitory circuits involving primary afferents in the substantia gelatinosa of the rat spinal dorsal horn in vitro.
T. Yasaka, G. Kato, H. Furue, M. H. Rashid, M. Sonohata, A. Tamae, Y. Murata, S. Masuko, and M. Yoshimura (2007)
J. Physiol. 581, 603-618
   Abstract »    Full Text »    PDF »
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K. Brune and D. E. Furst (2007)
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   Abstract »    Full Text »    PDF »
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M. Beato and L. G. Sivilotti (2007)
J. Physiol. 580, 497-506
   Abstract »    Full Text »    PDF »
Molecular Determinants for G Protein beta{gamma} Modulation of Ionotropic Glycine Receptors.
G. E. Yevenes, G. Moraga-Cid, L. Guzman, S. Haeger, L. Oliveira, J. Olate, G. Schmalzing, and L. G. Aguayo (2006)
J. Biol. Chem. 281, 39300-39307
   Abstract »    Full Text »    PDF »
The Voltage-Gated Sodium Channel Nav1.9 Is an Effector of Peripheral Inflammatory Pain Hypersensitivity.
F. Amaya, H. Wang, M. Costigan, A. J. Allchorne, J. P. Hatcher, J. Egerton, T. Stean, V. Morisset, D. Grose, M. J. Gunthorpe, et al. (2006)
J. Neurosci. 26, 12852-12860
   Abstract »    Full Text »    PDF »
Prostaglandin E2 Receptor EP4 Contributes to Inflammatory Pain Hypersensitivity.
C.-R. Lin, F. Amaya, L. Barrett, H. Wang, J. Takada, T. A. Samad, and C. J. Woolf (2006)
J. Pharmacol. Exp. Ther. 319, 1096-1103
   Abstract »    Full Text »    PDF »
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E. Garcia-Nicas, J. M. A. Laird, and F. Cervero (2006)
J Neurophysiol 96, 661-670
   Abstract »    Full Text »    PDF »
Distinct physiological mechanisms underlie altered glycinergic synaptic transmission in the murine mutants spastic, spasmodic, and oscillator..
B. A. Graham, P. R. Schofield, P. Sah, T. W. Margrie, and R. J. Callister (2006)
J. Neurosci. 26, 4880-4890
   Abstract »    Full Text »    PDF »
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C. Torsney and A. B. MacDermott (2006)
J. Neurosci. 26, 1833-1843
   Abstract »    Full Text »    PDF »
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G. P. Dugue, A. Dumoulin, A. Triller, and S. Dieudonne (2005)
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   Abstract »    Full Text »    PDF »
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P. P. Cherian, A. J. Siller-Jackson, S. Gu, X. Wang, L. F. Bonewald, E. Sprague, and J. X. Jiang (2005)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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