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Spinal Endocannabinoids and CB1 Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization
Alejandro J. Pernía-Andrade,1,*,
Ako Kato,1,9,*
Robert Witschi,1,9,*
Rita Nyilas,2
István Katona,2
Tamás F. Freund,2
Masahiko Watanabe,3
Jörg Filitz,4
Wolfgang Koppert,4,
Jürgen Schüttler,4
Guangchen Ji,5
Volker Neugebauer,5
Giovanni Marsicano,6
Beat Lutz,7
Horacio Vanegas,8
Hanns Ulrich Zeilhofer1,9,
Abstract:
Diminished synaptic inhibition in the spinal dorsal horn isa major contributor to chronic pain. Pathways that reduce synapticinhibition in inflammatory and neuropathic pain states havebeen identified, but central hyperalgesia and diminished dorsalhorn synaptic inhibition also occur in the absence of inflammationor neuropathy, solely triggered by intense nociceptive (C-fiber)input to the spinal dorsal horn. We found that endocannabinoids,produced upon strong nociceptive stimulation, activated type1 cannabinoid (CB1) receptors on inhibitory dorsal horn neuronsto reduce the synaptic release of -aminobutyric acid and glycineand thus rendered nociceptive neurons excitable by nonpainfulstimuli. Our results suggest that spinal endocannabinoids andCB1 receptors on inhibitory dorsal horn interneurons act asmediators of heterosynaptic pain sensitization and play an unexpectedrole in dorsal horn pain-controlling circuits.
1 Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. 2 Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary. 3 Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan. 4 Department of Anesthesiology, University of Erlangen-Nürnberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany. 5 Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555–1069, USA. 6 U862 Centre de Recherche INSERM François Magendie, 33077 Bordeaux, France. 7 Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University Mainz, D-55099 Mainz, Germany. 8 Instituto Venezolano de Investigaciones Cientificas, Apartado 20632, Caracas 1020A, Venezuela. 9 Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang Pauli Strasse 10, CH-8093 Zurich, Switzerland.
* These authors contributed equally to this work.
Present address: Institute of Physiology, University of Freiburg,Engesserstrasse 4, D-79108, Freiburg, Germany.
Present address: Department of Anesthesiology, Medical SchoolHannover, D-30625 Hannover, Germany.
To whom correspondence should be addressed. E-mail: zeilhofer{at}pharma.uzh.ch
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In Science Signaling
PERSPECTIVES
MacDonald J. Christie and Christophe Mallet (15 September 2009) Sci. Signal.2 (88), pe57.
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EDITORS' CHOICE
Peter R. Stern (11 August 2009) Sci. Signal.2 (83), ec269.
[DOI: 10.1126/scisignal.283ec269] |Abstract »
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Ako Kato,1,9
Jürgen Schüttler,4
Guangchen Ji,5
Volker Neugebauer,5
Giovanni Marsicano,6
Beat Lutz,7
Horacio Vanegas,8
Hanns Ulrich Zeilhofer1,9,
-aminobutyric acid and glycine and thus rendered nociceptive neurons excitable by nonpainful stimuli. Our results suggest that spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain-controlling circuits. 
Present address: Institute of Physiology, University of Freiburg, Engesserstrasse 4, D-79108, Freiburg, Germany. 
Present address: Department of Anesthesiology, Medical School Hannover, D-30625 Hannover, Germany. 
To whom correspondence should be addressed. E-mail: 
