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Science 325 (5941): 760-764

Copyright © 2009 by the American Association for the Advancement of Science

Spinal Endocannabinoids and CB1 Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization

Alejandro J. Pernía-Andrade,1,*,{dagger} 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,{ddagger} 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 is a major contributor to chronic pain. Pathways that reduce synaptic inhibition in inflammatory and neuropathic pain states have been identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C-fiber) input to the spinal dorsal horn. We found that endocannabinoids, produced upon strong nociceptive stimulation, activated type 1 cannabinoid (CB1) receptors on inhibitory dorsal horn neurons to reduce the synaptic release of {gamma}-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.

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.

{dagger} Present address: Institute of Physiology, University of Freiburg, Engesserstrasse 4, D-79108, Freiburg, Germany.

{ddagger} Present address: Department of Anesthesiology, Medical School Hannover, D-30625 Hannover, Germany.

§ To whom correspondence should be addressed. E-mail: zeilhofer{at}pharma.uzh.ch


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