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

Science, 7 August 2009
Vol. 325, Issue 5941, p. 760-764
DOI: 10.1126/science.1171870

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

  1. Alejandro J. Pernía-Andrade1,*,,
  2. Ako Kato1,9,*,
  3. Robert Witschi1,9,*,
  4. Rita Nyilas2,
  5. István Katona2,
  6. Tamás F. Freund2,
  7. Masahiko Watanabe3,
  8. Jörg Filitz4,
  9. Wolfgang Koppert4,,
  10. Jürgen Schüttler4,
  11. Guangchen Ji5,
  12. Volker Neugebauer5,
  13. Giovanni Marsicano6,
  14. Beat Lutz7,
  15. Horacio Vanegas8,
  16. Hanns Ulrich Zeilhofer1,9,§
  1. 1Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  2. 2Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary.
  3. 3Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
  4. 4Department of Anesthesiology, University of Erlangen-Nürnberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany.
  5. 5Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555–1069, USA.
  6. 6U862 Centre de Recherche INSERM François Magendie, 33077 Bordeaux, France.
  7. 7Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University Mainz, D-55099 Mainz, Germany.
  8. 8Instituto Venezolano de Investigaciones Cientificas, Apartado 20632, Caracas 1020A, Venezuela.
  9. 9Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang Pauli Strasse 10, CH-8093 Zurich, Switzerland.
  1. §To whom correspondence should be addressed. E-mail: zeilhofer{at}


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 γ-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.

  • * 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 School Hannover, D-30625 Hannover, Germany.

  • Received for publication 4 February 2009.
  • Accepted for publication 24 June 2009.


A. J. Pernía-Andrade, A. Kato, R. Witschi, R. Nyilas, I. Katona, T. F. Freund, M. Watanabe, J. Filitz, W. Koppert, J. Schüttler, G. Ji, V. Neugebauer, G. Marsicano, B. Lutz, H. Vanegas, and H. U. Zeilhofer, Spinal Endocannabinoids and CB1 Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization. Science 325, 760-764 (2009).

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