Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

Morphological, biophysical and synaptic properties of glutamatergic neurons of the mouse spinal dorsal horn.
P. Punnakkal, C. von Schoultz, K. Haenraets, H. Wildner, and H. U. Zeilhofer (2014)
J. Physiol. 592, 759-776
   Abstract »    Full Text »    PDF »
Genome-Wide Expression Analysis of Ptf1a- and Ascl1-Deficient Mice Reveals New Markers for Distinct Dorsal Horn Interneuron Populations Contributing to Nociceptive Reflex Plasticity.
H. Wildner, R. Das Gupta, D. Brohl, P. A. Heppenstall, H. U. Zeilhofer, and C. Birchmeier (2013)
J. Neurosci. 33, 7299-7307
   Abstract »    Full Text »    PDF »
Why do cannabinoid receptors have more than one endogenous ligand?.
V. Di Marzo and L. De Petrocellis (2012)
Phil Trans R Soc B 367, 3216-3228
   Abstract »    Full Text »    PDF »
Dynamic changes to the endocannabinoid system in models of chronic pain.
D. Rani Sagar, J. J. Burston, S. G. Woodhams, and V. Chapman (2012)
Phil Trans R Soc B 367, 3300-3311
   Abstract »    Full Text »    PDF »
Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoid/endovanilloid system.
K. Starowicz and B. Przewlocka (2012)
Phil Trans R Soc B 367, 3286-3299
   Abstract »    Full Text »    PDF »
Endocannabinoid-dependent plasticity at spinal nociceptor synapses.
A. Kato, P. Punnakkal, A. J. Pernia-Andrade, C. von Schoultz, S. Sharopov, R. Nyilas, I. Katona, and H. U. Zeilhofer (2012)
J. Physiol. 590, 4717-4733
   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 »
Gating the Polarity of Endocannabinoid-Mediated Synaptic Plasticity by Nitric Oxide in the Spinal Locomotor Network.
J. Song, A. Kyriakatos, and A. El Manira (2012)
J. Neurosci. 32, 5097-5105
   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 »
mGluR1, but not mGluR5, activates feed-forward inhibition in the medial prefrontal cortex to impair decision making.
H. Sun and V. Neugebauer (2011)
J Neurophysiol 106, 960-973
   Abstract »    Full Text »    PDF »
Mitochondrial Reactive Oxygen Species Are Activated by mGluR5 through IP3 and Activate ERK and PKA to Increase Excitability of Amygdala Neurons and Pain Behavior.
Z. Li, G. Ji, and V. Neugebauer (2011)
J. Neurosci. 31, 1114-1127
   Abstract »    Full Text »    PDF »
Reactive Oxygen Species Are Involved in Group I mGluR-Mediated Facilitation of Nociceptive Processing in Amygdala Neurons.
G. Ji and V. Neugebauer (2010)
J Neurophysiol 104, 218-229
   Abstract »    Full Text »    PDF »
Highlights From The Literature.
Physiology 25, 3-7
   Full Text »    PDF »
Endocannabinoids Can Open the Pain Gate.
M. J. Christie and C. Mallet (2009)
Science Signaling 2, pe57
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882