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The Journal of Neuroscience, November 12, 2008, 28(46):12136-12145; doi:10.1523/JNEUROSCI.3402-08.2008

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 Previous Article

Neurobiology of Disease
Interferon-{gamma} Is a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain

Ildiko Racz,1 * Xavier Nadal,3 * Judith Alferink,1,2 * Josep E. Baños,3 Jennifer Rehnelt,1 Miquel Martín,3 Belén Pintado,5 Alfonso Gutierrez-Adan,5 Elena Sanguino,6 Nicolas Bellora,4 Jorge Manzanares,6 Andreas Zimmer,1 and Rafael Maldonado3

1Institute of Molecular Psychiatry and 2Department of Psychiatry, University of Bonn, 53105 Bonn, Germany, 3Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, and 4Research Unit on Biomedical Informatics, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, 08003 Barcelona, Spain, 5Departamento de Reproducción Animal y Conservación de Recursos Zoogenéticos, Instituto Nacional de Investigación y Tecnología Agraria, 28040 Madrid, Spain, and 6Instituto de Neurociencias de Alicante, Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas, 03550 Alicante, Spain

Correspondence should be addressed to either of the following: Andreas Zimmer, Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany, Email: a.zimmer{at}uni-bonn.de; or Rafael Maldonado, Laboratori de Neurofarmacologia, Facultat de Ciéncies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Dr Aiguader 80, 08003 Barcelona, Spain, Email: rafael.maldonado{at}upf.edu

Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB2 receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury. Thus, neuropathic pain spreads in mice lacking CB2 receptors beyond the site of nerve injury. To further investigate the mechanisms leading to the enhanced manifestation of neuropathic pain, we have established expression profiles of spinal cord tissues from wild-type and CB2-deficient mice after nerve injury. An enhanced interferon-{gamma} (IFN-{gamma}) response was revealed in the absence of CB2 signaling. Immunofluorescence stainings demonstrated an IFN-{gamma} production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB2-deficient mice showed neuronal and astrocytic IFN-{gamma} immunoreactivity also in the contralateral region, thus matching the pattern of nociceptive hypersensitivity in these animals. Experiments in BV-2 microglia cells revealed that transcriptional changes induced by IFN-{gamma} in two key elements for neuropathic pain development, iNOS (inducible nitric oxide synthase) and CCR2, are modulated by CB2 receptor signaling. The most direct support for a functional involvement of IFN-{gamma} as a mediator of CB2 signaling was obtained with a double knock-out mouse strain deficient in CB2 receptors and IFN-{gamma}. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB2 knock-outs. These data clearly demonstrate that the CB2 receptor-mediated control of neuropathic pain is IFN-{gamma} dependent.

Key words: interferon-{gamma}; CB2 cannabinoid receptor; microglia; astrocytes; neuropathic pain; cytokine

Received July 18, 2008; revised Sept. 19, 2008; accepted Sept. 26, 2008.

Correspondence should be addressed to either of the following: Andreas Zimmer, Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany, Email: a.zimmer{at}uni-bonn.de; or Rafael Maldonado, Laboratori de Neurofarmacologia, Facultat de Ciéncies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Dr Aiguader 80, 08003 Barcelona, Spain, Email: rafael.maldonado{at}upf.edu


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