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The Journal of Neuroscience, November 12, 2008, 28(46):12125-12135; doi:10.1523/JNEUROSCI.3400-08.2008

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Neurobiology of Disease
Crucial Role of CB₂ Cannabinoid Receptor in the Regulation of Central Immune Responses 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,⁴ Alfonso Gutierrez-Adan,⁴ Elena Sanguino,⁵ Jorge Manzanares,⁵ 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, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, 08003 Barcelona, Spain, ⁴Departamento de Reproducción Animal y Conservación de Recursos Zoogenéticos, Instituto Nacional de Investigación y Tecnología Agraria, 28040 Madrid, Spain, and ⁵Instituto 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

Neuropathic pain is a clinical manifestation of nerve injury difficult to treat even with potent analgesic compounds. Here, we used different lines of genetically modified mice to clarify the role played by CB₂ cannabinoid receptors in the regulation of the central immune responses leading to the development of neuropathic pain. CB₂ knock-out mice and wild-type littermates were exposed to sciatic nerve injury, and both genotypes developed a similar hyperalgesia and allodynia in the ipsilateral paw. Most strikingly, knock-outs also developed a contralateral mirror image pain, associated with an enhanced microglial and astrocytic expression in the contralateral spinal horn. In agreement, hyperalgesia, allodynia, and microglial and astrocytic activation induced by sciatic nerve injury were attenuated in transgenic mice overexpressing CB₂ receptors. These results demonstrate the crucial role of CB₂ cannabinoid receptor in modulating glial activation in response to nerve injury. The enhanced manifestations of neuropathic pain were replicated in irradiated wild-type mice reconstituted with bone marrow cells from CB₂ knock-outs, thus demonstrating the implication of the CB₂ receptor expressed in hematopoietic cells in the development of neuropathic pain at the spinal cord.

Key words: CB₂ cannabinoid receptor; microglia; astrocytes; neuropathic pain; bone marrow chimera; neuroinflammation

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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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