Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain

Racz, Ildiko; Nadal i Roura, Xavier, 1980-; Alferink, Judith; Baños i Díez, Josep Eladi; Rehnelt, Jennifer; Martín, Miguel; Pintado, Belén; Gutierrez-Adan, Alfonso; Sanguino, Elena; Bellora Pereyra, Nicolás; Manzanares, Jorge; Zimmer, Andreas; Maldonado, Rafael, 1961-

Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain

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dc.contributor.author Racz, Ildikoca
dc.contributor.author Nadal i Roura, Xavier, 1980-ca
dc.contributor.author Alferink, Judithca
dc.contributor.author Baños i Díez, Josep Eladica
dc.contributor.author Rehnelt, Jenniferca
dc.contributor.author Martín, Miguelca
dc.contributor.author Pintado, Belénca
dc.contributor.author Gutierrez-Adan, Alfonsoca
dc.contributor.author Sanguino, Elenaca
dc.contributor.author Bellora Pereyra, Nicolásca
dc.contributor.author Manzanares, Jorgeca
dc.contributor.author Zimmer, Andreasca
dc.contributor.author Maldonado, Rafael, 1961-ca
dc.date.accessioned 2012-07-05T06:53:43Z
dc.date.available 2012-07-05T06:53:43Z
dc.date.issued 2008ca
dc.description.abstract 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 CB(2) 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 CB(2) 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 CB(2)-deficient mice after nerve injury. An enhanced interferon-gamma (IFN-gamma) response was revealed in the absence of CB(2) signaling. Immunofluorescence stainings demonstrated an IFN-gamma production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB(2)-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 CB(2) receptor signaling. The most direct support for a functional involvement of IFN-gamma as a mediator of CB(2) signaling was obtained with a double knock-out mouse strain deficient in CB(2) receptors and IFN-gamma. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB(2) knock-outs. These data clearly demonstrate that the CB(2) receptor-mediated control of neuropathic pain is IFN-gamma dependent.
dc.description.sponsorship This work was supported by grants from the National Institute on Drug Abuse (1R01-DA016768-0111) (R.M.,A.Z.), European Commission [Framework VI, GENADDICT OJ 2004/C164, 005166 (R.M., A.Z.); PHECOM, LSHM-CT-2007-037669 (R.M.)], Ministerio de Educación y Ciencia (BFU2004-00920/BFI; SAF2007-64062) (R.M.), Generalitat de Catalunya (R.M.), Deutsche Forschungsgemeinschaft (SFB645; FOR926) (A.Z.), and Bundesministerium für Bildung und Forschung (NGFN2) (A.Z.)
dc.format.mimetype application/pdfca
dc.identifier.citation Racz I, Nadal X, Alferink J, Baños JE, Rehnelt J, Martín M et al. Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J Neurosci. 2008;28(46):12136-45. DOI: 10.1523/JNEUROSCI.3402-08.2008ca
dc.identifier.doi http://dx.doi.org/10.1523/JNEUROSCI.3402-08.2008
dc.identifier.issn 0270-6474ca
dc.identifier.uri http://hdl.handle.net/10230/16659
dc.language.iso engca
dc.publisher Society for Neuroscienceca
dc.relation.ispartof Journal of Neuroscience. 2008;28(46):12136-45
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/BFU2004-00920
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/SAF2007-64062
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.subject.keyword Interferon- y
dc.subject.keyword CB2 cannabinoid receptor
dc.subject.keyword Microglia
dc.subject.keyword Astrocytes
dc.subject.keyword Neuropathic pain
dc.subject.keyword Cytokine
dc.subject.other Cannabinoides -- Receptors
dc.subject.other Cannabinoides -- Efectes fisiològics
dc.subject.other Dolor -- Tractament
dc.title Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic painca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersion

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