title: Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain.
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.
authors.affiliation: Institute of Molecular Psychiatry and Department of Psychiatry, University of Bonn, 53105 Bonn, Germany.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Racz
authors.forename: Xavier
authors.initials: X
authors.lastname: Nadal
authors.forename: Judith
authors.initials: J
authors.lastname: Alferink
authors.forename: Josep E
authors.initials: JE
authors.lastname: Baños
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rehnelt
authors.forename: Miquel
authors.initials: M
authors.lastname: Martín
authors.forename: Belén
authors.initials: B
authors.lastname: Pintado
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gutierrez-Adan
authors.forename: Elena
authors.initials: E
authors.lastname: Sanguino
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bellora
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology; D002478:Cells, Cultured; D055786:Gene Knockout Techniques / Q000379:methods; D006930:Hyperalgesia / Q000276:immunology / Q000503:physiopathology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009437:Neuralgia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009474:Neurons / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology / Q000378:metabolism; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000276:immunology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054390:Receptors, CCR2 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D015854:Up-Regulation / Q000276:immunology
chemical_list: C515335:Ccr2 protein, mouse; D043885:Receptor, Cannabinoid, CB2; D054390:Receptors, CCR2; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse