Interferon-γ is a critical modulator of CB2 cannabinoid receptor signaling during neuropathic pain

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-γ (IFN-γ) response was revealed in the absence of CB2 signaling. Immunofluorescence stainings demonstrated an IFN-γ 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-γ 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-γ 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-γ as a mediator of CB2 signaling was obtained with a double knock-out mouse strain deficient in CB2 receptors and IFN-γ. 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-γ dependent. Copyright © 2008 Society for Neuroscience.

Bibliographic Details

Main Authors:	Racz, I., Nadal, X., Alferink, J., Baños, J. E., Rehnelt, J., Martín, M., Pintado, B., Gutierrez-Adan, A., Sanguino, E., Bellora, N., Manzanares, J., Zimmer, A., Maldonado, R.
Format:	journal article biblioteca
Language:	eng
Published:	2008
Online Access:	http://hdl.handle.net/20.500.12792/3610
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