Interferon-γ Is a Critical Modulator of CB₂Cannabinoid 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-␥ (IFN-␥) response was revealed in the absence of CB 2 signaling. Immunofluorescence stainings demonstrated an IFN-␥ 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-␥ 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-␥ 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-␥ as a mediator of CB 2 signaling was obtained with a double knock-out mouse strain deficient in CB 2 receptors and IFN-␥. 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-␥ dependent.

Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice

“…At variance with our findings, previous studies on other experimental models of chronic inflammatory diseases, such as dermal fibrosis, atherosclerosis, and nerve injury, 10,12,25 have shown that enhanced monocyte infiltration is the predominant mechanism of the deleterious effects of CB2 −/− deletion. However, in these models, CB2 and CCR2 are weakly expressed by resident cells and predominantly exposed by infiltrating monocytes, whereas the opposite occurs within the glomeruli.…”

Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection

“…We observed that IFN-␥ increased in both mixed glial culture and BV-2 cells (a microglial cell line) after JEV infection. Both glia and neurons could be the source of IFN-␥ early in infection (55). Although the ability of glial cells to be infected by flavivirus remains debatable, the studies by us and others clearly show that they are well activated during JE (25,56).…”

Spinal Cord is the Primary Site of Action of the Cannabinoid CB2 Receptor Agonist JWH133 that Suppresses Neuropathic Pain: Possible Involvement of Microglia

“…The time course of increased CB 2 R expression is similar to that of microglial activation, and the upregulation of CB 2 Rs also occurs in other diseases associated with microglial activation [32,33]. It was reported that microglial activation in the spinal cord after PNI is suppressed by administration of CB 2 R agonists and in mice overexpressing CB 2 Rs [26,34]. Furthermore, CB 2 R agonists decrease the level of the proinflammatory cytokine IL-1 in the spinal cord [27].…”