Interferon-γ Is a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain
Interferon-γ Is a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain
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DOI：
10.1523/jneurosci.3402-08.2008
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发表时间：
2008-11-12
影响因子：
5.3
通讯作者：
Maldonado, Rafael
中科院分区：
文献类型：
--
作者：
Racz, Ildiko;Nadal, Xavier;Maldonado, Rafael
神经损伤常导致神经病理性疼痛综合征。导致该综合征的机制涉及局部炎症反应、神经胶质细胞活化和神经元伤害感受通路可塑性的改变。大麻素CB 2受体通过调节神经损伤后胶质细胞的活化来促进神经病理性疼痛的局部抑制。因此，神经性疼痛在缺乏CB 2受体的小鼠中扩散到神经损伤部位之外。为了进一步研究导致神经病理性疼痛表现增强的机制，我们建立了神经损伤后野生型和CB 2缺陷小鼠脊髓组织的表达谱。增强的干扰素-γ（IFN-γ）的反应，揭示了在CB 2信号的情况下。免疫荧光染色显示野生型动物神经损伤同侧的星形胶质细胞和神经元产生IFN-γ。与此相反，CB 2缺陷小鼠显示神经元和星形胶质细胞IFN-γ免疫反应性也在对侧区域，从而匹配的模式，在这些动物的伤害性超敏反应。在BV-2小胶质细胞中的实验揭示了由IFN-γ诱导的神经性疼痛发展的两个关键元件iNOS（诱导型一氧化氮合酶）和CCR 2中的转录变化由CB 2受体信号传导调节。对于IFN-γ作为CB 2信号传导的介体的功能参与的最直接的支持是用CB 2受体和IFN-γ缺陷的双敲除小鼠品系获得的。这些动物不再显示在CB 2敲除中观察到的神经性疼痛的增强表现。这些数据清楚地表明，CB 2受体介导的神经性疼痛的控制是IFN-γ依赖性的。
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-gamma (IFN-gamma) response was revealed in the absence of CB2 signaling. Immunofluorescence stainings demonstrated an IFN-gamma production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB2-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 CB2 receptor signaling. The most direct support for a functional involvement of IFN-gamma as a mediator of CB2 signaling was obtained with a double knock-out mouse strain deficient in CB2 receptors and IFN-gamma. 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-gamma dependent.