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首页> 外文期刊>Neurobiology of disease >The role of kinin B1 and B2 receptors in the persistent pain induced by experimental autoimmune encephalomyelitis (EAE) in mice: Evidence for the involvement of astrocytes
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The role of kinin B1 and B2 receptors in the persistent pain induced by experimental autoimmune encephalomyelitis (EAE) in mice: Evidence for the involvement of astrocytes

机译：激肽B1和B2受体在小鼠实验性自身免疫性脑脊髓炎（EAE）引起的持续性疼痛中的作用：星形胶质细胞参与的证据

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Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B1 (B1R) and B2 (B2R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B1R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B1R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B1R mRNA and protein level in the mouse spinal cord 14days after EAE immunization. Blockade of B1R significantly suppressed the levels of mRNAs for IL-17, IFN-γ, IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-α and IL-6 release in astrocyte culture. Finally, both B1R and B2R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocyte culture. The B1R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS.
机译：多发性硬化症（MS）是人类中枢神经系统（CNS）的进行性脱髓鞘炎性疾病。尽管MS的主要症状会影响运动功能，但现已认识到，慢性疼痛是一种影响动物和MS患者的相关症状。有证据表明，星形胶质细胞等神经胶质细胞在慢性疼痛的发生和维持中起着重要作用。激肽，特别是通过B1（B1R）和B2（B2R）受体起作用的缓激肽（BK），在疼痛和炎症过程中起着核心作用。然而，尚不清楚激肽受体是否参与MS的神经性疼痛。在这里，我们通过遗传和药理学方法调查了激肽受体在实验性自身免疫性脑脊髓炎（EAE）小鼠模型中诱发的神经性疼痛行为中的作用。我们的结果表明，激肽受体，特别是B1R的基因缺失或拮抗作用显着抑制了EAE动物的触觉和热超敏反应。相比之下，患有EAE并用B1R选择性激动剂治疗的动物显示出明显的触觉过敏。我们还观察到EAE免疫后14天，小鼠脊髓中B1R mRNA和蛋白水平显着增加。阻断B1R可以显着抑制IL-17，IFN-γ，IL-6，CXCL-1 / KC，COX-2和NOS2的mRNA水平，以及脊髓中的神经胶质细胞活化。值得注意的是，选择性B1拮抗剂DALBK始终抑制星形胶质细胞培养物中IFN诱导的TNF-α和IL-6释放的上调。最后，B1R和B2R拮抗剂均能显着抑制原代星形胶质细胞培养物中的COX-2和NOS2表达。在EAE治疗的动物的脊髓中，B1R与星形胶质细胞的免疫标记共定位。以上数据构成了令人信服的实验证据，表明这两种激肽受体，尤其是B1亚型，在建立EAE模型中观察到的持续性超敏反应中均起着关键作用，这种作用似乎涉及中枢性炎症过程，可能作用于星形胶质细胞。因此，B1选择性拮抗剂或减少激肽释放的药物可能具有治疗MS患者神经性疼痛的潜力。

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