Fingolimod reduces neuropathic pain behaviors in a mouse model of multiple sclerosis by a sphingosine-1 phosphate receptor 1-dependent inhibition of central sensitization in the dorsal horn.
Fingolimod reduces neuropathic pain behaviors in a mouse model of multiple sclerosis by a sphingosine-1 phosphate receptor 1-dependent inhibition of central sensitization in the dorsal horn.
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DOI：
10.1097/j.pain.0000000000001106
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发表时间：
2018-03
期刊：
影响因子：
7.4
通讯作者：
Taylor BK
中科院分区：
文献类型：
--
作者：
Doolen S;Iannitti T;Donahue RR;Shaw BC;Grachen CM;Taylor BK
多发性硬化症 (MS) 是一种自身免疫性炎症性神经退行性疾病，通常伴有使人衰弱的神经性疼痛。疾病缓解药物可以减缓多发性硬化症的进展并防止复发，但尚不清楚它们是否能产生镇痛作用。我们探索了芬戈莫德 (FTY720) 的镇痛潜力，芬戈莫德是 1-磷酸鞘氨醇受体 1 (S1PR1) 的激动剂和/或功能拮抗剂，因为它可以减少外周炎症和神经性疼痛模型中的痛觉过敏。我们使用了实验性自身免疫性脑脊髓炎的髓磷脂少突胶质细胞糖蛋白 35 至 55 (MOG35-55) 小鼠模型，经过修改以避免明显的麻痹，从而可以评估对体感刺激的退缩行为。每日腹腔注射芬戈莫德以剂量依赖性和可逆的方式减少中枢神经性疼痛（机械性和冷过敏）的行为体征。自身免疫性脑脊髓炎和芬戈莫德在改变运动功能之前都会改变痛觉过敏，这表明疼痛相关效应和临床神经功能缺损是独立调节的。芬戈莫德还降低了脊髓背角神经元中枢敏化的细胞标志物：谷氨酸诱发的 Ca21 信号传导和刺激诱发的磷酸细胞外信号相关激酶 ERK (pERK) 表达，以及星形胶质细胞 (GFAP) 和巨噬细胞/小胶质细胞 (Iba1) 免疫反应性的上调。芬戈莫德的抗痛觉过敏作用可被 S1PR1 拮抗剂 W146（每天 1 mg/kg，腹膜内注射）预防或逆转，并且可以通过重复或单次注射 S1PR1 选择性激动剂 SEW2871 来模拟。芬戈莫德没有改变脊髓膜 S1PR1 含量，反对功能性拮抗机制。我们得出的结论是，芬戈莫德作为 S1PR1 激动剂，通过逆转脊髓伤害性神经元的中枢敏化来减轻多发性硬化症的疼痛。
Multiple sclerosis (MS) is an autoimmune-inflammatory neurodegenerative disease that is often accompanied by a debilitating neuropathic pain. Disease-modifying agents slow down the progression of multiple sclerosis and prevent relapses, yet it remains unclear if they yield analgesia. We explored the analgesic potential of fingolimod (FTY720), an agonist and/or functional antagonist at the sphingosine-1-phosphate receptor 1 (S1PR1), because it reduces hyperalgesia in models of peripheral inflammatory and neuropathic pain. We used a myelin oligodendrocyte glycoprotein 35 to 55 (MOG35-55) mouse model of experimental autoimmune encephalomyelitis, modified to avoid frank paralysis, and thus, allow for assessment of withdrawal behaviors to somatosensory stimuli. Daily intraperitoneal fingolimod reduced behavioral signs of central neuropathic pain (mechanical and cold hypersensitivity) in a dose-dependent and reversible manner. Both autoimmune encephalomyelitis and fingolimod changed hyperalgesia before modifying motor function, suggesting that pain-related effects and clinical neurological deficits were modulated independently. Fingolimod also reduced cellular markers of central sensitization of neurons in the dorsal horn of the spinal cord: glutamate-evoked Ca21 signaling and stimulus-evoked phospho-extracellular signal-related kinase ERK (pERK) expression, as well as upregulation of astrocytes (GFAP) and macrophage/microglia (Iba1) immunoreactivity. The antihyperalgesic effects of fingolimod were prevented or reversed by the S1PR1 antagonist W146 (1 mg/kg daily, ip) and could be mimicked by either repeated or single injection of the S1PR1-selective agonist SEW2871. Fingolimod did not change spinal membrane S1PR1 content, arguing against a functional antagonist mechanism. We conclude that fingolimod behaves as an S1PR1 agonist to reduce pain in multiple sclerosis by reversing central sensitization of spinal nociceptive neurons.
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