Department of Physiology and the Center for Analgesia Research Excellence, University of Kentucky College of Medicine, Lexington, KY, USA. T. Iannitti current affiliation is KWS BioTest, Marine View Office Park, Portishead, Somerset BS20 7AW, United Kingdom.
Pain. 2018 Feb;159(2):224-238. doi: 10.1097/j.pain.0000000000001106.
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 Ca 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, i.p.) 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.
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，常伴有使人衰弱的神经性疼痛。疾病修正治疗药物可减缓多发性硬化症的进展并预防复发，但尚不清楚它们是否具有镇痛作用。我们研究了芬戈莫德（FTY720）的镇痛潜力，它是一种鞘氨醇-1-磷酸受体 1（S1PR1）的激动剂和/或功能拮抗剂，因为它可以减轻周围炎症和神经性疼痛模型中的痛觉过敏。我们使用了髓鞘少突胶质细胞糖蛋白 35-55（MOG35-55）实验性自身免疫性脑脊髓炎小鼠模型，该模型经过改良以避免明显瘫痪，从而可以评估对躯体感觉刺激的退缩行为。每日腹腔内给予芬戈莫德可剂量依赖性和可逆地减轻中枢性神经病理性疼痛（机械性和冷感觉过敏）的行为征象。自身免疫性脑脊髓炎和芬戈莫德都会改变痛觉过敏，然后才改变运动功能，这表明疼痛相关的影响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的中枢敏化的细胞标志物：谷氨酸诱发的 Ca 信号和刺激诱发的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。S1PR1 拮抗剂 W146（每天 1mg/kg，腹腔内注射）可预防或逆转芬戈莫德的抗痛觉过敏作用，而 S1PR1 选择性激动剂 SEW2871 的重复或单次注射也可模拟其作用。芬戈莫德不改变脊髓膜 S1PR1 含量，这表明其不是通过作为功能性拮抗剂发挥作用。我们的结论是，芬戈莫德作为 S1PR1 激动剂，通过逆转脊髓伤害感受神经元的中枢敏化来减轻多发性硬化症中的疼痛。
