Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Neuropharmacology. 2024 Dec 15;261:110165. doi: 10.1016/j.neuropharm.2024.110165. Epub 2024 Sep 18.
Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice. Daily injections of FTY720 for 14 days dose-dependently reversed CCI-induced mechanical allodynia without tolerance development, and concomitantly resulted in a dose-dependent reduction of G-protein activation by the S1PR1-selective agonist SEW2871 in the lumbar spinal cord and brain. These findings indicate FTY720-induced desensitization of S1PR1 signaling coincides with its anti-allodynic effects. Consistent with this finding, a single injection of FTY720 reversed mechanical allodynia while concomitantly producing partial desensitization of S1PR1-stimulated G-protein activation in the CNS. However, mechanical allodynia returned 24-hr post injection, despite S1PR1 desensitization at that time, demonstrating a dissociation between these measures. Furthermore, CCI surgery led to elevations of sphingolipid metabolites, including S1P, which were unaffected by daily FTY720 administration, suggesting FTY720 reversed mechanical allodynia by targeting S1PR1 rather than sphingolipid metabolism. Supporting this hypothesis, acute administration of the S1PR1-selective agonist CYM-5442 mimicked the anti-allodynic effect of FTY720. In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism.
鞘氨醇-1-磷酸（S1P）受体（S1PR）激动剂，如 fingolimod（FTY720），通过激活（激动）或抑制（功能拮抗）S1PR 型-1（S1PR1），在临床前疼痛模型中减轻疼痛。然而，逆转疼痛和调节 S1PR1 信号之间的剂量依赖性和时间关系尚未系统研究。本研究使用坐骨神经慢性缩窄损伤（CCI）模型检查了 FTY720 诱导的镇痛作用与 S1PR1 适应之间的关系，该模型用于雄性和雌性 C57Bl/6J 小鼠的神经病理性疼痛。每天注射 FTY720 14 天可剂量依赖性地逆转 CCI 诱导的机械性痛觉过敏，而无耐受性发展，同时导致 S1PR1 选择性激动剂 SEW2871 在腰椎脊髓和大脑中的 G 蛋白激活呈剂量依赖性降低。这些发现表明，FTY720 诱导的 S1PR1 信号脱敏与其抗痛觉过敏作用一致。与这一发现一致，单次注射 FTY720 可逆转机械性痛觉过敏，同时导致中枢神经系统中 S1PR1 刺激的 G 蛋白激活部分脱敏。然而，注射后 24 小时，机械性痛觉过敏恢复，尽管此时 S1PR1 脱敏，但这些措施之间存在分离。此外，CCI 手术导致鞘脂代谢物（包括 S1P）升高，而每天给予 FTY720 不会影响这些代谢物，这表明 FTY720 通过靶向 S1PR1 而不是鞘脂代谢来逆转机械性痛觉过敏。支持这一假说，急性给予 S1PR1 选择性激动剂 CYM-5442 模拟了 FTY720 的抗痛觉过敏作用。相比之下，S1PR1 选择性拮抗剂 NIBR-0213 可预防 FTY720 的抗痛觉过敏作用，但 NIBR-0213 单独给药不会影响疼痛。这些结果表明，FTY720 通过与功能拮抗不同的机制缓解 CCI 诱导的痛觉过敏。
