Dissociation between the anti-allodynic effects of fingolimod (FTY720) and desensitization of S1P1 receptor-mediated G-protein activation in a mouse model of sciatic nerve injury

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Abby M. Pondelick , Lauren V. Moncayo , Giulia Donvito , Virginia D. McLane , James C. Gillespie , Kurt F. Hauser , Sarah Spiegel , Aron H. Lichtman , Laura J. Sim-Selley , Dana E. Selley
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引用次数: 0

Abstract

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.
在坐骨神经损伤小鼠模型中,芬戈莫德(FTY720)的抗痛觉作用与 S1P1 受体介导的 G 蛋白激活脱敏之间的分离。
脑啡肽-1-磷酸(S1P)受体(S1PR)激动剂,如芬戈莫德(FTY720),通过激活(激动)或抑制(功能性拮抗)S1PR1型(S1PR1)来减轻临床前疼痛模型中的痛觉。然而,目前尚未系统研究痛觉逆转与 S1PR1 信号调节之间的剂量依赖性和时间关系。本研究使用坐骨神经慢性收缩损伤(CCI)神经病理性疼痛模型,在雄性和雌性 C57Bl/6J 小鼠中研究了 FTY720 诱导的抗痛觉与 S1PR1 适应性之间的关系。连续14天每天注射FTY720可剂量依赖性地逆转CCI诱导的机械异感,且不会产生耐受性,同时可剂量依赖性地减少腰脊髓和大脑中S1PR1选择性激动剂SEW2871对G蛋白的激活。这些发现表明,FTY720 诱导的 S1PR1 信号传导脱敏与其抗镇痛作用相吻合。与这一发现相一致的是,单次注射 FTY720 在逆转机械异感的同时,还能对中枢神经系统中 S1PR1 刺激的 G 蛋白激活产生部分脱敏作用。然而,尽管当时S1PR1已经脱敏,但在注射24小时后机械性异感又再次出现,这表明这些指标之间存在差异。此外,CCI手术导致包括S1P在内的鞘脂代谢物升高,而每天注射FTY720不会影响这些代谢物的升高,这表明FTY720是通过靶向S1PR1而不是鞘脂代谢来逆转机械异感的。为支持这一假设,急性给予 S1PR1 选择性激动剂 CYM-5442 可模拟 FTY720 的抗异感效应。相反,S1PR1 选择性拮抗剂 NIBR-0213 可阻止 FTY720 的抗痛觉作用,但单独服用 NIBR-0213 不会影响痛觉。这些结果表明,FTY720通过一种不同于功能拮抗的机制减轻了CCI诱导的异动症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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