Sphingosine-1-phosphate receptors as emerging targets for treatment of pain.
Sphingosine-1-phosphate receptors as emerging targets for treatment of pain.
复制标题
1-磷酸鞘氨醇受体作为治疗疼痛的新兴靶点。
DOI：
10.1016/j.bcp.2012.08.010
复制
发表时间：
2012
影响因子：
5.8
通讯作者：
Selley,DanaE
中科院分区：
文献类型：
--
作者：
Welch,SandraP;Sim-Selley,LauraJ;Selley,DanaE
溶血脂是多种生理过程中细胞通讯的重要介质。鞘氨醇-1-磷酸（S1 P）是包括中枢神经系统（CNS）在内的许多器官中的主要溶解脂质。这篇评论讨论了S1 P在调节疼痛感知中的作用的最新发现，并强调了该领域的进展和挑战。S1 P与多种细胞靶点相互作用，包括G蛋白偶联受体。已知的S1 P受体包括五种类型，其中四种在CNS中表达（S1 P 1、2、3、5），它们在CNS中定位于神经元和神经胶质上。S1 P受体介导的G蛋白激活已被证明在整个中枢神经系统，包括调节伤害感受的区域。S1 P受体与多种G蛋白偶联以产生各种细胞内反应，并且可以介导兴奋性和抑制性神经调节，这取决于受体类型和细胞环境。S1 P的抗伤害感受和促伤害感受作用均已报道，并且这两种作用均涉及S1 P1受体。目前的证据表明，抗伤害感受是由中枢神经系统神经元介导的，而亲伤害感受是由初级传入神经元或外周免疫细胞或中枢神经系统胶质细胞介导的。尽管如此，外周给予S1 P1，3，4，5激动剂前体药物FTY 720产生抗伤害感受。FTY 720被批准用于治疗多发性硬化症，并产生有效的抗炎作用，这表明它对疼痛的自身免疫性疾病具有潜在的效用。此外，有证据表明，S1 P系统与其他疼痛调节系统相互作用，如内源性大麻素和阿片系统，以及CNS中推定的新型鞘脂靶点。这些发现表明，靶向S1 P系统的药物可以开发为新型镇痛药，无论是作为单一疗法还是作为现有镇痛药的潜在替代品。
Lysolipids are important mediators of cellular communication in multiple physiological processes. Sphingosine-1-phosphate (S1P) is a major lysolipid in many organs, including the central nervous system (CNS). This commentary discusses recent findings on the role of S1P in regulating pain perception, and highlights advances and challenges in the field. S1P interacts with multiple cellular targets, including G-protein-coupled receptors. Known S1P receptors include five types, four of which are expressed in the CNS (S1P1,2,3,5) where they are localized on neurons and glia. S1P receptor-mediated G-protein activation has been demonstrated throughout the CNS, including regions that regulate nociception. S1P receptors couple to multiple G-proteins to produce various intracellular responses, and can mediate both excitatory and inhibitory neuromodulation, depending on the receptor type and cellular context. Both antinociceptive and pro-nociceptive effects of S1P have been reported, and both actions can involve S1P1receptors. Current evidence suggests that antinociception is mediated by CNS neurons, whereas pro-nociception is mediated by primary afferent neurons or immune cells in the periphery, or CNS glia. Nonetheless, peripheral administration of the S1P1,3,4,5agonist pro-drug, FTY720, produces antinociception. FTY720 is approved to treat multiple sclerosis, and produces potent anti-inflammatory effects, which suggests potential utility for painful autoimmune diseases. Furthermore, evidence suggests that the S1P system interacts with other pain-modulatory systems, such as endogenous cannabinoid and opioid systems, and putative novel sphingolipid targets in the CNS. These findings suggest that drugs targeting the S1P system could be developed as novel analgesics, either as monotherapy or potential adjuncts to established analgesics.