S1P Receptor Mechanisms in Neuropathic Pain

 描述（由申请人提供）：慢性疼痛降低了数百万患者的生活质量，但目前使用的镇痛药类别具有不同的疗效，并与各种不良副作用有关。因此，非常需要治疗慢性疼痛的新靶点和开发比现有药物疗法具有更好疗效和/或更少副作用的新药。一个特别有前途的目标是鞘氨醇-1-磷酸（S1 P）受体系统，介导中枢神经系统的神经调节功能。FTY 720-磷酸盐是FTY 720（FTY;芬戈莫德）的活性代谢产物，经FDA批准用于治疗复发性多发性硬化症，可作为五种S1 P受体中的四种（S1 P1，3，4，5）的激动剂。有趣的是，研究表明，FTY和其他S1 P受体（S1 PR）激动剂在急性热啮齿动物疼痛模型中产生抗伤害感受作用，这些作用可通过S1 P1选择性拮抗剂的中枢给药阻断。此外，FTY逆转啮齿动物神经性疼痛模型中的痛觉过敏状态。然而，目前尚不清楚S1 P1或其他S1 PR亚型是否介导这些作用及其作用位点。因此，本申请的总体假设是S1 P1受体代表了用于治疗神经性疼痛的新的且有希望的靶标。在这里，我们将测试是否在中枢神经系统中的S1 P1受体介导的抗痛觉过敏的作用，在小鼠神经性疼痛模型，使用药理学和基因靶向方法相结合。因此，具体目的是：1）确定S1 P1 R在S1 PR配体缓解神经性疼痛中的作用; 2）确定FTY诱导的S1 PR适应在FTY介导的神经性疼痛逆转中的作用; 3）确定脊髓胶质细胞中S1 P和S1 P1受体在CCI诱导的神经性疼痛和FTY逆转中的作用。本文提出的研究将确定FTY和选择性S1 PR配体是否逆转小鼠CCI神经性疼痛模型中的疼痛相关行为，神经系统中的S1 P1受体是否介导这些作用以及参与反应的特定细胞类型。为了有效治疗慢性疼痛，药物必须在长期治疗期间保持其有效性。因此，支持S1 P1在特定细胞类型中减少神经性疼痛而无耐受性或运动损伤的作用的证据将提供S1 P1受体是治疗神经性疼痛和可能的其他慢性疼痛相关病症的可行靶标的原理证明。

 DESCRIPTION (provided by applicant): Chronic pain diminishes the quality of life for millions of patients, but currently used classes of analgesics possess varied efficacy and are associated with a variety of untoward side effects. Thus, novel targets to treat chronic pain and development of new drugs that have better efficacy and/or fewer side effects than existing pharmacotherapies are greatly needed. A particularly promising target is the sphingosine-1-phosphate (S1P) receptor system, which mediates CNS neuromodulatory functions. FTY720-phosphate, the active metabolite of FTY720 (FTY; fingolimod), approved by the FDA for treatment of relapsing multiple sclerosis, acts as an agonist at four of the five S1P receptors (S1P1, 3, 4, 5). Interestingly, studies have demonstrated that FTY and other S1P receptor (S1PR) agonists produce antinociception in acute thermal rodent pain models and these effects are blocked by central administration of an S1P1-selective antagonist. Moreover, FTY reverses hyperalgesic states in rodent neuropathic pain models. However, it is unclear whether S1P1 or other S1PR subtypes mediate these effects and their site(s) of action. Thus, the overarching hypothesis of this application is that the S1P1 receptor represents a novel and promising target for the treatment of neuropathic pain. Here, we will test whether S1P1 receptors in the CNS mediate anti-hyperalgesic effects in a mouse neuropathic pain model, using a combination of pharmacological and gene targeting approaches. Therefore, the Specific Aims are to: 1) Determine the role of S1P1Rs in alleviation of neuropathic pain by S1PR ligands; 2) Determine the role of FTY-induced S1PR adaptation in FTY-mediated reversal of neuropathic pain; and 3) Determine the role of S1P and S1P1 receptors in spinal glia in CCI-induced neuropathic pain and its reversal by FTY. The studies proposed herein will establish whether FTY and selective S1PR ligands reverse pain-related behavior in the mouse CCI neuropathic pain model, whether S1P1 receptors in the nervous system mediate these actions and the specific cell types involved in the response. In order to be useful in treating chronic pain, the drug must retain its effectiveness during prolonged treatment. Thus, evidence supporting a role of S1P1 in specific cell types to reduce neuropathic pain without tolerance or motor impairment will provide proof of principle that S1P1 receptors are a viable target to treat neuropathic pain and possibly other chronic pain-related disorders.