S1P Receptor Mechanisms in Neuropathic Pain

 描述(申请人提供)：慢性疼痛降低了数百万患者的生活质量，但目前使用的各类止痛药具有不同的疗效，并与各种不良副作用有关。因此，迫切需要治疗慢性疼痛的新靶点和开发比现有药物疗法更有效和/或副作用更少的新药。一个特别有希望的靶点是鞘氨醇-1-磷酸(S1P)受体系统，它介导中枢神经调节功能。FTY720-磷酸是FTY720(FTY；Fingolimod)的活性代谢物，FDA批准用于治疗复发性多发性硬化症，它是五个S1P受体中的四个(S1P1、3、4、5)的激动剂。有趣的是，研究表明FTY和其他S1P受体(S1PR)激动剂在急性热性啮齿动物疼痛模型中产生抗伤害作用，这些作用可被中枢注射S1P1选择性拮抗剂阻断。此外，FTY逆转了啮齿动物神经病理性疼痛模型中的痛觉过敏状态。然而，目前尚不清楚S1P1或其他S1PR亚型是否介导了这些影响及其作用部位(S)。因此，这一应用的主要假设是S1P1受体代表了治疗神经病理性疼痛的一个新的和有希望的靶点。在这里，我们将使用药理学和基因靶向相结合的方法，在小鼠神经病理性疼痛模型中测试中枢神经系统中的S1P1受体是否介导了抗痛觉过敏效应。因此，本研究的具体目的是：1)确定S1P1Rs在S1PR配体减轻神经病理性疼痛中的作用；2)确定FTY诱导的S1PR适应在FTY介导的神经病理性疼痛逆转中的作用；3)确定脊髓胶质细胞S1P和S1P1受体在CCI诱导的神经病理性疼痛中的作用及其FTY的逆转作用。本文提出的研究将确定FTY和选择性S1PR配体是否逆转了小鼠CCI神经病理性疼痛模型中的疼痛相关行为，神经系统中的S1P1受体是否介导了这些行为，以及参与反应的特定细胞类型。为了有效地治疗慢性疼痛，这种药物必须在长期治疗过程中保持其有效性。因此，支持S1P1在特定细胞类型中发挥作用的证据将提供证据，证明S1P1受体是治疗神经性疼痛和其他可能的慢性疼痛相关疾病的可行靶点。

 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.