Sphingosine 1-Phosphate Receptors and Sensitization of Sensory Neurons

1-磷酸鞘氨醇受体和感觉神经元的敏化

• 批准号: 7895928
• 负责人: GRANT D NICOL
• 金额: $ 52.94万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895928
• 关键词: Action Potentials; Affect; Afferent Neurons; Animals; Behavior; Behavioral; Binding; Biochemical Pathway; Biological Models; Blood Platelets; Caliber; Capsaicin; Cardiac; Cells; Chemotaxis; Collaborations; Communication; Dinoprostone; Environment; Event; Exposure to; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Goals; Grant; Immune; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intervention; Ion Channel; Knowledge; Lead; Learning; Ligands; Lysophospholipids; Maintenance; Mediating; Membrane; Messenger RNA; Molecular; Names; Nerve Growth Factors; Neurons; Nociception; Pain; Pathway interactions; Perception; Perfusion; Physiological; Play; Population; Potassium; Principal Investigator; Rattus; Regulation; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Sodium; Sphingosine-1-Phosphate Receptor; Stimulus; System; TRPV1 gene; Tetrodotoxin; Therapeutic Intervention; United States National Institutes of Health; Work; afferent nerve; in vivo; knock-down; mast cell; member; migration; nerve injury; neuronal excitability; novel; patch clamp; receptor; research study; response; sphingosine 1-phosphate; tool

Inflammation can augment dramatically the sensitivity of nociceptive sensory neurons. In some cases, the actions of inflammatory mediators are fairly well understood; however, there are signalling pathways for which we have very little knowledge. Such a pathway is the one in which the activating ligand is sphingosine 1- phosphate (S1P). Upon activation, S1P is released from a variety of immuno-competent cells and appears to play an important role in their chemotaxis and migration. S1 P is the endogenous ligand for a family of G protein-coupled receptors originally named EDG receptors (endothelial differentiation gene) and are now known as the S1 P receptor family (S1 PRJ. Our understanding of the role of S1 P in the onset and regulation of the inflammatory response is very limited, even in model systems. In our work on NGF, we discovered that externally applied S1 P significantly increased neuronal excitability and that these neurons expressed the mRNA for S1 PRs. Because of the emerging importance of S1 P in the onset of inflammation, this raises the question whether S1 P is an important primary messenger communicating between inflammatory cells and sensory neurons. To answer this question, three SAs are proposed: SA1 will establish which S1 PRs are expressed in sensory neurons and whether these receptors co-localize with specific defined populations of sensory neurons. SA2 will determine, using patch-clamp recording, which specific membrane currents are modulated by S1 P and how these changes lead to enhanced neuronal firing. S1 PRs involved in this sensitization will be determined by single-cell RT-PCR analysis and siRNA to knock-down the expression of specific receptors. SA3 in collaboration with Dr. Jun-Ming Zhang, will determine the capacity of S1 P to affect nociceptive behaviors in rats wherein S1 P is perfused directly onto the L5 DRG. Results from such studies will provide an important understanding of the potential communication between the immune and neuronal systems and lead to interventions that reduce the enhanced pain associated with inflammation.

炎症可显著增加伤害性感觉神经元的敏感性。在某些情况下，炎症介质的作用是相当好的理解;然而，有信号通路，我们有很少的知识。这种途径是其中活化配体是1-磷酸鞘氨醇（S1 P）的途径。激活后，S1 P从多种免疫活性细胞中释放，并在其趋化性和迁移中发挥重要作用。SlP是最初称为EDG受体（内皮分化基因）的G蛋白偶联受体家族的内源性配体，现在称为SlP受体家族（SlPRJ）。即使在模型系统中，我们对S1 P在炎症反应的发生和调节中的作用的理解也非常有限。在我们对NGF的研究中，我们发现外部应用S1 P显著增加神经元的兴奋性，并且这些神经元表达S1 PR的mRNA。由于S1 P在炎症发作中的重要性，这提出了S1 P是否是炎症细胞和感觉神经元之间通信的重要初级信使的问题。为了回答这个问题，提出了三个SA：SA 1将确定哪些S1 PR在感觉神经元中表达，以及这些受体是否与特定的感觉神经元群体共定位。SA 2将使用膜片钳记录来确定哪些特定的膜电流被S1 P调节以及这些变化如何导致增强的神经元放电。通过单细胞RT-PCR分析和siRNA敲低特异性受体的表达来确定参与这种致敏的S1 PR。SA 3与Jun-Ming Zhang博士合作，将确定S1 P影响大鼠伤害感受行为的能力，其中S1 P直接灌注到L5 DRG上。这些研究的结果将为免疫和神经系统之间的潜在沟通提供重要的理解，并导致减少与炎症相关的疼痛增强的干预措施。