ACTIONS OF PROINFLAMMATORY CYTOKINES ON SENSORY NEURONS

促炎细胞因子对感觉神经元的作用

• 批准号: 6394014
• 负责人: GRANT D NICOL
• 金额: $ 29.98万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-10 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394014
• 关键词: cytokine; diacylglycerols; dorsal root; hyperalgesia; inflammation; interleukin 1; interleukin 6; laboratory rat; membrane potentials; neuroimmunomodulation; neuropeptides; neuropharmacology; second messengers; sensory neuropathy; somatic afferent nerve; sphingolipids; spinal ganglion; tissue /cell culture; tumor necrosis factor alpha; voltage /patch clamp

DESCRIPTION (applicant's abstract): Increasing evidence suggests that activation of various components of the immune system contribute to chronic pain and inflammation. A number of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1-beta (IL-1beta), and interleukin-6 (IL-6) are synthesized and released at sites of trauma and produce hyperalgesia in animal models of pain. One mechanism for cytokine-induced augmentation of pain perception could involve their direct actions on nociceptive sensory neurons to enhance excitability and/or sensitize them to physical or chemical stimuli. Despite abundant evidence that TNF-alpha, IL-1beta, and IL-6 produce hyperalgesia and inflammation, there is little information regarding their capacity to modulate intracellular signaling pathways that regulate sensory neuron function. The hypothesis of this proposal is that pro-inflammatory cytokines act directly on sensory neurons to enhance their excitability and sensitize these cells to noxious mechanical and chemical stimuli and, in turn, augment the release of neuroactive substances from these neurons. The proposed studies will utilize two approaches: patch-clamp electrophysiology to assess cytokine-induced alterations in membrane excitability in rat sensory neurons grown in culture and biochemical measurements of neuropeptide release in isolated sensory neurons grown in culture and an in vitro preparation of rat spinal cord slices. The aims of this proposal are: 1) to determine whether acute or chronic exposure to TNF-alpha, IL-1beta, or 1L-6 alters membrane excitability and/or sensitizes isolated sensory neurons to electrical or chemical stimuli, 2) to determine whether these pro-inflammatory cytokines stimulate and/or sensitize the release of SP and CGRP from rat sensory neurons grown in culture or from rat spinal cord slices; and 3) to determine the effects of pro-inflammatory cytokines on sphingolipid second messengers and diacylglycerol in sensory neurons and to establish causal relationships between changes in second messenger systems and cytokine-induced alterations in excitability and peptide release. Overall, the knowledge gained from these studies is critical for understanding the etiology of chronic pain and could eventually aid in designing interventions to alleviate the pain. The results of this work can increase the understanding of the cellular mechanisms mediating the interaction between the nervous system and the immune system and thus be applicable to other areas of neurobiology.

描述（申请人的摘要）：越来越多的证据表明，免疫系统各种成分的激活有助于慢性疼痛和炎症。在创伤部位合成并释放许多促炎性细胞因子，例如肿瘤坏死因子α（TNF-Alpha），白介素1-β（IL-1Beta）和白介素6（IL-6），并在创伤部位释放并释放。细胞因子引起的疼痛感知增强的一种机制可能涉及其对伤害感受感觉神经元的直接作用，以增强兴奋性和/或使其对物理或化学刺激的敏感性。尽管有充分的证据表明TNF-Alpha，IL-1Beta和IL-6产生了痛觉过敏和炎症，但关于它们调节调节感觉神经元功能的细胞内信号传导途径的能力的信息很少。该提议的假设是，促炎性细胞因子直接作用于感觉神经元，以增强其兴奋性并使这些细胞对有害的机械和化学刺激敏感，进而增强了这些神经元中神经活性物质的释放。拟议的研究将利用两种方法：斑块钳电生理学评估细胞因子诱导的膜兴奋性的改变，在培养物中培养和生物化学测量中生长的大鼠感觉神经元的膜兴奋性改变，在培养物中生长的分离性感觉神经元中神经肽释放的生化测量以及大鼠脊柱质质质质质质质质质的培养。 The aims of this proposal are: 1) to determine whether acute or chronic exposure to TNF-alpha, IL-1beta, or 1L-6 alters membrane excitability and/or sensitizes isolated sensory neurons to electrical or chemical stimuli, 2) to determine whether these pro-inflammatory cytokines stimulate and/or sensitize the release of SP and CGRP from rat sensory neurons grown in culture or from rat脊髓切片； 3）确定促炎性细胞因子对感觉神经元中鞘脂第二信使和二酰基甘油的影响，并在第二质体系统的变化与细胞因子诱导的兴奋性改变和肽释放的变化之间建立因果关系。总体而言，从这些研究中获得的知识对于理解慢性疼痛的病因至关重要，最终可能有助于设计干预措施以减轻疼痛。这项工作的结果可以增加对介导神经系统与免疫系统相互作用的细胞机制的理解，从而适用于神经生物学的其他领域。