Peptidergic Neurotransmission in the Spinal Cord

脊髓中的肽能神经传递

• 批准号: 7082619
• 负责人: Virginia S Seybold
• 金额: $ 0.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-05 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082619
• 关键词: Peptidergic; Neurotransmission; Spinal; Cord

DESCRIPTION (provided by applicant): Maintenance of hyperalgesia requires changes in the expression of proteins that lead to an increase in synaptic strength. Data generated in this proposal will test the hypothesis that peptides released in the spinal cord in response to tissue damaging stimuli activate receptors on spinal neurons that increase gene expression, resulting in increased expression of proteins that underlie hyperalgesia. We have shown that CGRP increases gene expression in spinal neurons through a CREB-dependent mechanism. We predict SP will increase protein expression through the transcription factor NFAT. Data will be generated to address the following questions: 1) Does SP activate NFAT-dependent gene transcription in spinal neurons? 2) Does SP facilitate effects of CGRP on CREB-dependent gene transcription in spinal neurons? 3) Do SP and CGRP increase expression of proteins relevant to hyperalgesia in spinal neurons in vitro? 4) Do SP and CGRP increase expression of these proteins in spinal neurons in vivo? 5) Do multiple treatments with SP and CGRP increase secondary hyperalgesia? 6) Do endogenous SP and CGRP contribute to the maintenance of secondary hyperalgesia during peripheral inflammation? Immunoblot analyses and real time PCR will be used to quantify the effects of SP and CGRP on the expression of four proteins that are known to be increased in the spinal cord during peripheral inflammation and that contribute to hyperalgesia: neurokinin-1 receptor, cyclo-oxygenase 2, type 1 nitric oxide synthase and inositol triphosphate receptor. Behavioral assays of nociception will be used to test whether multiple treatments with SP and CGRP are sufficient to increase hyperalgesia; antagonists of SP and CGRP receptors will be used to determine whether endogenous SP and CGRP are necessary to support the increase in nociceptive responses that occurs in a model of peripheral inflammation. The experiments will generate new information concerning the effects of SP and CGRP on protein expression in spinal neurons in general as well as 4 proteins that contribute to hyperalgesia. If the hypothesis is proven to be true, the data will provide evidence for a new therapeutic strategy that may be effective in treating peripheral inflammatory diseases. Because virtually all-mammalian peptides activate metabotropic receptors, the results will have broad implications for understanding the role of peptides in neurotransmission.

描述（由申请人提供）：维持痛觉过敏需要改变蛋白质的表达，这会导致突触强度的提高。该提案中产生的数据将检验以下假设：响应组织损伤刺激的脊髓中释放的肽激活了增加基因表达的受体，从而增加了基于超痛觉过敏的蛋白质的表达增加。我们已经表明，CGRP通过CREB依赖性机制增加了脊髓神经元中的基因表达。我们预测SP将通过转录因子NFAT增加蛋白质表达。将生成数据以解决以下问题：1）SP在脊柱神经元中是否激活NFAT依赖性基因转录？ 2）SP是否促进CGRP对脊柱神经元中CREB依赖性基因转录的影响？ 3）SP和CGRP是否会在体外增加与脊柱神经元中与痛痛相关的蛋白质的表达？ 4）SP和CGRP是否会增加体内脊柱神经元中这些蛋白质的表达？ 5）使用SP和CGRP的多种治疗方法会增加次级痛觉过敏吗？ 6）内源性SP和CGRP是否有助于在周围炎症期间维持继发性痛觉过敏？ Immunoblot analyses and real time PCR will be used to quantify the effects of SP and CGRP on the expression of four proteins that are known to be increased in the spinal cord during peripheral inflammation and that contribute to hyperalgesia: neurokinin-1 receptor, cyclo-oxygenase 2, type 1 nitric oxide synthase and inositol triphosphate receptor.伤害感受的行为测定将用于测试SP和CGRP的多种治疗是否足以增加痛觉过敏。 SP和CGRP受体的拮抗剂将用于确定内源性SP和CGRP是否需要用于支撑外周炎症模型中发生的伤害感受反应的增加。该实验将生成有关SP和CGRP对脊髓神经元中蛋白质表达的影响的新信息，以及4种导致痛觉过敏的蛋白质。如果该假设被证明是正确的，那么数据将为新的治疗策略提供证据，该策略可能有效地治疗周围炎症性疾病。由于实际上所有哺乳动物肽都激活了代谢受体，因此结果将对理解肽在神经传递中的作用具有广泛的影响。