Peptidergic Neurotransmission in the Spinal Cord

脊髓中的肽能神经传递

基本信息

批准号：
7161758
负责人：
Virginia S Seybold
金额：
$ 28.62万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/7161758
关键词：
Address Attenuated Behavioral Assay Biological Assay CREB1 gene Ca(2+)-Calmodulin Dependent Protein Kinase Calcitonin Gene-Related Peptide Calcitonin-Gene Related Peptide Receptor Cannulas Capsaicin Chemicals Continuous Infusion Data Disease Dominant-Negative Mutation Enzyme Inhibitor Drugs Enzyme Inhibitors Gastrocnemius Muscle Gene Activation Gene Expression Genetic Transcription Hyperalgesia ITPR1 gene Immunoblot Analysis In Vitro Inflammation Inflammatory Infusion procedures Lead Long-Term Effects Luciferases Maintenance Measures Mediating Messenger RNA Modeling NOS1 protein, human Neonatal Neurons Nociception Nociceptors Pathway interactions Peptides Peripheral Physiological Polymerase Chain Reaction Prostaglandin-Endoperoxide Synthase Proteins Publishing Rattus Receptor Inhibition Reporter Reporter Genes Secondary Hyperalgesias Signal Transduction Spinal Spinal Cord Stimulus Substance P Substance P Receptor Synapses TACR1 gene Testing Time Tissues base cyclooxygenase 1 cyclooxygenase 2 in vivo inhibitor/antagonist inositol-1,4,5-triphosphate receptor interdisciplinary approach neurotransmission nociceptive response novel therapeutics protein expression receptor receptor coupling research study response transcription factor treatment effect

项目摘要

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. 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) Does treatment with SP or CGRP increase secondary hyperalgesia? 6) Do endogenous SP and CGRP contribute to the maintenance of secondary hyperalgesia during peripheral inflammation? Immunoblot analysis 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 treatment with SP and CGRP is 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.

描述（由申请人提供）：维持痛觉过敏需要改变蛋白质的表达，从而导致突触强度的增加。该提案中生成的数据将检验以下假设：脊髓中响应组织损伤刺激而释放的肽会激活脊髓神经元上的受体，从而增加基因表达，从而导致痛觉过敏背后的蛋白质表达增加。将生成数据来解决以下问题：1）SP 是否激活脊髓神经元中 NFAT 依赖性基因转录？ 2) SP是否促进CGRP对脊髓神经元中CREB依赖性基因转录的影响？ 3）SP和CGRP是否会增加体外脊髓神经元中与痛觉过敏相关的蛋白质的表达？ 4) SP和CGRP是否会增加体内脊髓神经元中这些蛋白质的表达？ 5) SP 或 CGRP 治疗是否会增加继发性痛觉过敏？ 6) 内源性 SP 和 CGRP 是否有助于维持外周炎症期间继发性痛觉过敏？免疫印迹分析和实时 PCR 将用于量化 SP 和 CGRP 对四种蛋白质表达的影响，已知这些蛋白质在外周炎症期间在脊髓中增加，并导致痛觉过敏：神经激肽-1 受体、环加氧酶2、1型一氧化氮合酶和肌醇三磷酸受体。伤害感受的行为测定将用于测试 SP 和 CGRP 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 是否需要支持在疼痛中发生的伤害感受反应的增加。外周炎症模型。这些实验将产生有关 SP 和 CGRP 对脊髓神经元蛋白质表达以及 4 种导致痛觉过敏的蛋白质的影响的新信息。如果该假设被证明是正确的，这些数据将为可能有效治疗外周炎症性疾病的新治疗策略提供证据。