Mechanisms of Hyperalgesia in the Spinal Dorsal Horn

脊髓背角痛觉过敏的机制

基本信息

批准号：
7750000
负责人：
VJEKOSLAV MILETIC
金额：
$ 25.18万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750000
关键词：
Animals Attenuated Behavioral Code Cyclic AMP-Responsive DNA-Binding Protein Data Development Funding Future Gene Expression Genes Goals Homer protein Hour Hyperalgesia Immunofluorescence Immunologic Inflammation Injury Lead Ligation Link Measures Mediating Mediator of activation protein Messenger RNA Mitogen-Activated Protein Kinase 3 Modeling N-Methylaspartate Neurotrophic Tyrosine Kinase Receptor Type 2 Nociception Pain Pathway interactions Pattern Peripheral nerve injury Persistent pain Pharmaceutical Preparations Play Posterior Horn Cells Process Protein Biosynthesis Protein Isoforms Proteins Receptor Activation Regulation Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Small Interfering RNA Solid Specificity Spinal Staining method Stains Structure Subcellular Fractions Synapses Synaptic plasticity Therapeutic Therapeutic Intervention Thermal Hyperalgesias Transcription factor genes Translating Translations Western Blotting awake base density dorsal horn mechanical allodynia nerve injury novel painful neuropathy prevent programs protein activation receptor research study sciatic nerve

项目摘要

The processing of nociceptive information in the spinal dorsal horn may change significantlyfollowing peripheral nerve injury or inflammation to ultimately lead to the development of persistent pain. We previously established that loose ligation of the sciatic nerve was closely associated with (1) activity- dependent long-lasting synaptic plasticity and (2) the activation of cyclic AMP response element binding protein (CREB). CREB activation alters the expression of many genes, including those coding for the post- synaptic density (PSD) proteins Homer and Shank. The Homerla, Ib and Ic and Shankl and 2 isoforms may play important roles in the activity-dependent remodeling of the PSD that ultimately leads to increased synaptic efficacy. In the present application we will investigate the relationship between loose ligation of the sciatic nerve and these Homer and Shank isoforms. Our central hypothesis is that sciatic ligation-associated regulation of Homerla, Ib and Ic and Shankl & 2 gene expression promotes the remodeling of the post- synaptic density (PSD) in spinal dorsal horn neurons. We surmise that this remodeling critically contributes to the long-lasting increases in synaptic efficacy that eventually lead to neuropathic pain, hi Specific Aim 1 we will examine if selected pre-transcriptional mediators 'translate' the sciatic ligation into changes in Homer and Shank gene expression, hi Specific Aim 2 we will employ specific small interfering RNAs in an attempt to 'silence' Homer and Shank gene expression and establish whether this modifies their protein levels and distribution in the PSD of spinal dorsal horn neurons within hours of the sciatic ligation. In Specific Aim 3 we seek to establish if manipulations of Homer and Shank gene expression and protein levels alter mechanical allodynia and thermal hyperalgesia as behavioral signs of neuropathic pain several days after the sciatic ligation. We strive to achieve two main goals in this proposal. First, from a cellular perspective we wish to delineate the consequences of injury-elicited primary afferent activity on the PSD structure in the spinal dorsal horn. Second, from a therapeutic perspective, we seek to achieve better target specificity. The remodeled PSD may be a common reflection of injury-elicited changes in several receptors, pathways, transcription factors and genes. If our experiments suggest that regulation of Homer and Shank gene expression plays an important role in the remodeling of the 'pain' PSD then our successful completion of this proposal should provide a solid basis for future therapeutic interventions.

脊髓角喇叭中伤害感受信息的处理可能会发生明显变化周围神经损伤或炎症，最终导致持续性疼痛的发展。我们以前确定坐骨神经的松散连接与（1）活性密切相关 - 依赖性长期突触可塑性和（2）环状AMP响应元件结合的激活蛋白质（CREB）。 CREB激活改变了许多基因的表达，包括编码后的基因突触密度（PSD）蛋白质本垒打和小腿。 Homerla，Ib和Ic和Shankl以及2个同工型可能在PSD的活动依赖性重塑中起重要作用，最终导致增加突触功效。在本应用中，我们将调查宽松的连接之间的关系坐骨神经以及这些本垒打和柄同工型。我们的中心假设是坐骨神经肌相关 Homerla，IB和IC和Shankl＆2基因表达的调节促进了后期的重塑脊柱背角神经元中的突触密度（PSD）。我们推测，这种重塑有巨大的贡献突触功效最终导致神经性疼痛的长期增强，特异性目标1 我们将检查选定的转录前调解人是否将坐骨神经连接转换为变化荷马和柄基因表达，嗨，特定目的2我们将在一个特定的小干扰RNA中试图“沉默”本垒打和柄基因表达并确定是否修饰了其蛋白质坐骨结扎后数小时内，脊柱背角神经元的PSD的水平和分布。在特定目的3我们寻求确定荷马和柄基因表达和蛋白质水平的操纵是否改变机械性异常性异常和热痛觉过敏，作为神经性疼痛的行为迹象几天坐骨下结扎后。我们努力在该提案中实现两个主要目标。首先，来自细胞观点我们希望描述PSD受伤引起的主要传入活动的后果脊髓角的结构。第二，从治疗的角度来看，我们试图实现更好的目标特异性。重塑的PSD可能是几种受体中受伤变化的常见反映，途径，转录因子和基因。如果我们的实验表明对荷马和小腿的调节基因表达在“疼痛” PSD的重塑中起重要作用，然后我们成功完成该提案应为将来的治疗干预提供扎实的基础。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Early changes in Homer1 proteins in the spinal dorsal horn are associated with loose ligation of the rat sciatic nerve.

DOI：
10.1213/ane.0b013e3181beea9b
发表时间：
2009-12
期刊：
Anesthesia and analgesia
影响因子：
5.7
作者：
Miletic G;Driver AM;Miyabe-Nishiwaki T;Miletic V
通讯作者：
Miletic V

Loose ligation of the rat sciatic nerve elicits early accumulation of Shank1 protein in the post-synaptic density of spinal dorsal horn neurons.

DOI：
10.1016/j.pain.2010.02.001
发表时间：
2010-04
期刊：
Pain
影响因子：
7.4
作者：
Miletic G;Dumitrascu CI;Honstad CE;Micic D;Miletic V
通讯作者：
Miletic V

Differential effects of inorganic lead on hippocampal long-term potentiation in young rats in vivo.

无机铅对幼年大鼠体内海马长时程增强的不同影响。

DOI：
10.1016/s0006-8993(00)02657-3
发表时间：
2000
期刊：
Brain research
影响因子：
2.9
作者：
Zaiser,AE;Miletic,V
通讯作者：
Miletic,V

Changes in calcineurin message, enzyme activity and protein content in the spinal dorsal horn are associated with chronic constriction injury of the rat sciatic nerve.

DOI：
10.1016/j.neuroscience.2011.05.013
发表时间：
2011-08-11
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Miletic, G.;Sullivan, K. M.;Dodson, A. M. K.;Lippitt, J. A.;Schneider, J. A.;Miletic, V.
通讯作者：
Miletic, V.

Prenatal and postnatal chronic exposure to low levels of inorganic lead attenuates long-term potentiation in the adult rat hippocampus in vivo.

产前和产后长期接触低水平的无机铅会减弱成年大鼠体内海马体的长期增强作用。