Role of Medullary Substance P in Acute and Persistent Nociception

髓质 P 在急性和持续性伤害感受中的作用

基本信息

  • 批准号:
    7689323
  • 负责人:
  • 金额:
    $ 56.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-30 至 2013-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our understanding of the mechanisms by which inflammatory injury leads to sustained changes in the function and properties of pain modulatory neurons in the rostral ventromedial medulla (RVM) remains rudimentary. Substance P (SubP) contributes to central sensitization after injury, yet surprisingly little is known about its role in the modulation of nociception by the RVM, where it also exists in high concentrations. Pilot data indicate that SubP has both antinociceptive and pronociceptive actions in the RVM in the uninjured state, but acts to mediate and sustain hyperalgesia after inflammatory injury. These data support four related hypotheses. 1) SubP exerts both pronociceptive and antinociceptive effects in the uninjured state by time-dependent activation of pain inhibitory and pain facilitatory bulbospinal pathways. Behavioral pharmacological studies will establish the dose-dependence and duration of SubP effects in the RVM of rats in the uninjured state, and confirm the role of neurokinin-1 (NK1) receptors. The bulbospinal pathways that mediate the effects of SubP will be determined by challenge with spinally-administered receptor antagonists before and at various times after SubP injection. 2) SubP is released in the RVM in response to inflammatory injury, where it plays a pronociceptive role in the development of hyperalgesia. The role of endogenous SubP released in the RVM after injury will be assessed by NK1 receptor internalization and by microinjection of NK receptor antagonists in the RVM of rats with acute and persistent hyperalgesia induced by complete Freund's adjuvant (CFA). 3) SubP effects reflect the expression of the NK1 receptor by specific types of RVM neurons, a pattern that may change after injury. Tract tracing and immunohistochemistry will identify RVM neurons that express NK1 receptors by their neurotransmitter content and projections to the spinal cord and DLPT. Subsequent studies will determine whether this expression changes after CFA, and will identify the types of RVM neurons in which NK1 receptor internalization (indicative of SubP release) occurs after injury. 4) SubP acts at specific populations of spinally-projecting RVM neurons and, in CFA-treated rats, enhances excitatory inputs to specific types of RVM neurons to mediate hyperalgesia. Whole-cell patch clamp recording from RVM neurons, coupled with retrograde labeling and immunohistochemical staining, will identify which types of RVM neurons express functional NK1 receptors and determine how the actions of SubP change after CFA. Extracellular recordings will determine the effect of SubP on ON, OFF and NEUTRAL cells and its role in the sensitization of these neurons after CFA. These studies will provide a mechanistic framework in which the antinociceptive and pronociceptive effects of SubP are related to specific populations of RVM neurons. These data in turn may enable us to identify their function (pro- vs antinociceptive). Collectively, these results will advance our understanding of the means and mechanisms by which peripheral inflammatory injury alters the responses and function of critical brainstem pain modulatory systems, and inform a more rationale development of centrally-acting analgesics for the relief of persistent pain. PUBLIC HEALTH RELEVANCE Persistent pain of an inflammatory nature, such as that associated with arthritis or soft tissue injury, exacts a significant financial, emotional and physical toll on its sufferers. The results of these studies will identify how persistent pain changes the function of brainstem pathways that are critically involved in the regulation of nociception and the production of analgesia. Insights gain from this work will guide the development of new, more effective pharmacotherapies or cognitive approaches for the relief of persistent pain.
描述(由申请人提供):我们对炎性损伤导致延髓头端腹内侧(RVM)疼痛调节神经元功能和特性持续变化的机制的理解仍然是初步的。P物质(SubP)有助于损伤后的中枢致敏,但令人惊讶的是,它在RVM的伤害感受调制中的作用知之甚少,它也以高浓度存在。初步数据表明,SubP在未受伤状态下在RVM中具有抗伤害感受和原伤害感受作用,但在炎症损伤后介导和维持痛觉过敏。这些数据支持四个相关假设。1)SubP在未损伤状态下通过时间依赖性激活疼痛抑制和疼痛易化的球脊髓通路发挥疼痛感受和抗伤害感受作用。行为药理学研究将建立剂量依赖性和持续时间的SubP的影响,在RVM的大鼠在未受伤的状态,并确认神经激肽-1(NK 1)受体的作用。介导SubP作用的球脊髓通路将通过在SubP注射之前和之后的不同时间用脊髓给予的受体拮抗剂进行激发来确定。2)SubP在RVM中响应于炎性损伤而释放,在那里它在痛觉过敏的发展中发挥原伤害感受作用。将通过NK 1受体内化和通过在具有由完全弗氏佐剂(CFA)诱导的急性和持续性痛觉过敏的大鼠的RVM中微量注射NK受体拮抗剂来评估损伤后RVM中释放的内源性SubP的作用。3)SubP效应反映了特定类型RVM神经元的NK 1受体表达,这种模式可能在损伤后发生变化。束追踪和免疫组织化学将通过其神经递质含量和向脊髓和DLPT的投射来识别表达NK 1受体的RVM神经元。随后的研究将确定CFA后这种表达是否发生变化,并将确定损伤后发生NK 1受体内化(指示SubP释放)的RVM神经元的类型。4)SubP作用于特定群体的脊髓投射RVM神经元,并在CFA处理的大鼠中,增强对特定类型的RVM神经元的兴奋性输入以介导痛觉过敏。RVM神经元的全细胞膜片钳记录,加上逆行标记和免疫组织化学染色,将确定哪些类型的RVM神经元表达功能性NK 1受体,并确定CFA后SubP的作用如何变化。细胞外记录将确定SubP对ON、OFF和NEUTRAL细胞的影响及其在CFA后这些神经元敏化中的作用。这些研究将提供一个机制框架,其中SubP的抗伤害性和原伤害性效应与RVM神经元的特定群体有关。这些数据反过来可以使我们能够确定它们的功能(亲与抗伤害)。总的来说,这些结果将促进我们的理解的手段和机制,外周炎症损伤改变的反应和关键脑干疼痛调节系统的功能,并通知一个更合理的开发中枢作用镇痛剂的缓解持续性疼痛。 与公共卫生的相关性炎症性质的持续性疼痛,例如与关节炎或软组织损伤相关的疼痛,对患者造成重大的经济、情感和身体损失。这些研究的结果将确定持续性疼痛如何改变脑干通路的功能,这些通路与伤害感受的调节和镇痛的产生密切相关。从这项工作中获得的见解将指导开发新的,更有效的药物疗法或认知方法来缓解持续性疼痛。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

DONNA L HAMMOND其他文献

DONNA L HAMMOND的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('DONNA L HAMMOND', 18)}}的其他基金

Mechanistic Studies of the Natural Product Nicotinamide Riboside for Relief of Painful Sensory Neuropathy
天然产物烟酰胺核苷缓解疼痛性感觉神经病的机制研究
  • 批准号:
    10087890
  • 财政年份:
    2018
  • 资助金额:
    $ 56.7万
  • 项目类别:
Phase II Trial of Nicotinamide Riboside for Relief of Taxane-Induced Sensory Neuropathy
烟酰胺核苷缓解紫杉烷引起的感觉神经病的 II 期试验
  • 批准号:
    9336864
  • 财政年份:
    2016
  • 资助金额:
    $ 56.7万
  • 项目类别:
Iowa Post-Baccalaureate Research Education in the Biomedical Sciences
爱荷华州生物医学学士后研究教育
  • 批准号:
    9251301
  • 财政年份:
    2016
  • 资助金额:
    $ 56.7万
  • 项目类别:
Iowa Post-Baccalaureate Research Education in the Biomedical Sciences
爱荷华州生物医学学士后研究教育
  • 批准号:
    8998703
  • 财政年份:
    2016
  • 资助金额:
    $ 56.7万
  • 项目类别:
Olympus VS-120 Virtual Slide Scanning System
奥林巴斯 VS-120 虚拟载玻片扫描系统
  • 批准号:
    8448459
  • 财政年份:
    2013
  • 资助金额:
    $ 56.7万
  • 项目类别:
Role of Medullary Substance P in Acute and Persistent Nociception
髓质 P 在急性和持续性伤害感受中的作用
  • 批准号:
    8266450
  • 财政年份:
    2008
  • 资助金额:
    $ 56.7万
  • 项目类别:
Role of Medullary Substance P in Acute and Persistent Nociception
髓质 P 在急性和持续性伤害感受中的作用
  • 批准号:
    7858259
  • 财政年份:
    2008
  • 资助金额:
    $ 56.7万
  • 项目类别:
Role of Medullary Substance P in Acute and Persistent Nociception
髓质 P 在急性和持续性伤害感受中的作用
  • 批准号:
    8074480
  • 财政年份:
    2008
  • 资助金额:
    $ 56.7万
  • 项目类别:
Role of Medullary Substance P in Acute and Persistent Nociception
髓质 P 在急性和持续性伤害感受中的作用
  • 批准号:
    7577168
  • 财政年份:
    2008
  • 资助金额:
    $ 56.7万
  • 项目类别:
Interdisciplinary Training in Pain Research
疼痛研究跨学科培训
  • 批准号:
    9104214
  • 财政年份:
    2004
  • 资助金额:
    $ 56.7万
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
  • 批准号:
    2244994
  • 财政年份:
    2023
  • 资助金额:
    $ 56.7万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了