Amygdala Serotonin Neurotransmission and Neuropathic Pain

杏仁核血清素神经传递和神经性疼痛

基本信息

项目摘要

DESCRIPTION (provided by applicant): The multidimensional character of pain presents a therapeutic challenge that would benefit greatly from a better understanding of higher brain functions that regulate its complex emotional-affective aspects. Neuropathic pain is generally believed to result from maladaptive neuroplasticity but underlying mechanisms, particularly those in higher brain centers, are not well understood. This project will focus on abnormal function of the amygdala, a brain area that is recognized as a key player in the emotional-affective dimension of pain. Our goal is to mitigate maladaptive amygdala plasticity and block the development of chronic neuropathic pain. A critical determinant, we believe, is pain-related plasticity of serotonin 5-HT2C receptor (5-HT2CR) control of corticotropin-releasing factor (CRF) signaling in the amygdala because CRF is associated with 5-HT2CR- mediated negative affective states and CRF1 receptors mediate amygdala plasticity in inflammatory pain. Here we advance the novel concept that abnormal function of 5-HT2CR in the amygdala is a critical mechanism of chronic neuropathic pain and its emotional-affective component, and is also the likely cause of the limited efficacy of selective serotonin reuptake inhibitors (SSRIs) to treat neuropathic pain. Specifically, we propose the novel hypothesis that 5-HT2CR in the basolateral amygdala (BLA, amygdala input region), drives a vicious cycle involving CRF1 receptors that results in abnormal activity in the central nucleus (CeA, output region). 5- HT2CR-driven maladaptive plasticity in the BLA-CeA circuitry plays a critical role in chronic neuropathic pain. Three Specific Aims (SAs) will determine synaptic and cellular mechanisms and behavioral consequences of manipulation of 5-HT2CR function in the amygdala in the spinal nerve ligation (SNL) rat model of neuropathic pain. Complementary pharmacological and novel viral vector knockdown strategies will be utilized in all aims for local inactivation or elimination of 5-HT2CR in the amygdala. Behavioral experiments (SA1) will determine the role of 5-HT2CR and CRF1 in the BLA in the emotional-affective component of neuropathic pain. Electrophysiology in vivo (SA2) will examine the hypothesis that 5-HT2CR in the BLA drives CRF1 activation and central sensitization of CeA output neurons. Patch-clamp studies in brain slices (SA3) will determine excitatory and (dis-)inhibitory synaptic and cellular mechanisms of plasticity in the BLA-CeA network that results from abnormal 5-HT2CR function driving persistent CRF1 signaling. Systemic application of a 5-HT2CR antagonist and SSRI in SA1 and SA2 will validate their clinical utility and viability. These conceptually novel studies will characterize the 5-HT2CR/CRF1 interaction in the amygdala as an important mechanism of chronic neuropathic pain. We will also identify strategies to eliminate or disrupt this signaling mechanism to block maladaptive amygdala plasticity and thus neuropathic pain. The mechanistic analysis of higher brain functions and drug targets in pain will boost basic science knowledge required for evidence-based medicine and provide translational strategies for pharmacotherapeutics and/or gene therapy.
描述(由申请人提供):疼痛的多维特征提出了一个治疗挑战,这将大大受益于更好地理解调节其复杂情感方面的高级大脑功能。神经病理性疼痛通常被认为是由适应不良的神经可塑性引起的,但其潜在的机制,特别是那些在更高的大脑中心,还没有得到很好的理解。这个项目将集中在杏仁核的异常功能,这是一个被认为是疼痛的情绪情感维度的关键球员的大脑区域。我们的目标是减轻适应不良的杏仁核可塑性,并阻止慢性神经性疼痛的发展。我们认为,一个关键的决定因素是杏仁核中5-羟色胺5-HT 2C受体(5-HT 2CR)控制促肾上腺皮质激素释放因子(CRF)信号传导的疼痛相关可塑性,因为CRF与5-HT 2CR介导的负性情感状态相关,CRF 1受体介导炎症性疼痛中的杏仁核可塑性。在这里,我们提出了新的概念,5-HT 2CR在杏仁核的功能异常是慢性神经性疼痛及其情绪情感成分的关键机制,也是选择性5-羟色胺再摄取抑制剂(SSRIs)治疗神经性疼痛的疗效有限的可能原因。具体而言,我们提出了新的假设,即5-HT 2CR在基底外侧杏仁核(BLA,杏仁核输入区),驱动一个恶性循环,涉及CRF 1受体,导致异常活动的中央核(CeA,输出区)。5-在BLA-CeA回路中HT 2CR驱动的适应不良可塑性在慢性神经性疼痛中起着关键作用。三个具体目标(SA)将确定突触和细胞机制和行为后果的操纵5-HT 2CR功能的杏仁核脊神经结扎(SNL)大鼠模型的神经性疼痛。互补药理学和新型病毒载体敲除策略将用于杏仁核中5-HT 2CR的局部失活或消除的所有目的。行为实验(SA 1)将确定5-HT 2CR和CRF 1在BLA中的作用,在神经性疼痛的情绪情感成分。体内电生理学(SA 2)将检查BLA中的5-HT 2CR驱动CRF 1激活和CeA输出神经元的中枢致敏的假设。脑切片中的膜片钳研究(SA 3)将确定BLA-CeA网络中可塑性的兴奋性和(非)抑制性突触和细胞机制,该网络由驱动持续CRF 1信号传导的异常5-HT 2CR功能引起。在SA 1和SA 2中系统应用5-HT 2CR拮抗剂和SSRI将验证其临床实用性和可行性。这些概念新颖的研究将表征杏仁核中的5-HT 2CR/CRF 1相互作用作为慢性神经病理性疼痛的重要机制。我们还将确定消除或破坏这种信号传导机制的策略,以阻断适应不良的杏仁核可塑性,从而阻断神经性疼痛。对疼痛中的高级脑功能和药物靶点的机制分析将促进循证医学所需的基础科学知识,并为药物治疗和/或基因治疗提供转化策略。

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 }}

Thomas Arthur Green其他文献

Thomas Arthur Green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('Thomas Arthur Green', 18)}}的其他基金

Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
  • 批准号:
    10430263
  • 财政年份:
    2020
  • 资助金额:
    $ 45.19万
  • 项目类别:
Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
  • 批准号:
    10663801
  • 财政年份:
    2020
  • 资助金额:
    $ 45.19万
  • 项目类别:
Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
  • 批准号:
    10271267
  • 财政年份:
    2020
  • 资助金额:
    $ 45.19万
  • 项目类别:
Gpr12: a novel factor for addiction and mental health
Gpr12:成瘾和心理健康的新因素
  • 批准号:
    9813292
  • 财政年份:
    2019
  • 资助金额:
    $ 45.19万
  • 项目类别:
Retinoic acid signaling: a novel factor for addiction-related behavior
视黄酸信号传导:成瘾相关行为的新因素
  • 批准号:
    10425348
  • 财政年份:
    2018
  • 资助金额:
    $ 45.19万
  • 项目类别:
Retinoic acid signaling: a novel factor for addiction-related behavior
视黄酸信号传导:成瘾相关行为的新因素
  • 批准号:
    10177986
  • 财政年份:
    2018
  • 资助金额:
    $ 45.19万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    8576928
  • 财政年份:
    2013
  • 资助金额:
    $ 45.19万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    8917636
  • 财政年份:
    2013
  • 资助金额:
    $ 45.19万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    8843055
  • 财政年份:
    2013
  • 资助金额:
    $ 45.19万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    9039670
  • 财政年份:
    2013
  • 资助金额:
    $ 45.19万
  • 项目类别:

相似海外基金

Affective Computing Models: from Facial Expression to Mind-Reading
情感计算模型:从面部表情到读心术
  • 批准号:
    EP/Y03726X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Standard Grant
Affective Computing Models: from Facial Expression to Mind-Reading ("ACMod")
情感计算模型:从面部表情到读心术(“ACMod”)
  • 批准号:
    EP/Z000025/1
  • 财政年份:
    2024
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Research Grant
Interface: Transplants, Aesthetics and Technology (Previously About Face: The affective and cultural history of face transplants)
界面:移植、美学和技术(之前关于面部:面部移植的情感和文化历史)
  • 批准号:
    MR/Y011627/1
  • 财政年份:
    2024
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Fellowship
Individual differences in affective processing and implications for animal welfare: a reaction norm approach
情感处理的个体差异及其对动物福利的影响:反应规范方法
  • 批准号:
    BB/X014673/1
  • 财政年份:
    2024
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Research Grant
Affective and Immaterial Labour in Latin(x) American Culture
拉丁美洲文化中的情感和非物质劳动
  • 批准号:
    AH/V015834/2
  • 财政年份:
    2023
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Fellowship
Home/bodies: Exploring the affective experiences of people at home using scenographic practice and ecological thinking
家/身体:利用场景实践和生态思维探索人们在家中的情感体验
  • 批准号:
    2888014
  • 财政年份:
    2023
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Studentship
Imagination under Racial Capitalism: the Affective Salience of Racialised and Gendered Tropes of 'Black excellence'
种族资本主义下的想象力:“黑人卓越”的种族化和性别化比喻的情感显着性
  • 批准号:
    2889627
  • 财政年份:
    2023
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Studentship
Tracing the brain mechanisms of affective touch.
追踪情感触摸的大脑机制。
  • 批准号:
    23K19678
  • 财政年份:
    2023
  • 资助金额:
    $ 45.19万
  • 项目类别:
    Grant-in-Aid for Research Activity Start-up
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了