Neuropathic Pain-induced Depression: the Role of mPFC Endocannabinoids
神经性疼痛诱发的抑郁症:mPFC 内源性大麻素的作用
基本信息
- 批准号:10440264
- 负责人:
- 金额:$ 37.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-15 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:2-arachidonylglycerolAbsence of pain sensationAcuteAcute PainAddressAdverse effectsAffectiveAnatomyAnimalsAntidepressive AgentsAreaBehaviorBehavioralBindingBiological AssayBrainCNR1 geneChronicChronic PhaseChronic stressClinical ResearchCoupledDataDevelopmentDiseaseDown-RegulationElectrophysiology (science)ElementsEndocannabinoidsEnzymesFemaleFluoxetineFoundationsFunctional disorderGTP-Binding ProteinsGene ActivationGenetically Modified AnimalsGoalsHyperactivityImmediate-Early GenesInjectionsInterneuronsLeadLinkMass Spectrum AnalysisMeasuresMedialMental DepressionModelingMolecularNatureNeuraxisNeuronsNeuropharmacologyNociceptionOpioidPainPathway interactionsPeripheralPeripheral nerve injuryPersistent painPharmacogeneticsPhasePhysiologicalPrefrontal CortexPresynaptic TerminalsProcessProductionPublic HealthRadiolabeledRattusRegulationReporterResearchRoleSignal PathwaySignal TransductionSliceSpinocerebellar TractsStressSynapsesSynaptic TransmissionSynaptic plasticitySystemTestingThalamic structureTherapeuticTimeTransgenic Organismsbasebeta-arrestinbiopsychosocialchronic painchronic pain patientchronic painful conditiondepression modeldesensitizationeffective interventionendocannabinoid signalingendogenous cannabinoid systemexperimental studygamma-Aminobutyric Acidhippocampal pyramidal neuronin vivoinsightintraperitonealmalenerve injurynerve supplynon-opioid analgesicnovelnovel therapeuticspainful neuropathypreclinical studypreventprogramsreceptor downregulationrelating to nervous systemselective preventionsomatosensorysynaptic functiontreatment strategy
项目摘要
Chronic pain is a major public health challenge that is inadequately addressed. The neural substrate of chronic
pain includes disruption of numerous central nervous system (CNS) processes, and depression is a common
consequence of chronic pain. The medial prefrontal cortex (mPFC) is a key brain area that regulates depres-
sion, and the development of depression has been linked to disrupted synaptic function in the mPFC involving
signaling through the endocannabinoid (eCB) system. Additionally, anatomical and electrophysiological studies
show that afferent nociceptive pathways connect to the mPFC. We hypothesize that acute pain initially induces
excess CB1R activation that eventually leads to CB1R downregulation, resulting in elevated GABAergic inner-
vation of mPFC pyramidal neurons that persists as a chronic phase of reduced mPFC activity, with the final
result being behavioral depression. This hypothesis is supported by preliminary data that reveal increased ac-
tivity of mPFC pyramidal neurons and elevated 2-arachidonoylglycerol during the acute phase of nerve injury
pain, and chronically desensitized CB1Rs that results in deactivation of mPFC pyramidal neurons, and deacti-
vation of mPFC pyramidal neurons that cause depression-like behavior in animals. The proposed experiments
will substantiate these promising findings, probe mechanistic details, and explore possible therapies. Specifi-
cally, Aim 1 experiments will identify time courses of eCB signaling, mPFC activity, and depression-like behav-
ior at early and late phases of neuropathic pain. Aim 2 will examine the state of mPFC synaptic function after
initiation of pain and the causal linkage between eCB levels and synaptic function under these conditions. Fi-
nally, Aim 3 will use diverse approaches to modulate this signaling pathway in order to verify the mechanistic
findings of Aim 1 and 2, and to lay the groundwork for potential therapeutic strategies. Completion of the pro-
posed project will not only generate new insights into the genesis of depression in neuropathic pain, but also
may provide the proof-of-concept foundation for novel antidepressant treatments based on selective prevention
or reversal of pain-induced CNS synaptic plasticity.
慢性疼痛是一项尚未得到充分解决的重大公共卫生挑战。慢性病的神经基质
疼痛包括许多中枢神经系统 (CNS) 过程的破坏,而抑郁症是一种常见的
慢性疼痛的后果。内侧前额叶皮层 (mPFC) 是调节抑郁的关键大脑区域。
抑郁症的发生与 mPFC 中突触功能的破坏有关,其中包括
通过内源性大麻素(eCB)系统发出信号。此外,解剖学和电生理学研究
表明传入伤害感受通路与 mPFC 连接。我们假设急性疼痛最初会引起
过度的 CB1R 激活最终导致 CB1R 下调,导致 GABA 能内源升高
mPFC 锥体神经元的变化持续作为 mPFC 活动降低的慢性阶段,最终
结果是行为抑郁。这一假设得到了初步数据的支持,这些数据揭示了ac-
神经损伤急性期 mPFC 锥体神经元的活性和 2-花生四烯酰甘油升高
疼痛和 CB1R 长期脱敏,导致 mPFC 锥体神经元失活,并导致 mPFC 锥体神经元失活
导致动物抑郁样行为的 mPFC 锥体神经元的变化。拟议的实验
将证实这些有希望的发现,探讨机制细节,并探索可能的治疗方法。具体-
具体而言,Aim 1 实验将确定 eCB 信号传导、mPFC 活动和抑郁样行为的时间进程。
ior 在神经性疼痛的早期和晚期阶段。目标 2 将检查 mPFC 突触功能的状态
在这些条件下疼痛的发生以及 eCB 水平和突触功能之间的因果关系。菲-
最后,Aim 3将使用多种方法来调节该信号通路,以验证其机制
目标 1 和 2 的发现,并为潜在的治疗策略奠定基础。完成亲
提出的项目不仅会对神经性疼痛中抑郁症的起源产生新的见解,而且
可以为基于选择性预防的新型抗抑郁治疗提供概念验证基础
或逆转疼痛引起的中枢神经系统突触可塑性。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Repetitive Mild Traumatic Brain Injury in Rats Impairs Cognition, Enhances Prefrontal Cortex Neuronal Activity, and Reduces Pre-synaptic Mitochondrial Function.
- DOI:10.3389/fncel.2021.689334
- 发表时间:2021
- 期刊:
- 影响因子:5.3
- 作者:Feng Y;Li K;Roth E;Chao D;Mecca CM;Hogan QH;Pawela C;Kwok WM;Camara AKS;Pan B
- 通讯作者:Pan B
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{{ truncateString('Bin Pan', 18)}}的其他基金
Neuropathic Pain-induced Depression: the Role of mPFC Endocannabinoids
神经性疼痛诱发的抑郁症:mPFC 内源性大麻素的作用
- 批准号:
9797432 - 财政年份:2019
- 资助金额:
$ 37.48万 - 项目类别: