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.
慢性疼痛是一项未得到充分解决的重大公共卫生挑战。慢性的神经基质
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: