Modulation of the prefrontal cortical network in neuropathic pain
神经性疼痛中前额皮质网络的调节
基本信息
- 批准号:10612376
- 负责人:
- 金额:$ 49.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylcholineAcuteAffectAnalgesicsAnimalsAttentionBehaviorBehavioralBiological ProcessCholinergic ReceptorsCognitiveControl AnimalDataDecision MakingDrug Delivery SystemsDrug PrescriptionsElectrophysiology (science)EmotionalFemaleGeneticGoalsHealth Care CostsHigh PrevalenceImpaired cognitionImpairmentIndividualInterneuronsLaboratoriesLightMedialMediatingMedicalModelingMolecularMuscarinic M1 ReceptorMuscarinicsNeurobehavioral ManifestationsNeurobiologyNeuronsOpioidOpioid abuserOutputPainPain managementPatientsPharmacological TreatmentPhenotypePositioning AttributePrefrontal CortexPriceProductivityPyramidal CellsRattusRiskRodent ModelRoleSensoryShapesShort-Term MemorySignal TransductionSliceSymptomsTechniquesTestingWorkaddictionantagonistbasal forebrainbehavior testcholinergicchronic painchronic pain managementcognitive performancecognitive taskcost estimateeconomic costeffective therapyemotional symptomhippocampal pyramidal neuronin vivoinsightmalenerve injuryneurobiological mechanismnon-opioid analgesicoptogeneticspain perceptionpainful neuropathypatch clamppharmacologicprescription opioidreceptorsexside effectsocioeconomicsspared nervesuccessvirtual
项目摘要
Summary
The neurobiological basis of chronic pain is poorly understood and no scientifically validated therapies exist for
such condition. Yet, chronic pain has an enormous socio-economic price, estimated to reach US$ 635 billion
annually in healthcare costs and lost productivity. To make things worse, the majority of opioid abusers begin
their addiction with prescription medications for chronic pain. Consequently, the search for new, non-opioid,
pharmacological treatments for chronic pain constitutes one of the most urgent unmet medical needs. Beside
its sensory symptoms, chronic pain is characterized by impairment of cognitive tasks such as attention and
working memory, which depend on cholinergic modulation of medial prefrontal cortex (mPFC). Accordingly,
mPFC deactivation was found to have a causal role for the neuropathic pain phenotype, and our preliminary
data show that excitatory cholinergic modulation is severely impaired in mPFC pyramidal neurons of male rats.
Yet, the precise mechanisms mediating the mPFC deactivation, how this deactivation influences pain
perception and cognitive performance, and whether it similarly impacts males and females remain largely
unknown. Our preliminary data show that a current mediated by the M1 receptor is critical for mPFC pyramidal
cell excitability and is strongly reduced in neuropathic pain; our overarching hypothesis is that impaired
cholinergic modulation of the mPFC represents a major mechanism of mPFC deactivation in neuropathic pain
and mediates several of the sensory, cognitive and emotional symptoms. In particular, we hypothesize that in
neuropathic pain: (1) cholinergic modulation of mPFC activity is disrupted and this critically contributes to the
global mPFC deactivation in both sexes; (2) blockade of M1-mediated mPFC excitation is sufficient to mimic, at
least in part, the neuropathic pain phenotype; (3) pharmacological manipulations that counterbalance the
cholinergic disruption and restore mPFC output ameliorate cognitive and sensory symptoms of neuropathic
pain. To test these hypotheses we will take advantage of the Spared-Nerve-Injury (SNI) model of neuropathic
pain to pursue two specific aims. In Aim 1 we will combine optogenetic activation of individual cholinergic
inputs, patch clamp recordings in acute slices and PCR analysis, to test the hypothesis that impaired
cholinergic modulation contributes to the global mPFC deactivation, to determine the identity of the receptors
involved, and to dissect the relative impact of cholinergic inputs from local interneurons and from the basal
forebrain on mPFC activity in both females and males. In Aim 2 we will test the behavioral effects of impaired
mPFC cholinergic modulation. We will use in-vivo chemogenetic and pharmacological modulation of the mPFC
to reverse the SNI phenotype. We obtained preliminary data showing that enhancing mPFC excitability through
pharmacological antagonism of the 5HT1a receptor has potent analgesic effects. Conversely, we will also
investigate whether blockade of M1-mediated mPFC excitation in naive animals is sufficient to mimic the SNI
phenotype. Our work will thus identify new potential targets for non-opioid neuropathic pain treatment.
概括
人们对慢性疼痛的神经生物学基础知之甚少,并且没有经过科学验证的治疗方法
这样的情况。然而,慢性疼痛造成巨大的社会经济代价,估计达到 6,350 亿美元
每年的医疗费用和生产力损失。更糟糕的是,大多数阿片类药物滥用者开始
他们对治疗慢性疼痛的处方药上瘾。因此,寻找新的非阿片类药物
慢性疼痛的药物治疗是最紧迫的未满足的医疗需求之一。旁
慢性疼痛的感觉症状是注意力和注意力等认知任务受损。
工作记忆,依赖于内侧前额皮质(mPFC)的胆碱能调节。因此,
研究发现 mPFC 失活对神经性疼痛表型具有因果作用,我们的初步研究
数据显示,雄性大鼠 mPFC 锥体神经元的兴奋性胆碱能调节严重受损。
然而,介导 mPFC 失活的精确机制以及这种失活如何影响疼痛
感知和认知表现,以及它是否同样影响男性和女性仍然在很大程度上
未知。我们的初步数据表明,M1 受体介导的电流对于 mPFC 锥体至关重要
细胞兴奋性,在神经性疼痛时大大降低;我们的总体假设是受损
mPFC 的胆碱能调节是神经性疼痛中 mPFC 失活的主要机制
并介导一些感觉、认知和情绪症状。特别是,我们假设在
神经性疼痛:(1) mPFC 活性的胆碱能调节被破坏,这对
男女中 mPFC 整体失活; (2) 阻断 M1 介导的 mPFC 兴奋足以模拟,
至少部分是神经性疼痛表型; (3) 平衡药物作用的药物操作
胆碱能破坏和恢复 mPFC 输出可改善神经病的认知和感觉症状
疼痛。为了检验这些假设,我们将利用神经病理性神经损伤(SNI)模型
追求两个特定目标的痛苦。在目标 1 中,我们将结合个体胆碱能的光遗传学激活
输入、急性切片中的膜片钳记录和 PCR 分析,以检验受损的假设
胆碱能调节有助于整体 mPFC 失活,以确定受体的身份
参与,并剖析来自局部中间神经元和基础神经元的胆碱能输入的相对影响
前脑对女性和男性 mPFC 活动的影响。在目标 2 中,我们将测试受损者的行为影响
mPFC 胆碱能调节。我们将使用 mPFC 的体内化学遗传学和药理学调节
逆转 SNI 表型。我们获得的初步数据表明,通过增强 mPFC 的兴奋性
5HT1a受体的药理拮抗作用具有强效镇痛作用。反过来,我们也会
研究在初始动物中阻断 M1 介导的 mPFC 兴奋是否足以模拟 SNI
表型。因此,我们的工作将确定非阿片类神经病理性疼痛治疗的新潜在目标。
项目成果
期刊论文数量(0)
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MARCO MARTINA其他文献
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{{ truncateString('MARCO MARTINA', 18)}}的其他基金
Modulation of the prefrontal cortical network in neuropathic pain
神经性疼痛中前额皮质网络的调节
- 批准号:
9980663 - 财政年份:2020
- 资助金额:
$ 49.83万 - 项目类别:
Modulation of the prefrontal cortical network in neuropathic pain
神经性疼痛中前额皮质网络的调节
- 批准号:
10162103 - 财政年份:2020
- 资助金额:
$ 49.83万 - 项目类别:
Modulation of the prefrontal cortical network in neuropathic pain
神经性疼痛中前额皮质网络的调节
- 批准号:
10379923 - 财政年份:2020
- 资助金额:
$ 49.83万 - 项目类别:
Modulation of the prefrontal cortical network in neuropathic pain
神经性疼痛中前额皮质网络的调节
- 批准号:
10533432 - 财政年份:2020
- 资助金额:
$ 49.83万 - 项目类别:
L-type channels as pharmacological targets for the treatment and prevention of febrile seizures
L型通道作为治疗和预防热性惊厥的药理学靶点
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9229071 - 财政年份:2016
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$ 49.83万 - 项目类别:
Molecular mechanisms of central chemoreception in breathing
呼吸中枢化学感受的分子机制
- 批准号:
8133490 - 财政年份:2010
- 资助金额:
$ 49.83万 - 项目类别:
Molecular mechanisms of central chemoreception in breathing
呼吸中枢化学感受的分子机制
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7792180 - 财政年份:2010
- 资助金额:
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Molecular mechanisms of central chemoreception in breathing
呼吸中枢化学感受的分子机制
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8320326 - 财政年份:2010
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