Central oxytocin mechanisms of pain recovery following nerve injury
Central oxytocin mechanisms of pain recovery following nerve injury
批准号:
10332264
负责人:
THOMAS JEFFREY MARTIN
金额:
$33.3万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-04-15 至 2027-03-31
关键词:
AblationAffectiveAmygdaloid structureAnalgesicsAnimal ModelAnimalsAttentionBehaviorBehavioralBloodBolus InfusionBrainCASP3 geneClinicCognitiveComplexComputersDataDiseaseDoseDrug KineticsEngineeringEnterobacteria phage P1 Cre recombinaseExposure toFemaleFrightHumanImpaired cognitionImpairmentInfusion proceduresInjectionsInjuryKnowledgeLeadLiteratureMethodsModalityModelingMovementMutateNervous system structureNeuronsNociceptionOutcome MeasureOxytocinOxytocin ReceptorPainPain managementPathway interactionsPenetrancePerioperativePeripheralPeripheral nerve injuryPersistent painPhysiologyPlasmaProgram Research Project GrantsRattusRecoveryReflex actionResolutionRodentRoleRouteSensorySignal TransductionSpinalSpinal nerve structureSurfaceTestingTimeTransgenic OrganismsTranslatingTraumaViralaffective disturbanceantagonistawakebehavior measurementbehavioral studychronic paindesigndorsal hornexperimental studyinjury recoveryinnovationmalemidbrain central gray substancenerve injurynovelpain behaviorpain chronificationpharmacokinetic modelpre-clinicalresponse
中文摘要
催产素在啮齿类动物的各种疼痛状态下产生抗伤害感受,然而,
发生这种情况的机制以及外周效应与中枢效应的重要性,
不清楚先前的研究通常使用催产素的全身给药,
在缺乏药代动力学数据或考虑脑转移的情况下,
这些研究只能在确定相关给药参数后外推至临床。
通过实验确定啮齿动物的外周和中枢催产素暴露
和人,并使用这些参数来比较针对不同的抗伤害性功效。
结果测量,随后探索潜在的机制。这个项目
翻译并由项目1和3提供信息,以定义催产素在
唤醒和麻醉大鼠的脑和血液,并确定外周和
催产素对神经损伤后复杂行为的中枢作用。三个具体目标是
提出了第一个目标将使用以下方法定义催产素在血浆和脑中的药代动力学:
静脉推注,这些数据将用于设计目标浓度输注范例,
PK/PD核心还将评估脑进入和丢失率。第二个目标将采取
本研究组开发的表达Cre重组酶的新型转基因大鼠的优点
选择性地在催产素能神经元中。我们将确定内源性催产素回路的作用
Cre依赖性神经元对周围神经损伤后复杂行为的调节
消融策略,在靶向神经元中表达突变的caspase 3。我们已经开发
新的行为方法,评估注意力障碍,恐惧回避,情感和
神经损伤后疼痛的感觉方式,并使用这些创新的行为方法,
这个目标。第三个目标结合了目标1和目标2中获得的知识,
催产素减轻周围神经损伤引起的行为变化的功效,
测试催产素在行为方面产生持久的、疾病缓解效果的潜力
和传入生理学,以及内源性回路在这些效应中的作用。这个项目
与项目1相互作用,以评估改变的初级感觉传入信号的贡献,
复杂的行为和催产素的相关性,并与项目3,以目标相关的周边
催产素在人类外周和中枢作用的水平。
英文摘要
Oxytocin produces antinociception in rodents in a variety of pain states, however the
mechanisms by which this occurs and the importance of peripheral versus central effects are
unclear. Prior studies have typically used systemic administration of oxytocin, with dosing-to-
effect strategies in the absence of pharmacokinetic data or consideration of brain penetrance.
These studies can only be extrapolated to the clinic after relevant dosing parameters have been
determined experimentally to achieve peripheral and central oxytocin exposure across rodents
and humans, and using such parameters to compare antinociceptive efficacy against different
outcome measures, with subsequent exploration of potential mechanisms. This Project
translates and is informed by Projects 1 and 3 to define the pharmacokinetics of oxytocin in
awake and anesthetized rats in brain and blood and determine the relevance of peripheral and
central action of oxytocin on complex behaviors following nerve injury. Three specific aims are
proposed. The first aim will define the pharmacokinetics of oxytocin in plasma and brain using
i.v. bolus, and these data will be used to design targeted concentration infusion paradigms in
the PK/PD core. The rate of brain entry and loss will also be assessed. The second aim will take
advantage of a novel transgenic rat developed by our group that expresses Cre recombinase
selectively in oxytocinergic neurons. We will determine the role of endogenous oxytocin circuits
in modulation of complex behaviors after peripheral nerve injury using Cre dependent neuronal
ablative strategies, expressing mutated caspase 3 in targeted neurons. We have developed
novel behavioral methods that assess impairment of attention, fear avoidance, and affective and
sensory modalities of pain after nerve injury and use these innovative behavioral methods for
this aim. The third aim combines the knowledge gained from Aims 1 and 2 to assess the
efficacy of oxytocin in mitigating the behavioral changes induced by peripheral nerve injury,
tests the potential for oxytocin to produce long-lasting, disease-modifying effects in behavior
and afferent physiology, and the role of endogenous circuits in these effects. This project
interacts with Project 1 to assess the contribution of altered primary sensory afferent signaling in
complex behaviors and the relevance of oxytocin and with Project 3 to target relevant peripheral
levels of oxytocin in humans for peripheral and central action.
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会议论文
Administrative Core
-
批准号:10332260
-
项目类别:
-
资助金额:$33.3万
-
财政年份:2022
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Administrative Core
-
批准号:10609943
-
项目类别:
-
资助金额:$14.9万
-
财政年份:2022
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Central oxytocin mechanisms of pain recovery following nerve injury
-
批准号:10609950
-
项目类别:
-
资助金额:$29.44万
-
财政年份:2022
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Cell-directed gene therapy for pain recovery after surgery and inflammation
-
批准号:10546458
-
项目类别:
-
资助金额:$45.9万
-
财政年份:2022
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Cell-directed gene therapy for pain recovery after surgery and inflammation
-
批准号:10390750
-
项目类别:
-
资助金额:$46.53万
-
财政年份:2022
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
The Monogamous Prairie Vole: A Model for the Study of Social Behavior and Pain
-
批准号:8929319
-
项目类别:
-
资助金额:$19.38万
-
财政年份:2014
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
The Monogamous Prairie Vole: A Model for the Study of Social Behavior and Pain
-
批准号:8823884
-
项目类别:
-
资助金额:$23.13万
-
财政年份:2014
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Behavioral effects of deep brain stimulation in rats with chronic pain
-
批准号:8310618
-
项目类别:
-
资助金额:$22.2万
-
财政年份:2012
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Behavioral effects of deep brain stimulation in rats with chronic pain
-
批准号:8472548
-
项目类别:
-
资助金额:$17.85万
-
财政年份:2012
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Role of the Amygdala in Opioid Self-administration in Rats with Chronic Pain.
-
批准号:7460617
-
项目类别:
-
资助金额:$21.51万
-
财政年份:2006
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Role of the Amygdala in Opioid Self-administration in Rats with Chronic Pain.
-
批准号:7662536
-
项目类别:
-
资助金额:$21.51万
-
财政年份:2006
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Role of the Amygdala in Opioid Self-administration in Rats with Chronic Pain.
-
批准号:7193654
-
项目类别:
-
资助金额:$22.6万
-
财政年份:2006
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Role of the Amygdala in Opioid Self-administration in Rats with Chronic Pain.
-
批准号:7291048
-
项目类别:
-
资助金额:$21.95万
-
财政年份:2006
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Chronic opioid self administration in the presence of neuropathic pain
-
批准号:6575405
-
项目类别:
-
资助金额:$20.62万
-
财政年份:2002
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
Core--Animal and general research services
-
批准号:6575411
-
项目类别:
-
资助金额:$20.62万
-
财政年份:2002
-
负责人:THOMAS JEFFREY MARTIN
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依托单位:
OPIOID SELF ADMINISTRATION IN CHRONIC PAIN
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批准号:6187443
-
项目类别:
-
资助金额:$17.51万
-
财政年份:1999
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负责人:THOMAS JEFFREY MARTIN
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依托单位:
OPIOID SELF ADMINISTRATION IN CHRONIC PAIN
-
批准号:2904748
-
项目类别:
-
资助金额:$18.31万
-
财政年份:1999
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负责人:THOMAS JEFFREY MARTIN
-
依托单位:
OPIOID SELF ADMINISTRATION IN CHRONIC PAIN
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批准号:6394053
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项目类别:
-
资助金额:$18.06万
-
财政年份:1999
-
负责人:THOMAS JEFFREY MARTIN
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依托单位:
FUNCTIONAL SIGNIFICANCE OF MU OPIOID RECEPTOR TURNOVER
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批准号:2116281
-
项目类别:
-
资助金额:$8.75万
-
财政年份:1994
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负责人:THOMAS JEFFREY MARTIN
-
依托单位:
FUNCTIONAL SIGNIFICANCE OF MU OPIOID RECEPTOR TURNOVER
-
批准号:2116282
-
项目类别:
-
资助金额:$9.08万
-
财政年份:1994
-
负责人:THOMAS JEFFREY MARTIN
-
依托单位:
海外基金