Circuit mechanisms for opioid analgesia and addiction in prefrontal cortex
前额皮质阿片类镇痛和成瘾的回路机制
基本信息
- 批准号:10607118
- 负责人:
- 金额:$ 3.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:Absence of pain sensationAcademic Medical CentersAcuteAffectAnalgesicsAreaBehaviorBiological AssayBrainCalciumCellsChronicColorComplexCorpus striatum structureDataDissociationDoctor of PhilosophyDrug PrescriptionsElectrophysiology (science)EnvironmentFutureGeneticGenetic SuppressionGlutamatesGoalsHistologyHyperalgesiaImageImplantable PumpInterneuronsKnowledgeMechanicsMedialMediatingMedicineModelingMorphineMotivationMusNaloxoneNervous SystemNeuroanatomyNeuronsNorth CarolinaOpiate AddictionOpioidOpioid AnalgesicsOralOutputOxycodonePainPain managementPatternPharmaceutical PreparationsPhysiciansPopulationPostoperative PainPrefrontal CortexPropertyProxyPyramidal TractsReceptor SignalingRelapseReporterResearchResearch ProposalsRewardsRiskRoleScientistSelf AdministrationSignal TransductionTestingTherapeuticTissuesTrainingUnited StatesUniversitiesVentilatory DepressionWithdrawaladdictioncell typeconditioned place preferenceexperimental studyhippocampal pyramidal neuronimaging approachinnovationmouse modelmu opioid receptorsneuralneural circuitopioid epidemicopioid exposureopioid usepain behaviorpain reliefprogramsreceptor expressionreceptor functionreward circuitrysingle-cell RNA sequencingskillssubcutaneous
项目摘要
PROJECT SUMMARY (ABSTRACT)
The mu opioid receptor (MOR) is widely expressed throughout the nervous system and mediates both analgesic
and addictive effects of opioids. Despite the current opioid crisis in the United States, opioid drugs offer
unparalleled analgesic efficacy and are prescribed for a variety of pain conditions. To dissociate opioid analgesic
and addictive effects, it is essential to determine which neural circuits and cell types mediate each of these
effects. MOR signaling in medial prefrontal cortex (mPFC) is of particular significance due to the mPFC function
as a key integrative node in ascending and descending pain circuits and its strong connectivity to subcortical
reward circuitry. However, how opioids eventually alter the activity of glutamatergic mPFC output neurons to
modulate opioid addiction and pain behaviors is unknown. The main outputs of the cortex include two distinct
populations of layer 5 glutamatergic projection neurons: intratelencephalic (IT) and pyramidal tract (PT) neurons.
IT neurons predominantly project intracortically and to striatum, while PT neurons project broadly and are poised
to directly modulate neural activity throughout the brain. Despite evidence supporting a MOR-dependent role for
mPFC in pain and addiction, preliminary data suggest that MOR is not expressed directly on IT or PT cells.
This project aims to (1) determine how opioid exposure impacts mPFC IT and PT cell activity in mice and (2)
delineate the contribution of mPFC IT and PT cells to opioid addiction and analgesia. In order to determine how
opioids modulate IT and PT cell activity, dual-color calcium imaging will be used as a proxy for neuronal activity.
Neural dynamics of each population will be characterized at baseline, during acute and chronic morphine
exposure through subcutaneously implanted pumps, and during naloxone-precipitated withdrawal. To assess
the contribution of IT and PT cells to opioid addiction, mPFC IT or PT cell activity will be chemogenetically
suppressed in addiction models including morphine conditioned place preference and oxycodone self-
administration. Finally, the contribution of IT and PT cells to morphine analgesia and opioid-induced tolerance
and hyperalgesia will be assessed through chemogenetic suppression of mPFC IT or PT cells after acute and
chronic morphine exposure in assays for thermal (hotplate) and mechanical (von Frey) pain. This project will
establish foundational knowledge in the dissociation of the addictive and analgesic effects of opioids,
illuminating targets for nonaddictive pain therapies.
Through this research proposal and associated training plan, I will gain excellent training in neuroanatomy,
addiction and pain behaviors, and neural dynamics in a supportive training environment at the University of North
Carolina MD/PhD Program. This training will provide me with the technical and professional skills necessary to
become a leader at an academic medical center and pursue my goals of practicing pain medicine and
researching innovative non-addictive therapies for pain as a physician-scientist.
项目总结(摘要)
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Nicole Elise Ochandarena其他文献
Dissecting The Cellular And Molecular Architecture Of Opioid-Sensitive Neurons Throughout The Brain Using Deep Single-Cell Transcriptomics
利用深度单细胞转录组学剖析整个大脑中阿片类药物敏感神经元的细胞和分子结构
- DOI:
10.1016/j.jpain.2023.02.202 - 发表时间:
2023-04-01 - 期刊:
- 影响因子:4.000
- 作者:
Jesse Niehaus;Nicole Elise Ochandarena;Hongkui Zeng;Greg Scherrer - 通讯作者:
Greg Scherrer
Nicole Elise Ochandarena的其他文献
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