Opioid control of midline thalamo-cortico-striatal glutamate transmission
阿片类药物控制中线丘脑皮质纹状体谷氨酸传输
基本信息
- 批准号:9810457
- 负责人:
- 金额:$ 28.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-01 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectAffectiveAgonistAnalgesicsAnatomyAnteriorAnterior Nuclear GroupAreaBasal GangliaBrainBrain regionCellsChronicCollaborationsCorpus striatum structureDependenceDevelopmentDimensionsDopamineDorsalElectric StimulationEmotionsFentanylFoundationsFunctional ImagingFutureGene DeliveryGlutamatesGoalsInjectionsInvestigationIon Channel GatingKnock-in MouseKnowledgeLeadLimbic SystemLocationMeasuresMedialMediatingMorphineMotivationMusNeuronsNucleus AccumbensOpioidOpioid ReceptorOpioid agonistPainPain DisorderPain managementPathway interactionsPatientsPerceptionPharmaceutical PreparationsPhosphorylationPlayPopulation HeterogeneityPropertyRewardsRoleSignal TransductionSiteSliceSourceStimulusSynapsesSystemThalamic NucleiThalamic structureTreatment ProtocolsVentral StriatumViralWhole-Cell RecordingsWild Type MouseWithdrawalWorkaddictionbasebrain dysfunctionchronic paincingulate cortexclassical conditioningclinically relevantdesensitizationexperimental studyglutamatergic signalingimaging studylight gatedmu opioid receptorsnerve supplyopioid abuseopioid misuseoptogeneticspain perceptionpain reliefpostsynapticpresynapticreceptorreceptor functionresponsereward circuitrytargeted treatmenttraffickingtransmission process
项目摘要
Project Summary
Opioids such as morphine are effective at relieving pain but can also be addictive due to their rewarding
properties. Brain areas that include the medial and anterior thalamus, prefrontal and anterior cingulate
cortices, and the dorsomedial striatum and nucleus accumbens are involved in the affective and motivational
aspects of pain perception. Projections from cortical and thalamic regions converge on the striatum providing
two important sources of excitatory innervation to the limbic system and basal ganglia. This proposal will use
viral based gene delivery to express light-gated ion channels in thalamic and cortical brain regions to achieve
selective excitation of thalamo-striatal and cortico-striatal glutamate afferents in the dorsomedial striatum of
mice. Whole cell recordings will be used in brain slices with the goal of understanding the location and
mechanism of opioid receptor action within this medial pain pathway.
The first aim will address the location of μ-opioid receptors (MOPr) in these pathways. The hypothesis is that
the major effect of opioids is to inhibit thalamic projections to the striatum and cortex through
a presynaptic mechanism while the cortico-striatal projections are insensitive to opioids.
Aim 2 will investigate the effect of chronic treatment with the clinically relevant opioids morphine and
fentanyl. These agonists differ substantially in efficacy and the induction of MOPr phosphorylation. Recent
work shows definitively that phosphorylation of MOPr plays a role in trafficking and function measured
postsynaptically but it is not known how or if phosphorylation affects presynaptic function. Wild-type mice and
a newly generated knock-in mouse expressing phosphorylation-deficient MOPr will be acutely and chronically
treated with morphine and fentanyl with the hypothesis that drug-induced MOPr phosphorylation will
lead to a decrease in the efficiency of opioid receptor dependent inhibition of thalamic
glutamate release (receptor tolerance) following chronic opioid treatment. The phosphorylation-
deficient MOPr mouse is therefore expected to show less receptor tolerance than wild type mice.
The results from these aims will describe the location and action of MOPr within these thalamo-cortico-striatal
circuits and determine the receptor- and cellular-level adaptations that result from chronic opioid treatment. A
better understanding of this circuitry may lead to approaches or treatment regimens that better manage the
treatment of pain and limit reinforcing and rewarding properties of opioids.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('William T Birdsong', 18)}}的其他基金
Opioid control of midline thalamo-cortico-striatal glutamate transmission
阿片类药物控制中线丘脑皮质纹状体谷氨酸传输
- 批准号:
10063507 - 财政年份:2017
- 资助金额:
$ 28.08万 - 项目类别:
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