Endocannabinoid signaling in a model of cancer pain
癌痛模型中的内源性大麻素信号传导
基本信息
- 批准号:8588291
- 负责人:
- 金额:$ 31.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-12-16 至 2014-11-30
- 项目状态:已结题
- 来源:
- 关键词:2-arachidonylglycerolAccountingAddressAdvanced Malignant NeoplasmAfferent NeuronsAnalgesicsAttenuatedBehavior assessmentBiochemicalBiological AssayBone PainCNR1 geneCNR2 geneCalcium SignalingCancer Pain ManagementCancer PatientCannabinoidsCannabis sativa plantCatabolismCellsCoculture TechniquesCutaneousDataDevelopmentDoseEndocannabinoidsEnzyme Inhibitor DrugsEnzyme InhibitorsEnzymesEpidermisEsthesiaHyperalgesiaHypersensitivityIn VitroInflammationIpsilateralMalignant Bone NeoplasmMalignant NeoplasmsMechanicsMediatingMembraneMessenger RNAMetabolismModelingMonoacylglycerol LipasesMusNeoplasm MetastasisNeuronsOpioidPainPatientsPhospholipidsPlayPropertyProteinsPublishingRelative (related person)RoleSamplingShapesSignal TransductionSkinSourceSpinal GangliaStimulusSyndromeTestingTissuesUnited Statesanandamidebasebonecancer cellcancer paincannabinoid receptorchronic paincopingenzyme activityfatty acid amide hydrolasefibrosarcomagene therapyimmunoreactivityin vivoinhibitor/antagonistinsightkeratinocytemu opioid receptorsneoplastic cellnovelnovel strategiesnovel therapeuticsprotein degradationprotein expressionpublic health relevancereceptorreceptor expressionresponsesomatosensorytumortumor progressionvoltage
项目摘要
DESCRIPTION (provided by applicant): As cancer progresses, pain is increasingly associated with destruction of tissue, and severe pain occurs with bone destruction. Derivatives of Cannabis sativa (cannabinoids) are potent analgesics, and endogenous cannabinoids share this property. Anandamide (AEA) and 2-arachidonoylglycerol (2AG) are two endocannabinoids that are synthesized on demand from membrane phospholipids, and they may play fundamental roles in modulating our sensitivity to noxious stimuli. Indeed, we have generated evidence that increased degradation of AEA in skin is associated with mechanical hyperalgesia in a murine model of bone cancer pain. Cannabinoid-1 receptors mediate the inhibitory effects of AEA on somatosensory neurons, and expression of these receptors is increased in dorsal root ganglion neurons ipsilateral to tumors in tumor bearing mice. Activation of the increased pool of receptors by endogenous AEA can be manipulated by decreasing AEA degradation, resulting in prolonged anti-hyperalgesia in tumor-bearing mice. These data provide evidence to support the hypothesis that the local inhibition of endocannabinoid degradation in the periphery reduces mechanical hypersensitivity in a murine model of bone cancer pain through CB1 and CB2 receptor-dependent mechanisms. Studies outlined in this proposal will test this hypothesis further and address specific aims that explore 2AG metabolism in the same model of bone cancer pain. Specific aim 1 addresses whether inhibition of 2AG degradation is more effective than inhibition of AEA degradation in attenuating mechanical hypersensitivity in tumor-bearing mice. Monoglyceride lipase (MGL) degrades 2AG in vivo. Specific aim 2 examines the sources of MGL and cannabinoid receptors that underlie the anti- hyperalgesic effect of MGL inhibition in the periphery and whether expression of these proteins changes in tumor-bearing mice. Specific aim 3 examines the capacities of cells relevant to cutaneous mechanosensation to synthesize AEA and 2AG and whether the capacity for synthesis is changed in the cancer condition. Specific aim 4 addresses whether an MGL inhibitor acts directly on sensory neurons to reduce a depolarization-evoked calcium signal. Together with parallel data generated for AEA signaling, the data generated under specific aims 1-4 will provide extensive information on the cellular mechanisms through which inhibitors of AEA and 2AG degradation reduce mechanical hyperalgesia in cancer pain. The data will provide a rationale for the manipulation of endocannabinoids as a novel therapeutic strategy in the treatment of cancer pain.
描述(由申请人提供):随着癌症的进展,疼痛与组织破坏越来越大,骨骼破坏发生了严重的疼痛。大麻壁c(大麻素)的衍生物是有效的镇痛药,内源性大麻素共享此特性。 Anandamide(AEA)和2-芳基烯丙基甘油(2AG)是两个内源性大麻素,它们是根据膜磷脂的需求合成的,它们可能在调节我们对有害刺激的敏感性方面起着基本作用。确实,我们已经产生了证据表明,在骨癌疼痛的鼠模型中,皮肤中AEA降解的降解与机械性痛觉过敏有关。大麻素-1受体介导了AEA对体感神经元的抑制作用,并且在背根神经元神经元同侧对肿瘤小鼠肿瘤的表达增加。通过降低AEA降解,可以操纵通过内源性AEA增加受体池的激活,从而导致肿瘤小鼠的抗高疗法延长。这些数据提供了证据,以支持以下假设:在外围局部抑制内源性大麻素降解可以通过CB1和CB2受体依赖性机制的骨癌疼痛模型中降低机械性超敏反应。该提案中概述的研究将进一步检验该假设,并探讨在骨癌疼痛模型中探索2AG代谢的特定目的。具体目的1解决了对2AG降解的抑制是否比抑制AEA降解在衰减肿瘤小鼠的机械性超敏反应方面更有效。单甘油酸脂肪酶(MGL)在体内降解2AG。具体目标2研究了MGL和大麻素受体的来源,这些源是MGL抑制在周围抑制的抗高染色性作用,以及这些蛋白质的表达是否在耐肿瘤小鼠中发生变化。具体目标3研究了与皮肤机械敏化合成AEA和2AG相关的细胞能力,以及在癌症条件下合成的能力是否改变。具体目标4解决了MGL抑制剂是否直接作用于感觉神经元以减少去极化诱发的钙信号。连同为AEA信号传导生成的并行数据,在特定目标1-4下生成的数据将提供有关细胞机制的广泛信息,其中AEA和2AG降解降低了癌症疼痛中的机械痛觉过敏。该数据将为操纵内源性大麻素作为治疗癌症疼痛的一种新型治疗策略提供理由。
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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Virginia S Seybold其他文献
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{{ truncateString('Virginia S Seybold', 18)}}的其他基金
Endocannabinoid signaling in a model of cancer pain
癌痛模型中的内源性大麻素信号传导
- 批准号:
8390500 - 财政年份:2009
- 资助金额:
$ 31.56万 - 项目类别:
Endocannabinoid signaling in a model of cancer pain
癌痛模型中的内源性大麻素信号传导
- 批准号:
8006407 - 财政年份:2009
- 资助金额:
$ 31.56万 - 项目类别:
Endocannabinoid signaling in a model of cancer pain
癌痛模型中的内源性大麻素信号传导
- 批准号:
8197830 - 财政年份:2009
- 资助金额:
$ 31.56万 - 项目类别:
Endocannabinoid signaling in a model of cancer pain
癌痛模型中的内源性大麻素信号传导
- 批准号:
7782038 - 财政年份:2009
- 资助金额:
$ 31.56万 - 项目类别:
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