Neuro-immune mechanisms of minor cannabinoids in inflammatory and neuropathic pain
次要大麻素在炎症和神经性疼痛中的神经免疫机制
基本信息
- 批准号:10462497
- 负责人:
- 金额:$ 56.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acute PainAffectAfferent NeuronsAnalgesicsAnti-Inflammatory AgentsAntiinflammatory EffectBehavioral ModelBindingBiologyBlocking AntibodiesBlood VesselsBone MarrowCNR1 geneCalciumCannabidiolCannabinoidsCannabinolCannabisCell LineageCell physiologyCellsChimera organismClassificationDataDependenceDevelopmentDiseaseDopamineEndocannabinoidsEndothelial CellsEndotheliumEndotoxinsExposure toFutureG-Protein-Coupled ReceptorsHealthHumanImmunologyIn VitroIndividualInflammationInflammatoryInjuryIntegration Host FactorsInterleukin-10Knockout MiceLegalLeukocytesLipopolysaccharidesMediatingMedicalMinorModalityModern MedicineMusN-arachidonoyl dopamineNeurobiologyNeuroimmunomodulationNeurologicNeuronsNeuropathyNociceptorsPainPain managementPeripheralPermeabilityPlasmaPopulationProductionPropertyPublic HealthReportingResearchRoleScheduleSensorySpecificitySystemTestingTetrahydrocannabinolTherapeuticTimeUnited StatesVanilloidanandamidebasecannabichromenecannabigerolchronic painchronic pain managementcytokinedesensitizationendogenous cannabinoid systemendovanilloidimprovedin vivoin vivo Modelindexinginflammatory paininterleukin-10 receptormarijuana usenerve injurypain behaviorpain modelpain reductionpainful neuropathyphytocannabinoidpsychologicreceptorrelease factorresponseresponse to injurytargeted treatmenttherapeutic developmenttissue injury
项目摘要
PROJECT SUMMARY
Chronic pain is a substantial public health problem, and the current treatment modalities are insufficient.
Cannabis and cannabis extracts have been used for thousands of years for medicinal purposes, and following
its legalization in a number of states, is increasingly being used to manage neurological, psychological, and
inflammatory conditions. However, research on the efficacy, mechanisms of action, and effects of cannabis
and its components on human and health and disease in the United States has been limited by its DEA
Schedule 1 classification. The principal components of cannabis, THC and CBD, are believed to have pain
reducing effects. THC has been most extensively studied, and although it has analgesic properties, its
psychotropic properties limit its utility for pain management. Notably the minor cannabinoids are emerging as
potential natural compounds with anti-inflammatory and pain reducing effects, but without the unwanted
psychotropic effects of THC. At the same time, anti-inflammatory strategies are being explored for treating
chronic pain. We have found that the endocannabinoids anandamide, N-arachidonoyl dopamine and N-oleoyl
dopamine, and the phytocannabinoid, Δ-9-THC, all have anti-inflammatory effects and improve functional
indices in mice treated with LPS. They each profoundly up-regulate plasma levels of IL-10 in LPS-treated mice.
Using bone marrow chimeras, we determined that NADA mediates its anti-inflammatory effects in LPS-treated
mice via the TRPV1 expressed by non-myeloid cell lineages. In contrast, our preliminary data suggest that Δ-9-
THC exerts its anti-inflammatory effects via cannabinoid receptor 1 (CB1R), rather than TRPV1. In preliminary
studies we have found that Cannabidiol (CBD), Cannabinol (CBN), Cannabigerol (CBG) and
Cannabichromene (CBC) modulate inflammatory activation of human microvascular endothelial cells. We
broadly hypothesize that minor cannabinoids reduce inflammatory and neuropathic pain via anti-inflammatory
mechanisms mediated through the activation of peripheral TRPV1 and CB1R in sensory neurons. We will
leverage the expertise of the PIs in neurobiology, pain biology, TRPV1, immunology, vascular biology and
injury to study the anti-inflammatory and pain reducing effects of CBD, CBN, CBG, and CBC, and other minor
cannabinoids in vitro and in vivo in models of inflammatory and neuropathic pain. In Aim #1 we will define the
ability of minor cannabinoids to modulate inflammatory activation and function of nociceptors, leukocytes, and
endothelial cells, and determine their dependence on TRPV1 and CB1R. In Aim #2 we will determine the role
of anti-inflammatory mechanisms in reducing pain behaviors in inflammatory and neuropathic pain models in
mice. In Aim #3 we will determine how minor cannabinoids reduce inflammatory and neuropathic pain
behaviors through TRPV1- and CB1R- expressed in nociceptors. These studies will advance the understanding
of the endovanilloid and endocannabinoid systems in pain, and will pave the way for future development of
minor cannabinoid-based therapies targeting the endovanilloid and endocannabinoid systems for pain.
项目摘要
慢性疼痛是一个重大的公共卫生问题,目前的治疗方式是不够的。
大麻和大麻提取物用于药用已有数千年的历史,
它在一些州合法化,越来越多地被用来管理神经,心理和
炎性条件。然而,关于大麻的功效、作用机制和效果的研究
在美国,其对人类健康和疾病的影响受到其DEA的限制,
附表1分类。大麻的主要成分THC和CBD被认为具有疼痛
减少影响。四氢大麻酚已被最广泛的研究,虽然它具有镇痛作用,
抗精神病的特性限制了其用于疼痛管理的效用。值得注意的是,次要的大麻素正在成为
潜在的天然化合物,具有抗炎和减轻疼痛的作用,但没有不必要的
THC的精神影响。与此同时,正在探索抗炎策略以治疗
慢性疼痛我们发现内源性大麻素花生四烯酸、N-花生四烯酸多巴胺和N-油酰
多巴胺和植物大麻素Δ-9-THC都具有抗炎作用,
用LPS处理的小鼠中的指数。在LPS处理的小鼠中,它们各自显著上调IL-10的血浆水平。
使用骨髓嵌合体,我们确定NADA介导了LPS治疗的小鼠的抗炎作用。
小鼠通过非髓系细胞谱系表达的TRPV 1。相反,我们的初步数据表明,Δ-9-
THC通过大麻素受体1(CB 1 R)而不是TRPV 1发挥其抗炎作用。初步
研究发现,大麻二酚(CBD),大麻酚(CBN),大麻酚(CBG)和
大麻色烯(CBC)调节人微血管内皮细胞的炎症活化。我们
广泛假设少量大麻素通过抗炎作用减轻炎症和神经性疼痛
在感觉神经元中通过外周TRPV 1和CB 1 R的激活介导的机制。我们将
利用PI在神经生物学、疼痛生物学、TRPV 1、免疫学、血管生物学和
研究CBD,CBN,CBG和CBC的抗炎和减轻疼痛的作用,以及其他轻微的
大麻素在体外和体内的炎症和神经性疼痛模型。在目标#1中,我们将定义
次要大麻素调节炎症激活和伤害感受器、白细胞和
内皮细胞,并确定其对TRPV 1和CB 1 R的依赖性。在目标#2中,我们将确定角色
在炎症和神经性疼痛模型中,
小鼠在目标#3中,我们将确定微量大麻素如何减少炎症和神经性疼痛
行为通过TRPV 1和CB 1 R在伤害感受器中表达。这些研究将促进理解
内源性香草素和内源性大麻素系统在疼痛中的作用,并将为未来的发展铺平道路,
以内源性香草素和内源性大麻素系统为靶点的次要大麻素类疗法。
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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Judith Hellman其他文献
Judith Hellman的其他文献
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{{ truncateString('Judith Hellman', 18)}}的其他基金
TRPV1-dependent neuro-immune modulation and regulation of endogenous acyl-dopamines in sepsis and acute inflammation
脓毒症和急性炎症中内源性酰基多巴胺的 TRPV1 依赖性神经免疫调节和调节
- 批准号:
10634744 - 财政年份:2022
- 资助金额:
$ 56.41万 - 项目类别:
Neuro-immune mechanisms of minor cannabinoids in inflammatory and neuropathic pain
次要大麻素在炎症和神经性疼痛中的神经免疫机制
- 批准号:
9895397 - 财政年份:2019
- 资助金额:
$ 56.41万 - 项目类别:
Neuro-immune mechanisms of minor cannabinoids in inflammatory and neuropathic pain
次要大麻素在炎症和神经性疼痛中的神经免疫机制
- 批准号:
10017874 - 财政年份:2019
- 资助金额:
$ 56.41万 - 项目类别:
The study of Gpr149 in nociception and the peripheral action of minor cannabinoids
Gpr149 在伤害感受和次要大麻素外周作用中的研究
- 批准号:
10174525 - 财政年份:2019
- 资助金额:
$ 56.41万 - 项目类别:
Neuro-immune mechanisms of minor cannabinoids in inflammatory and neuropathic pain
次要大麻素在炎症和神经性疼痛中的神经免疫机制
- 批准号:
10655599 - 财政年份:2019
- 资助金额:
$ 56.41万 - 项目类别:
Neuro-immune mechanisms of minor cannabinoids in inflammatory and neuropathic pain
次要大麻素在炎症和神经性疼痛中的神经免疫机制
- 批准号:
10225473 - 财政年份:2019
- 资助金额:
$ 56.41万 - 项目类别:
TLR2 in Sepsis-Induced Coagulopathy, Endothelial Leak, and Pulmonary Dysfunction
TLR2 在脓毒症引起的凝血病、内皮渗漏和肺功能障碍中的作用
- 批准号:
7860482 - 财政年份:2004
- 资助金额:
$ 56.41万 - 项目类别:
Modulation of inflammation and sepsis by bacterial PAL
细菌 PAL 对炎症和脓毒症的调节
- 批准号:
6821965 - 财政年份:2004
- 资助金额:
$ 56.41万 - 项目类别:
Modulation of inflammation and sepsis by bacterial PAL
细菌 PAL 对炎症和脓毒症的调节
- 批准号:
7234110 - 财政年份:2004
- 资助金额:
$ 56.41万 - 项目类别:
Modulation of inflammation and sepsis by bacterial PAL
细菌 PAL 对炎症和脓毒症的调节
- 批准号:
6895453 - 财政年份:2004
- 资助金额:
$ 56.41万 - 项目类别:
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