Effect of Cannabidiol on Microglial Activation and Central Pain-Sensitization
Effect of Cannabidiol on Microglial Activation and Central Pain-Sensitization
批准号:
9895343
负责人:
MOHINI RANGANATHAN
金额:
$3.0万
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
项目状态:
已结题
起止时间:
2019-09-27 至 2021-08-31
关键词:
AcuteAffinityAgonistAnimal ModelAnimalsAnti-inflammatoryAstrocytesBehaviorBilateralBindingBiologicalBrainBrain regionCNR2 geneCannabidiolCannabinoidsCannabisCapsaicinCationsCellsChronicChronic low back painDataDoseEsthesiaFibromyalgiaFunctional disorderGenotypeGoalsHumanHyperalgesiaIndividualInflammationIntradermal TestsLaboratoriesLigand BindingLigandsLipopolysaccharidesMacrophage Colony-Stimulating Factor ReceptorMarijuanaMeasurementMeasuresMediatingMethodsMicrogliaMidbrain structureMinorModelingMolecularNeurobiologyNeuronsOuter Mitochondrial MembranePainPeripheralPhysiologicalPilot ProjectsPlacebosPositron-Emission TomographyPrevalencePropertyProteinsReportingRoleSecondary HyperalgesiasSensorySpecificitySpinalTRPV1 geneTechniquesThalamic structureTherapeuticUnited Statesallodyniabaseburden of illnesscentral painchronic painchronic painful conditioncostdesignfrontal lobein vivoindexinginhibitor/antagonistinterestneuroinflammationnovelpain reductionpainful neuropathypreclinical studypreventputamenradioligandreceptor
中文摘要
背景:来自临床前研究、动物治疗研究、
和轶事报告表明,大麻二酚(CBD)可能具有治疗作用,
慢性疼痛障碍新出现的神经生物学证据表明,
急性至慢性疼痛由a)增加的脑小胶质细胞的生物学机制介导,
激活和B)增加的中枢疼痛敏感化的生理机制。然而,在这方面,
CBD是否调节人类大脑小胶质细胞激活和中枢疼痛敏感化还没有
到目前为止已经检查过了。皮内辣椒素诱导的继发性痛觉过敏(ICSH)是一种有效的
与特定脑区的激活相关的中枢疼痛敏感性的测量。
我们已经证明,在试点数据中,ICSH对大麻素的影响敏感(如
THC)在实验室的范例。低剂量脂多糖(LPS)已被证明,
增加大脑小胶质细胞活化。LPS和辣椒素皮内注射的组合
提供了一个独特的实验范式,以检查脑小胶质细胞之间的关系,
激活和中枢疼痛敏感化。利用高灵敏度和分子
特异性的正电子发射断层扫描(PET)成像,我们已经证明在体内
使用[11 C] PBR 28,LPS后脑小胶质细胞活化增加的证据。此外,本发明还
LPS已被证明导致辣椒素诱导的继发性痛觉过敏增加2倍
(ICSH).因此,LPS与皮内辣椒素(pLPS-IC)的组合提供了经验证的和有效的抗氧化剂。
可靠的模型来检查CBD对a)增加大脑的生物学机制的影响
小胶质细胞活化和B)增加的中枢疼痛敏感化的生理机制。
假设#1:CBD预处理将导致较低的脑小胶质细胞活化(特别是在
丘脑)与安慰剂相比。目标1:检查效果
CBD预处理对人类体内脑小胶质细胞活化的影响
LPS激发模式和[11 C] PBR 28 PET成像。假设#2:减少的程度
用CBD预处理的脑小胶质细胞活化将与
中枢疼痛敏感化目标#2:检查小胶质细胞激活与
使用pLPS-IC中的[11 C] PRB 28和ICSH测量CBD预处理的中枢疼痛敏感性
范例
英文摘要
Background: Converging lines of evidence from preclinical studies, treatment studies in animals,
and anecdotal reports suggest that cannabidiol (CBD) may have a therapeutic role in
chronic pain disorders. Emerging neurobiological evidence suggests that the transition from
acute to chronic pain is mediated by a) the biological mechanism of increased brain microglial
activation and b) the physiological mechanism of increased central pain-sensitization. However,
whether CBD modulates brain microglial activation and central pain-sensitization in humans has not
been examined to-date. Intradermal capsaicin-induced secondary hyperalgesia (ICSH) is a validated
measure of central pain-sensitization related to activation of specific brain regions.
We have demonstrated, in pilot data, that ICSH is sensitive to the effects of cannabinoids (such
as THC) in a laboratory paradigm. Low-dose lipopolysaccharide (LPS) has been shown to
increase brain microglial activation. The combination of LPS and intradermal capsaicin
provides a unique experimental paradigm to examine the relationship between brain microglial
activation and central pain-sensitization. Harnessing the high sensitivity and molecular
specificity of positron emission tomography (PET) imaging, we have demonstrated in vivo
evidence of increased brain microglial activation following LPS, using [11C]PBR28. Additionally,
LPS has been shown to result in a 2-fold increase in capsaicin-induced secondary hyperalgesia
(ICSH). The combination of LPS with intradermal capsaicin (pLPS-IC) thus provides a validated and
reliable model to examine the effects of CBD on a) the biological mechanism of increased brain
microglial activation and b) the physiological mechanism of increased central pain-sensitization.
Hypothesis #1: CBD pretreatment will result in lower brain microglial activation (specifically in
the thalamus) compared to placebo in healthy individuals. Aim#1: To examine the effect
of CBD pretreatment on brain microglial activation in vivo in humans using a
LPS-challenge paradigm and [11C]PBR28 PET imaging. Hypothesis #2: The degree of reduction in
brain microglial activation with CBD pretreatment will correlate with the degree of reduction in
central pain-sensitization. Aim#2: To examine the relationship between microglial activation and
central pain-sensitization with CBD pretreatment, measured using [11C]PRB28 and ICSH in a pLPS-IC
paradigm.
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会议论文
Effect of Cannabidiol on Microglial Activation and Central Pain-Sensitization
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批准号:10847024
-
项目类别:
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资助金额:$5.2万
-
财政年份:2019
-
负责人:MOHINI RANGANATHAN
-
依托单位:
Effect of Cannabidiol on Microglial Activation and Central Pain-Sensitization
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负责人:MOHINI RANGANATHAN
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Effect of Cannabidiol on Microglial Activation and Central Pain-Sensitization
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海外基金