Effect of Cannabidiol on Microglial Activation and Central Pain-Sensitization

大麻二酚对小胶质细胞激活和中枢疼痛敏化的影响

• 批准号: 9895343
• 负责人: MOHINI RANGANATHAN
• 金额: $ 3万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-27 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895343
• 关键词: Acute; Affinity; Agonist; Animal Model; Animals; Anti-inflammatory; Astrocytes; Behavior; Bilateral; Binding; Biological; Brain; Brain region; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Capsaicin; Cations; Cells; Chronic; Chronic low back pain; Data; Dose; Esthesia; Fibromyalgia; Functional disorder; Genotype; Goals; Human; Hyperalgesia; Individual; Inflammation; Intradermal Tests; Laboratories; Ligand Binding; Ligands; Lipopolysaccharides; Macrophage Colony-Stimulating Factor Receptor; Marijuana; Measurement; Measures; Mediating; Methods; Microglia; Midbrain structure; Minor; Modeling; Molecular; Neurobiology; Neurons; Outer Mitochondrial Membrane; Pain; Peripheral; Physiological; Pilot Projects; Placebos; Positron-Emission Tomography; Prevalence; Property; Proteins; Reporting; Role; Secondary Hyperalgesias; Sensory; Specificity; Spinal; TRPV1 gene; Techniques; Thalamic structure; Therapeutic; United States; allodynia; base; burden of illness; central pain; chronic pain; chronic painful condition; cost; design; frontal lobe; in vivo; indexing; inhibitor/antagonist; interest; neuroinflammation; novel; pain reduction; painful neuropathy; preclinical study; prevent; putamen; radioligand; receptor

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.

背景：来自临床前研究、动物治疗研究、