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: 10074663
• 负责人: MOHINI RANGANATHAN
• 金额: $ 22.13万
• 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/10074663
• 关键词: Acute; Affinity; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; 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、 和轶事报告表明，大麻二酚（CBD）可能具有治疗作用， 慢性疼痛病症。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。脂多糖和皮内辣椒素的组合 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证明LPS后脑小胶质细胞活化增加。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 中枢疼痛敏感化目的#2：检查小胶质细胞活化与 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