Effect of Cannabidiol on Microglial Activation and Central Pain-Sensitization

背景：来自临床前研究、动物治疗研究、 坊间报道表明，大麻二醇(CBD)可能对 慢性疼痛障碍。新出现的神经生物学证据表明，从 急性到慢性疼痛是由a)脑小胶质细胞增多的生物学机制介导的 激活和b)中枢痛敏增强的生理机制。然而， CBD是否调节人类大脑小胶质细胞的激活和中枢性痛敏 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 与特定大脑区域的激活有关的中枢疼痛敏感度的测量。 我们已经在试点数据中证明，ICSH对大麻素(如 如THC)在实验室范例中。低剂量的脂多糖(LPS)已被证明可以 增加脑内小胶质细胞的活性。脂多糖与辣椒素皮内注射的联合应用 提供了一种独特的实验范式来研究脑小胶质细胞之间的关系 激活和中枢疼痛敏感化。利用高敏感度和分子 正电子发射断层扫描(PET)成像的特异性，我们已经在体内证明了 使用[11C]PBR28的证据表明脂多糖后脑小胶质细胞激活增加。另外， 脂多糖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，内毒素与皮内辣椒素(PLPS-IC)的结合提供了一种有效的和 可靠的模型来检验CBD对a)脑增加的生物学机制的影响 小胶质细胞激活和b)中枢痛敏增强的生理机制。 假设1：CBD预处理将导致脑小胶质细胞激活程度降低(尤其是在 在健康个体中与安慰剂进行比较。目标1：检查效果 CBD预处理对活体人脑小胶质细胞激活的影响 LP-挑战范式和[11C]PBR28 PET成像。假设2：减少的程度 CBD预处理的脑小胶质细胞激活将与脑缺血再灌注损伤程度相关 中枢疼痛敏感化。目的#2：探讨小胶质细胞活化与脑出血的关系 在PLPS-IC中使用[11C]PRB28和ICSH测量CBD预处理的中枢疼痛敏感度 范例。

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.