Effect of Cannabidiol on Microglial Activation and Central Pain-Sensitization

背景：来自临床前研究、动物治疗研究的证据的汇集， 轶事报告表明大麻二酚 (CBD) 可能具有治疗作用 慢性疼痛疾病。新出现的神经生物学证据表明，从 急性至慢性疼痛是由以下因素介导的：a) 大脑小胶质细胞增多的生物学机制 激活和b）增加中枢疼痛敏感性的生理机制。然而， CBD 是否调节人类大脑小胶质细胞激活和中枢疼痛敏化尚未确定 迄今为止已进行过检查。皮内辣椒素诱导的继发性痛觉过敏 (ICSH) 是一种经过验证的方法 与特定大脑区域激活相关的中枢疼痛敏感度的测量。 我们在试点数据中证明，ICSH 对大麻素（例如 如 THC）在实验室范例中。低剂量脂多糖（LPS）已被证明可以 增加大脑小胶质细胞的激活。 LPS与皮内辣椒素的组合 提供了一个独特的实验范式来检查大脑小胶质细胞之间的关系 激活和中枢疼痛敏化。利用高灵敏度和分子 我们已经在体内证明了正电子发射断层扫描 (PET) 成像的特异性 使用 [11C]PBR28，LPS 后大脑小胶质细胞活化增加的证据。另外， LPS 已被证明可使辣椒素引起的继发性痛觉过敏增加 2 倍 （国际安全卫生中心）。因此，LPS 与皮内辣椒素 (pLPS-IC) 的组合提供了经过验证的、 可靠的模型来检查 CBD 对 a) 增加大脑的生物机制的影响 小胶质细胞激活和 b) 中枢疼痛敏化增强的生理机制。 假设#1：CBD 预处理将导致大脑小胶质细胞活化程度降低（特别是在 丘脑）与健康个体中的安慰剂进行比较。目标#1：检查效果 CBD 预处理对人体内脑小胶质细胞激活的影响 LPS 挑战范例和 [11C]PBR28 PET 成像。假设#2：减少的程度 CBD 预处理后大脑小胶质细胞的激活将与减少的程度相关 中枢疼痛敏感。目标#2：检查小胶质细胞激活与 CBD 预处理的中枢疼痛敏化，使用 pLPS-IC 中的 [11C]PRB28 和 ICSH 进行测量 范式。

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.