Neuro-immune mechanisms of minor cannabinoids in inflammatory and neuropathic pain

项目摘要 慢性疼痛是一个重大的公共卫生问题，目前的治疗方式是不够的。 大麻和大麻提取物用于药用已有数千年的历史， 它在一些州合法化，越来越多地被用来管理神经，心理和 炎性条件。然而，关于大麻的功效、作用机制和效果的研究 及其对美国人类健康和疾病的影响受到DEA的限制 附表1分类。大麻的主要成分THC和CBD被认为具有疼痛 减少影响。四氢大麻酚已被最广泛的研究，虽然它具有镇痛作用， 抗精神病的特性限制了其用于疼痛管理的效用。值得注意的是，次要的大麻素正在成为 潜在的天然化合物，具有抗炎和减轻疼痛的作用，但没有不必要的 THC的精神影响。与此同时，正在探索抗炎策略以治疗 慢性疼痛我们发现内源性大麻素花生四烯酸、N-花生四烯酸多巴胺和N-油酰 多巴胺和植物大麻素Δ-9-THC都具有抗炎作用， 用LPS处理的小鼠中的指数。在LPS处理的小鼠中，它们各自显著上调IL-10的血浆水平。 使用骨髓嵌合体，我们确定NADA介导了LPS治疗的小鼠的抗炎作用。 小鼠通过非髓系细胞谱系表达的TRPV 1。相反，我们的初步数据表明，Δ-9- THC通过大麻素受体1（CB 1 R）而不是TRPV 1发挥其抗炎作用。初步 研究发现，大麻二酚（CBD），大麻酚（CBN），大麻酚（CBG）和 大麻色烯（CBC）调节人微血管内皮细胞的炎症活化。我们 广泛假设少量大麻素通过抗炎作用减轻炎症和神经性疼痛 在感觉神经元中通过外周TRPV 1和CB 1 R的激活介导的机制。我们将 利用PI在神经生物学、疼痛生物学、TRPV 1、免疫学、血管生物学和 研究CBD，CBN，CBG和CBC的抗炎和减轻疼痛的作用，以及其他轻微的 大麻素在体外和体内的炎症和神经性疼痛模型。在目标#1中，我们将定义 次要大麻素调节炎症激活和伤害感受器、白细胞和 内皮细胞，并确定其对TRPV 1和CB 1 R的依赖性。在目标#2中，我们将确定角色 在炎症和神经性疼痛模型中， 小鼠在目标#3中，我们将确定微量大麻素如何减少炎症和神经性疼痛 行为通过TRPV 1和CB 1 R在伤害感受器中表达。这些研究将促进理解 内源性香草素和内源性大麻素系统在疼痛中的作用，并将为未来的发展铺平道路， 以内源性香草素和内源性大麻素系统为靶点的次要大麻素类疗法。

PROJECT SUMMARY Chronic pain is a substantial public health problem, and the current treatment modalities are insufficient. Cannabis and cannabis extracts have been used for thousands of years for medicinal purposes, and following its legalization in a number of states, is increasingly being used to manage neurological, psychological, and inflammatory conditions. However, research on the efficacy, mechanisms of action, and effects of cannabis and its components on human and health and disease in the United States has been limited by its DEA Schedule 1 classification. The principal components of cannabis, THC and CBD, are believed to have pain reducing effects. THC has been most extensively studied, and although it has analgesic properties, its psychotropic properties limit its utility for pain management. Notably the minor cannabinoids are emerging as potential natural compounds with anti-inflammatory and pain reducing effects, but without the unwanted psychotropic effects of THC. At the same time, anti-inflammatory strategies are being explored for treating chronic pain. We have found that the endocannabinoids anandamide, N-arachidonoyl dopamine and N-oleoyl dopamine, and the phytocannabinoid, Δ-9-THC, all have anti-inflammatory effects and improve functional indices in mice treated with LPS. They each profoundly up-regulate plasma levels of IL-10 in LPS-treated mice. Using bone marrow chimeras, we determined that NADA mediates its anti-inflammatory effects in LPS-treated mice via the TRPV1 expressed by non-myeloid cell lineages. In contrast, our preliminary data suggest that Δ-9- THC exerts its anti-inflammatory effects via cannabinoid receptor 1 (CB1R), rather than TRPV1. In preliminary studies we have found that Cannabidiol (CBD), Cannabinol (CBN), Cannabigerol (CBG) and Cannabichromene (CBC) modulate inflammatory activation of human microvascular endothelial cells. We broadly hypothesize that minor cannabinoids reduce inflammatory and neuropathic pain via anti-inflammatory mechanisms mediated through the activation of peripheral TRPV1 and CB1R in sensory neurons. We will leverage the expertise of the PIs in neurobiology, pain biology, TRPV1, immunology, vascular biology and injury to study the anti-inflammatory and pain reducing effects of CBD, CBN, CBG, and CBC, and other minor cannabinoids in vitro and in vivo in models of inflammatory and neuropathic pain. In Aim #1 we will define the ability of minor cannabinoids to modulate inflammatory activation and function of nociceptors, leukocytes, and endothelial cells, and determine their dependence on TRPV1 and CB1R. In Aim #2 we will determine the role of anti-inflammatory mechanisms in reducing pain behaviors in inflammatory and neuropathic pain models in mice. In Aim #3 we will determine how minor cannabinoids reduce inflammatory and neuropathic pain behaviors through TRPV1- and CB1R- expressed in nociceptors. These studies will advance the understanding of the endovanilloid and endocannabinoid systems in pain, and will pave the way for future development of minor cannabinoid-based therapies targeting the endovanilloid and endocannabinoid systems for pain.