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

次要大麻素在炎症和神经性疼痛中的神经免疫机制

基本信息

批准号：
9895397
负责人：
Judith Hellman
金额：
$ 58.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895397
关键词：
Acute Pain Affect Afferent Neurons Analgesics Anti-inflammatory Antiinflammatory Effect Behavioral Model Binding Biology Blocking Antibodies Blood Vessels Bone Marrow CNR1 gene Calcium Cannabidiol Cannabinoids Cannabinol Cannabis Cell Lineage Cell physiology Cells Chimera organism Classification Data Dependence Development Disease Dopamine Endocannabinoids Endothelial Cells Endothelium Endotoxins Exposure to Future G-Protein-Coupled Receptors Health Human Immunology In Vitro Individual Inflammation Inflammatory Injury Integration Host Factors Interleukin-10 Knockout Mice Legal Leukocytes Lipopolysaccharides Mediating Medical Minor Modality Modern Medicine Mus N-arachidonoyl dopamine Neurobiology Neuroimmunomodulation Neurologic Neurons Neuropathy Nociceptors Pain Pain management Peripheral Permeability Plasma Population Production Property Public Health Reporting Research Role Schedule Sensory Specificity System Testing Tetrahydrocannabinol Therapeutic Time Tissues United States Vanilloid anandamide base cannabichromene cannabigerol chronic pain cytokine desensitization endogenous cannabinoid system endovanilloid improved in vivo in vivo Model indexing inflammatory neuropathic pain interleukin-10 receptor marijuana use nerve injury pain behavior pain model pain reduction painful neuropathy phytocannabinoid psychologic receptor release factor response response to injury targeted treatment therapeutic development

项目摘要

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.

项目摘要慢性疼痛是一个实质性的公共卫生问题，目前的治疗方式不足。大麻和大麻提取物已被用于医疗目的数千年，并遵循它在许多州的合法化，越来越多地用于管理神经，心理和炎症条件。但是，研究大麻的有效性，作用机理和影响及其在美国的人类和健康与疾病的组成部分受到DEA的限制附表1分类。据信大麻，THC和CBD的主要组成部分已支付减少效果。 THC一直是最广泛的研究，尽管它具有镇痛特性，但精神属性限制了其用于疼痛管理的效用。值得注意的是，次要大麻素正在出现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的精神作用。同时，正在探索用于治疗的抗炎策略慢性疼痛。我们发现内源性大麻素anandamide，n- arachidonoyl多巴胺和N-蛋白酶多巴胺和植物大麻素（δ-9-THC）都具有抗炎作用并提高功能用LPS处理的小鼠的指标。他们每个人都深刻地上调了经LPS处理的小鼠IL-10的血浆水平。使用骨髓嵌合体，我们确定NADA介导了LPS处理的抗炎作用通过非乳突细胞谱系表达的TRPV1小鼠。相反，我们的初步数据表明δ-9- THC通过大麻素受体1（CB1R）而不是TRPV1发挥其抗炎作用。在初步研究我们发现大麻二酚（CBD），大麻醇（CBN），大麻醇（CBG）和大麻酚（CBC）调节人微血管内皮细胞的炎症激活。我们广泛地假设小大麻素通过抗炎减少炎症和神经性疼痛通过感官神经元中的外周TRPV1和CB1R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，TRPV1，免疫学，血管生物学和研究CBD，CBN，CBG和CBC的抗炎和疼痛减轻作用的伤害大麻素体外和体内炎症和神经性疼痛模型中的体内。在AIM＃1中，我们将定义次要大麻素调节伤害感受器，白细胞和功能的能力内皮细胞，并确定它们对TRPV1和CB1R的依赖性。在目标2中，我们将确定角色减少炎症和神经性疼痛模型中疼痛行为的抗炎机制老鼠。在AIM＃3中，我们将确定如何减少炎症和神经性疼痛通过在伤害感受器中表达的TRPV1和CB1R的行为。这些研究将提高理解疼痛中的内托氨基烷和内源性大麻素系统，并将为未来的发展铺平道路针对疼痛的腹膜内甲虫和内源性大麻素系统的较小基于大麻素的疗法。