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.

项目概要慢性疼痛是一个重大的公共卫生问题，目前的治疗方式还不够。大麻和大麻提取物用于药用已有数千年的历史，它在许多州合法化，越来越多地用于治疗神经、心理和然而，对大麻的功效、作用机制和作用的研究。其成分对人类健康和疾病的影响在美国受到DEA的限制附表1分类。大麻的主要成分THC和CBD被认为具有止痛作用。 THC 的减少作用已得到最广泛的研究，尽管它具有镇痛作用，但其作用有限。精神药物特性限制了其在疼痛治疗方面的效用，值得注意的是，次要大麻素正在成为新兴的药物。具有抗炎和减轻疼痛作用的潜在天然化合物，但不含不需要的成分 THC 的精神作用同时，正在探索治疗的抗炎策略。我们发现内源性大麻素 anandamide、N-花生四烯酰多巴胺和 N-油酰。多巴胺和植物大麻素 Δ-9-THC 均具有抗炎作用并改善功能用 LPS 处理的小鼠的指数均显着上调 LPS 处理的小鼠的血浆 IL-10 水平。使用骨髓嵌合体，我们确定 NADA 在 LPS 治疗中介导其抗炎作用相比之下，我们的初步数据表明 Δ-9- 通过非骨髓细胞谱系表达的 TRPV1 小鼠。 THC 初步通过大麻素受体 1 (CB1R) 而不是 TRPV1 发挥抗炎作用。研究发现，大麻二酚（CBD）、大麻酚（CBN）、大麻酚（CBG）和大麻环烯 (CBC) 调节人微血管内皮细胞的炎症激活。广泛地说，次要大麻素通过抗炎作用减轻炎症和神经性疼痛我们将通过激活感觉神经元中的外周 TRPV1 和 CB1R 介导的机制。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 以及其他轻微损伤的抗炎和减轻疼痛作用在炎症和神经性疼痛模型中的体外和体内大麻素在目标#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，我们将确定其作用。抗炎机制在减少炎症和神经病理性疼痛模型中的疼痛行为方面的作用在目标#3中，我们将确定少量大麻素如何减轻炎症和神经性疼痛。这些研究将加深对伤害感受器中表达的 TRPV1- 和 CB1R- 的行为的理解。内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针对内香草素和内源性大麻素系统治疗疼痛的次要大麻素疗法。