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

• 批准号: 10225473
• 负责人: Judith Hellman
• 金额: $ 56.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225473
• 关键词: Acute Pain; Affect; Afferent Neurons; Analgesics; Anti-Inflammatory Agents; 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; United States; Vanilloid; anandamide; base; cannabichromene; cannabigerol; chronic pain; cytokine; desensitization; endogenous cannabinoid system; endovanilloid; improved; in vivo; in vivo Model; indexing; inflammatory 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; tissue injury

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.

项目总结 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。 大麻和大麻提取物几千年来一直被用于医疗目的，此后 它在许多州合法化，正越来越多地被用于管理神经、心理和 炎症状态。然而，对大麻的功效、作用机制和影响的研究 它在美国关于人类、健康和疾病的组成部分一直受到其DEA的限制 附表1分类。大麻的主要成分THC和CBD被认为有疼痛 减少影响。THC得到了最广泛的研究，尽管它有止痛特性，但它的 精神药物的特性限制了它在疼痛治疗中的应用。值得注意的是，次要的大麻素正在成为 潜在的天然化合物，具有消炎和止痛作用，但不含有害物质 四氢呋喃的精神作用。同时，抗炎策略也在探索中。 慢性疼痛。我们发现内源性大麻素、N-花生四烯基多巴胺和N-油酰基 多巴胺和植物大麻素Δ-9-THC都有抗炎作用，并改善功能 脂多糖组小鼠的各项指标。它们都能显著上调脂多糖处理小鼠的血浆IL-10水平。 利用骨髓嵌合体，我们确定了NADA在内毒素治疗中介导其抗炎作用 小鼠通过非髓系细胞系表达的TRPV1。相比之下，我们的初步数据表明，Δ-9- THC通过大麻素受体1(CB1R)发挥抗炎作用，而不是通过TRPV1。在预赛中 研究发现，大麻二醇(CBD)、大麻酚(CBN)、大麻酚(CBG)和 大麻酚(CBC)调节人微血管内皮细胞的炎症激活。我们 广泛假设小麻素通过抗炎减轻炎性和神经病理性疼痛 感觉神经元外周TRPV1和CB1R激活的机制。我们会 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、CBC等对损伤小鼠的抗炎止痛作用 大麻素在体外和体内炎症和神经病理性疼痛模型中的作用。在目标#1中，我们将定义 少量大麻素调节炎症激活和伤害性感受器、白细胞和 内皮细胞，并确定其对TRPV1和CB1R的依赖性。在目标2中，我们将确定角色 在炎性和神经病理性疼痛模型中减轻疼痛行为的抗炎机制 老鼠。在目标3中，我们将确定小麻素如何减轻炎症和神经病理性疼痛。 通过TRPV1-和CB1R-在伤害感受器中表达的行为。这些研究将促进对 研究了内源性大麻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 针对止痛的内源性大麻素和内源性大麻素系统的轻微大麻类药物治疗。