The study of Gpr149 in nociception and the peripheral action of minor cannabinoids

Gpr149 在伤害感受和次要大麻素外周作用中的研究

• 批准号: 10174525
• 负责人: Judith Hellman
• 金额: $ 16.15万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174525
• 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; Nociception; 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; behavior change; 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; tissue injury

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. Taken together, we broadly hypothesize that minor cannabinoids reduce inflammatory and neuropathic pain via antiinflammatory 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, endothelial cells and determine their dependence on TRPV1 / CB1R and Gpr149. In Aim #2 we will determine the role of anti-inflammatory mechanisms in reducing pain behaviors and changes in Gpr149 expression 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.

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。拍摄 我们总体上假设小大麻素通过抗炎而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。 我们将利用神经生物学，疼痛生物学，TRPV1，免疫学，血管生物学的专业知识 以及研究CBD，CBN，CBG和CBC的抗炎和疼痛减轻作用的伤害 炎症和神经性疼痛模型中的体外和体内次要大麻素。在AIM＃1中，我们将 定义次要大麻素调节伤害感受器的炎症激活和功能的能力， 白细胞，内皮细胞并确定其对TRPV1 / CB1R和GPR149的依赖性。在目标2中，我们将 确定抗炎机制在减少疼痛行为和GPR149变化中的作用 小鼠炎症和神经性疼痛模型中的表达。在AIM＃3中，我们将确定如何较小 大麻素通过TRPV1-和CB1R（在 伤害感受器。这些研究将提高对内托藻和内源性大麻素系统的理解 在痛苦中，将为未来开发的基于大麻素的疗法铺平 内托氨基菌和内源性大麻素系统用于疼痛。