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

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，抗炎策略正在探索中。 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。已被占用 总而言之，我们大致假设，少量大麻类物质通过抗炎减轻炎症性和神经病理性疼痛。 感觉神经元外周TRPV1和CB1R激活的机制。 我们将利用PI在神经生物学、疼痛生物学、TRPV1、免疫学、血管生物学方面的专业知识 和损伤，研究CBD、CBN、CBG和CBC等的抗炎止痛作用 在炎症性和神经病理性疼痛模型中体内和体外的少量大麻素。在目标1中，我们将 确定小麻素调节炎性激活和伤害性感受器功能的能力， 白细胞、内皮细胞，并确定它们对TRPV1/CB1R和Gpr149的依赖性。在目标2中，我们将 确定抗炎机制在减轻疼痛行为和Gpr149变化中的作用 小鼠炎性和神经病理性疼痛模型的表达。在目标3中，我们将确定多小 大麻素通过TRPV1和CB1R表达减少炎症性和神经病理性疼痛行为 痛觉感受器。这些研究将促进对内源性大麻素和内源性大麻素系统的理解。 并将为未来开发以大麻素为基础的针对 止痛的内源性香草素和内源性大麻素系统。

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.