Mechanistic studies on analgesic effects of terpene enriched extracts from hops

啤酒花萜类提取物镇痛作用的机理研究

• 批准号: 9895181
• 负责人: Isaac Ming-Cheng Chiu
• 金额: $ 24.18万
• 依托单位: EMORY UNIVERSITY
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895181
• 关键词: Absence of pain sensation; Acute Pain; Affect; Analgesics; Animal Model; Astrocytes; Attenuated; Beer; Behavior; Behavioral; Benchmarking; Botanicals; Calcium; Cannabinoids; Cannabis; Cannabis sativa plant; Capsaicin; Carbon Dioxide; Cells; Chemicals; Complex; Cone; Conflict (Psychology); Disease; Electrophysiology (science); Ethnobotany; Evaluation; Family; Family member; Food; Formulation; Freund' s Adjuvant; Goals; Health; Hemp family; Human; Humulus; Ibuprofen; Image; Individual; Industry; Inflammation; Inflammatory; Injections; Injury; Investigation; Laboratories; Laws; Lead; Libraries; Mass Fragmentography; Medical; Medicine; Methods; Microglia; Modality; Modeling; Molecular; Mus; Natural Products; Nerve; Neural Pathways; Neurobiology; Neuroimmune; Neurons; Nociception; Nociceptors; Opiate Addiction; Opioid Analgesics; Opium; Pain; Pain management; Papaver; Papaveraceae; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmacology; Plants; Plasma; Play; Population; Preparation H; Recording of previous events; Regulatory Pathway; Resolution; Rheumatism; Role; Scientific Inquiry; Signal Pathway; Site; Source; Spinal Cord; Stimulus; TRPV1 gene; Techniques; Terpenes; Testing; Text; Therapeutic; Tissues; Universities; Work; analytical tool; animal tissue; attenuation; base; chronic neuropathic pain; chronic pain; economic cost; field study; gabapentin; gastrointestinal; immune activation; in vitro Model; in vivo; inflammatory neuropathic pain; inflammatory pain; innovation; interdisciplinary approach; linalool; marijuana use; metabolomics; nerve injury; neuroimmunology; non-opioid analgesic; opioid epidemic; pain model; painful neuropathy; patch clamp; relating to nervous system; sedative; socioeconomics; spared nerve; synergism

ABSTRACT Chronic pain affects up to 1/5 of the world population. It is a debilitating health condition with significant socio- economic costs. Management of chronic pain continues to present therapeutic hurdles, and the utility of opiate analgesics has reached a plateau as more and more people have fallen victim to opiate addiction, contributing to the opiate crisis. Plants of the Cannabaceae family, such as Cannabis sativa (cannabis) and Humulus lupulus (hops), have a long history of traditional use in the mitigation of pain and inflammation, yet the mechanistic basis for these activities and the identities of the compounds responsible are not well understood. In the proposed work, we will take a multidisciplinary approach to investigate the analgesic effects of terpenes from the Cannabaceae family. Rather than use cannabis, whose study and product market is complicated by conflicting federal and state laws, we will focus on terpenes found in hops, which is a related species and shares a very similar terpene profile. We will acquire botanically authenticated hops cones materials for extraction by supercritical CO2 methods to create terpene enriched and depleted hops extracts for study, enabling assessment of synergy between terpenes. We will also use individual terpene standards in our proposed studies. Extracts will be chemically characterized by GC-MS and NMR and assessed for bioactivity using in vitro models to assess the capacity to affect excitability and sensitization of cultured DRG nociceptive neurons. We will analyze the ability of Hops extracts or candidate terpenes to modulate nociceptor TRPV1 sensitization by inflammatory stimuli using calcium imaging, and examine the capacity of terpenes to modulate nociceptor excitability use whole cell patch clamp electrophysiology. PCA and Compound Activity Mapping analyses on chemical features and bioactivities observed will guide selection of the most active constituents, including consideration of synergistic combinations of terpenes. In the second part of our project, we will assess the efficacy of the most promising hops terpene-enriched extracts or isolated terpenes to mitigate pain and immune activation in animal models of inflammatory (CFA) and neuropathic (SNI) pain. Plasma and tissues from mice will also be assessed for the levels of specific terpenes and their metabolites via a targeted high-resolution metabolomics approach. In addition to behavioral analysis, we will analyze plantar and DRG immune activation, as well as microglia and astrocyte activation in the spinal cord. This study is responsive to the RFA-AT-19-009 objectives to 1) investigate the mechanisms by which terpenes may affect pain pathways, including ascending and/or descending neural pathways, cellular and molecular signaling pathways, neuroimmune interactions, or other innovative regulatory pathways related to pain; and to 2) explore analgesic potential of terpenes for different pain modalities. This interdisciplinary project leverages the complementary expertise of the Quave laboratory in ethnobotany and medicinal chemistry, and the Chiu laboratory in neuroimmunology and pain.

抽象的 慢性疼痛影响着世界上多达 1/5 的人口。这是一种使人衰弱的健康状况，具有严重的社会影响 经济成本。慢性疼痛的治疗仍然存在治疗障碍，阿片类药物的用途 随着越来越多的人成为鸦片成瘾的受害者，镇痛药已达到一个平台期，导致 鸦片危机。大麻科植物，例如大麻和葎草 狼疮（啤酒花）在缓解疼痛和炎症方面有着悠久的传统用途，但 这些活动的机制基础和负责化合物的身份尚不清楚。 在拟议的工作中，我们将采取多学科方法来研究萜烯的镇痛作用 来自大麻科。而不是使用大麻，其研究和产品市场因以下因素而变得复杂 与联邦和州法律相冲突，我们将重点关注啤酒花中发现的萜烯，这是一种相关物种，并且 具有非常相似的萜烯特征。我们将获取经过植物学验证的啤酒花球果材料 通过超临界 CO2 方法提取，以产生富含萜烯和贫萜的啤酒花提取物以供研究， 能够评估萜烯之间的协同作用。我们还将在我们的产品中使用单独的萜烯标准品 拟议的研究。提取物将通过 GC-MS 和 NMR 进行化学表征并评估生物活性 使用体外模型评估影响培养的 DRG 伤害感受的兴奋性和敏感性的能力 神经元。我们将分析啤酒花提取物或候选萜烯调节伤害感受器 TRPV1 的能力 使用钙成像通过炎症刺激致敏，并检查萜烯的调节能力 伤害感受器兴奋性使用全细胞膜片钳电生理学。 PCA 和化合物活性图谱 对观察到的化学特征和生物活性的分析将指导最活跃成分的选择， 包括考虑萜烯的协同组合。在我们项目的第二部分，我们将 评估最有希望的富含啤酒花萜烯的提取物或分离的萜烯在减轻疼痛方面的功效 炎症（CFA）和神经性（SNI）疼痛动物模型中的免疫激活。血浆和 还将通过有针对性的方法评估小鼠组织中特定萜烯及其代谢物的水平 高分辨率代谢组学方法。除了行为分析之外，我们还将分析足底和 DRG 免疫激活，以及脊髓中的小胶质细胞和星形胶质细胞激活。这项研究响应 RFA-AT-19-009 的目标是 1) 研究萜烯可能影响疼痛通路的机制， 包括上行和/或下行神经通路、细胞和分子信号传导通路， 神经免疫相互作用，或与疼痛相关的其他创新调节途径； 2）探索镇痛药 萜烯对不同疼痛方式的潜力。这个跨学科项目利用了互补性 Quave 实验室在民族植物学和药物化学方面的专业知识，以及 Chiu 实验室在 神经免疫学和疼痛。