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: 10018714
• 负责人: Isaac Ming-Cheng Chiu
• 金额: $ 20.42万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018714
• 关键词: Absence of pain sensation; Acute Pain; Affect; Analgesics; Animal Model; Astrocytes; Attenuated; Beer; Behavior; Behavioral; Benchmarking; Beta-caryophyllene; 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; 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 慢性疼痛影响多达1/5的世界人口。这是一种使人衰弱的健康状况，具有重要的社会状况 经济成本。慢性疼痛的管理继续出现治疗障碍和鸦片的实用性 随着越来越多的人成为鸦片成瘾的受害者，镇痛学已经达到了高原 到鸦片危机。大麻家族的植物，例如大麻（大麻）和胡乌斯 lupulus（啤酒花），在缓解疼痛和炎症方面具有悠久的传统用途历史，但是 这些活动的机械基础和负责的化合物的身份尚不清楚。 在拟议的工作中，我们将采用多学科的方法来研究萜烯的镇痛作用 来自大麻科家族。而不是使用大麻，他们的研究和产品市场变得复杂 相互矛盾的联邦和州法律，我们将专注于在啤酒花中发现的萜烯，这是一个相关物种， 共享非常相似的萜烯概况。我们将获取植物身份验证的啤酒锥材料 通过超临界二氧化碳方法提取，以创建萜烯富集和耗尽的啤酒花提取物进行研究， 能够评估萜烯之间的协同作用。我们还将在我们的 拟议的研究。提取物将通过GC-MS和NMR化学特征，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化的能力 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，并检查萜烯调节的能力 伤害感受器的兴奋性使用全细胞贴片夹电生理学。 PCA和复合活动映射 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，即 包括考虑萜烯的协同组合。在我们项目的第二部分中，我们将 评估最有希望的啤酒花萜烯富含提取物或孤立的萜烯的功效，以减轻疼痛 炎症（CFA）和神经性（SNI）疼痛的动物模型中的免疫激活。等离子体和 还将通过目标评估小鼠的组织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。这项研究对 RFA-AT-19-009目标1）研究萜烯可能影响疼痛途径的机制， 包括上升和/或下降神经途径，细胞和分子信号通路， 神经免疫相互作用或其他与疼痛有关的创新调节途径； 2）探索镇痛 萜烯对不同疼痛方式的潜力。这个跨学科项目利用了补充 民族植物和药物化学方面的磨牙实验室的专业知识，以及Chiu实验室 神经免疫学和疼痛。