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.

摘要