Modulation of pain mechanisms by cannabis-derived phytochemicals.

大麻衍生的植物化学物质调节疼痛机制。

基本信息

批准号：
10530646
负责人：
Kenneth Mackie
金额：
$ 63.82万
依托单位：
QUEEN'S MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10530646
关键词：
Abate Acceleration Acute Address Affect Agonist American Analgesics Animal Model Anti Inflammatory Analgesics Anti-Inflammatory Agents Autoimmune Diseases Binding Proteins Biochemical Biological Biological Assay Biology Biophysics CNR1 gene CNR2 gene Calcium Signaling Cannabinoids Cannabis Cannabis sativa plant Cell Line Cells Cellular Assay Cessation of life Chronic Data Drug Kinetics Electrophysiology (science)Endocannabinoids Evaluation Excretory function Flavonoids Freund&apos s Adjuvant G-Protein-Coupled Receptors GPR55 receptor GTP-Binding Proteins Genetic Human Immune Immunoassay In Vitro Individual Inflammation Inflammation Mediators Inflammatory Ion Channel Lignans Link Macrophage Maintenance Malignant Neoplasms Measures Mediating Membrane Potentials Metabolism Microglia Microsomes Molecular Molecular Target Natural Products Chemistry Nature Neurologic Dysfunctions Neuropathy Nociception Opioid Analgesics Paclitaxel Pain Pathway interactions Pharmacology Phytochemical Plants Plasma Proteins Potassium Channel Property Public Health Research Signal Pathway Signal Transduction Small Interfering RNA Solubility System T-Lymphocyte TRP channel TRPV1 gene Terpenes Therapeutic Western Blotting Work absorption animal pain aqueous cellular imaging chronic pain combinatorial cytokine economic cost efficacy evaluation experimental study high throughput screening human model in vivo in vivo Model inflammatory pain inhibitor knowledge base mast cell monocyte mouse model musculoskeletal injury nervous system disorder neutrophil opioid epidemic opioid overdose opioid use pain model painful neuropathy patch clamp pharmacologic receptor screening side effect sulfated glycoprotein 2

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic pain – often arising from musculoskeletal injury, neurological dysfunction, cancer, or autoimmune disorders – affects ~100 million Americans. Overreliance on opioid analgesics has resulted in a national public health crisis in which opioid overdoses have claimed over 47,000 lives in 2017 and are now the leading cause of avoidable deaths in the nation. The Cannabis plant has analgesic and anti‐inflammatory properties owing to its rich content of cannabinoids, terpenes, lignans, and flavonoids. However, research on the biological effects and molecular mechanisms of the numerous bioactive phytochemicals – alone or in combination (entourage effect) – has been limited. We have assembled a complementary and interdisciplinary team that combines expertises in molecular and cellular signaling, ion channel biology, natural products chemistry, and molecular pharmacology as well as all aspects of endocannabinoid biology. Our preliminary high‐ throughput screening (HTS) bioassays have identified several cannabinoids that inhibit calcium signaling in immune cells and may therefore reduce inflammation and the associated pain. Results from the work proposed here will identify the anti‐inflammatory molecules contained in Cannabis sativa and characterize the mechanisms of action they engage. We hypothesize that specific phytochemicals in Cannabis suppress cellular Ca2+ signaling and subsequent release of pro‐ inflammatory cytokines in immunocytes that contribute to inflammatory pain. We further hypothesize that combinations of Cannabis phytochemicals synergistically inhibit certain ion channels and G protein‐coupled receptors involved in immunocyte Ca2+ signaling and cytokine release, thereby ameliorating inflammatory pain. We propose to perform pharmacological profiling of individual and entourage effects of Cannabis phytochemicals on Ca2+ signaling in 5 specific pro‐inflammatory human immune cells (Aim 1A). We will determine the cellular and molecular Ca2+ mobilizing mechanisms engaged by active Cannabis phytochemicals in these immune cells (Aim 1B); and profile Cannabis phytochemicals on established molecular targets of nociceptive, inflammatory and neuropathic pain (specific TRP channels and G‐proteins) using heterologous expression systems, HTS bioassays and single cell electrophysiology (Aim 1C). In Aim 2 will assess analgesic properties of active cannabinoids and combinations using in vivo mouse models of inflammatory and neuropathic pain. Here, we will first determine in vitro “Absorption, Distribution, Metabolism, and Excretion” (ADME) properties (Aim 2A) and in vivo pharmacokinetics (Aim 2B) of said cannabinoids. We will then assess the most favorable cannabinoid(s) in Complete Freund's Adjuvant (CFA)‐induced inflammation and paclitaxel‐mediated toxic neuropathic pain (Aim 2C). Together, these studies will create a comprehensive and mechanistic knowledge base about the efficacy, potency and suitability of Cannabis‐derived phytochemicals as anti‐inflammatory analgesics and may contribute to ameliorating the current opioid epidemic.

项目概要/摘要慢性疼痛——通常由肌肉骨骼损伤、神经功能障碍、癌症或自身免疫性疾病引起—— 影响约 1 亿美国人对阿片类镇痛药的过度依赖导致了一场全国性的公共卫生危机。 2017 年，阿片类药物过量服用已夺去了 47,000 多人的生命，目前已成为该国可避免死亡的主要原因。大麻植物由于含有丰富的大麻素、萜烯、然而，木酚素和黄酮类化合物的生物效应和分子机制研究众多。植物化学物质 - 单独或组合（随行效应） - 已被限制我们已经组装了一个补充。跨学科团队，结合了分子和细胞信号传导、离子通道生物学、自然产品化学、分子药理学以及内源性大麻素生物学的各个方面。通量筛选（HTS）生物测定已鉴定出几种抑制大麻素中钙信号传导的大麻素细胞，因此可以减少炎症和相关的疼痛，本文提出的工作结果将确定。大麻中含有的抗炎分子并描述了它们所涉及的作用机制。我们寻找大麻中的特定植物化学物质抑制细胞 Ca2+ 信号传导以及随后释放的前体我们进一步捕获了导致炎症疼痛的免疫细胞中的炎症细胞因子。大麻植物化学物质协同抑制某些离子通道和 G 蛋白偶联受体免疫细胞 Ca2+ 信号传导和细胞因子释放，从而减轻炎症疼痛。我们建议对大麻植物化学物质对个体和随行人员的影响进行药理学分析 5 种特定促炎性人类免疫细胞中的 Ca2+ 信号传导（目标 1A）我们将确定细胞和分子。这些免疫细胞中活性大麻植物化学物质参与的 Ca2+ 动员机制（目标 1B）；大麻植物化学物质对伤害性疼痛、炎症性疼痛和神经性疼痛（特定 TRP 通道和 G 蛋白）使用异源表达系统、HTS 生物测定和单细胞电生理学（Aim 1C) 中，目标 2 将使用体内小鼠模型评估活性大麻素及其组合的镇痛特性。在这里，我们将首先确定体外“吸收、分布、代谢和”。然后我们将评估所述大麻素的“排泄”（ADME）特性（目标 2A）和体内药代动力学（目标 2B）。在完全弗氏佐剂（CFA）诱导的炎症和紫杉醇介导的炎症中最有利的大麻素中毒性神经性疼痛（目标 2C）。这些研究将共同创建一个关于功效、效力和作用的全面、机械的知识库。大麻衍生的植物化学物质作为抗炎镇痛药的适用性，可能有助于改善当前阿片类药物流行。