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。

• 批准号: 10307602
• 负责人: Kenneth Mackie
• 金额: $ 64.37万
• 依托单位: QUEEN'S MEDICAL CENTER
• 依托单位国家: 美国
• 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/10307602
• 关键词: Abate; 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 Studies; Excretory function; Flavonoids; Freund' 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; Maintenance; Malignant Neoplasms; Measures; Mediating; Membrane Potentials; Metabolism; Microglia; Microsomes; Molecular; Molecular Target; Natural Products; 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; experimental study; high throughput screening; human model; in vivo; in vivo Model; inflammatory pain; inhibitor; knowledge base; macrophage; mast cell; monocyte; mouse model; musculoskeletal injury; nervous system disorder; neutrophil; opioid epidemic; opioid overdose; opioid use; pain model; painful neuropathy; patch clamp; receptor; screening; side effect; sulfated glycoprotein 2

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.

项目总结/文摘