Endocannabinoid Modulation of Pruritus

内源性大麻素对瘙痒的调节

基本信息

批准号：
7680475
负责人：
Joel Evan Schlosburg
金额：
$ 3.04万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2010-05-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7680475
关键词：
2-arachidonylglycerol Academy Address Affect Afferent Neurons Agent 48-80 Agonist American Amides Analgesics Anemia Anti-Inflammatory Agents Anti-inflammatory Antihistamines Area Behavior Behavioral Binding Brain Cannabinoids Cellular Membrane Characteristics Clinical Clinical Research Data Dermatologic Dermatology Disease Endocannabinoids Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Esthesia Fatty Acids Genetic Models Goals HIV Immune Targeting Incidence Injection of therapeutic agent Kidney Diseases Ligands Liver Marijuana Mediating Mediator of activation protein Medical Motor Mus Muscle relaxation phase Neurons Nociception Pain Parasites Pathway interactions Perception Phenotype Phospholipids Physiological Prevalence Pruritus Quality of life Receptor Activation Reflex action Research Role Secondary Insomnia Sedation procedure Signal Transduction Site Skin Sleeplessness Spinal Cord Steroids Stress System Thyroid Diseases Tissues Transgenic Mice Vertebral column Wild Type Mouse anandamide base cannabinoid receptor common treatment cost fatty acid amide hydrolase inhibitor/antagonist interest irritation mast cell mouse model receptor relating to nervous system research study response rimonabant skin disorder therapeutic target tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Pruritus is the clinical term for itch, an unpleasant nocifensive sensation that results in the desire to scratch the affected area. Pruritus can greatly reduce the quality of life of those inflicted, and further consequences of pruritus can include scratching-based irritations and abrasion, and commonly insomnia. Due to the variety of pathophysiological conditions (e.g., allergenic, dermatologic, and systemic) underlying pruritus symptomology, common treatments are not always effective. While there are no collective data on the prevalence of treatment seeking for pruritus, the numbers on skin diseases alone estimates an incidence of 1 in 3 Americans afflicted at any given moment, and costing a yearly $28.3 billion in medical treatment according to the American Academy of Dermatology. Pruritus shares much of its neural substrates and signaling characteristics with that of another nocifensive sensation, pain. Cannabinoids, which bind to the same receptors as THC (the primary active component in marijuana), produce analgesic effects mediated through combined action of cannabinoid receptors in the periphery, spine, and brain. Cannabinoids have also shown effective blockade of itch perception in small clinical studies, but the mechanistic actions of Cannabinoids in pruritus are not well characterized. The discovery of endogenous ligands for the cannabinoid receptors derived from phospholipids within cellular membranes (e.g., anandamide and 2-AG) has generated increasing interest in the endocannabinoid system, and the enzymatic regulators that control endocannabinoid tone. The goal of this project is investigating the alterations in scratching response, by the endocannabinoid system, using a behavioral mouse model of pruritus. Mice are treated with the mast cell degranulator compound 48/80, or other pruritogenic mediators, to induce stable levels of scratching behavior. Approaches will combine both genetic models (i.e. transgenic mice) and pharmacological tools (e.g., receptor antagonists and enzyme inhibitors) to investigate the receptor mechanisms, anatomical loci, and physiologic response of endocannabinoids in management of itch. Finally, LC-MS quantification of anandamide, and levels of other fatty acid amides, in key anatomical tissues will allow examination of the physiologic response of the endocannabinoid system under conditions of pruritic stress. These studies will further the understanding of the physiological functions of the endocannabinoid system, as well as elucidate potential targets and treatments of pruritus mediated through the endocannabinoid system.

描述（由申请人提供）：瘙痒症是瘙痒的临床术语，是一种令人不愉快的伤害性感觉，导致想要抓挠受影响区域。瘙痒症会大大降低患者的生活质量，瘙痒症的进一步后果可能包括抓挠引起的刺激和擦伤，以及通常的失眠。由于瘙痒症状的病理生理学状况（例如过敏性、皮肤病性和全身性）多种多样，常见的治疗方法并不总是有效。虽然没有关于寻求治疗瘙痒症的流行情况的集体数据，但根据美国皮肤病学会的数据，仅皮肤病的数据就估计，在任何特定时刻，三分之一的美国人患有这种疾病，每年的医疗费用为 283 亿美元。皮肤科。瘙痒症与另一种伤害性感觉（疼痛）有许多相同的神经基质和信号特征。大麻素与 THC（大麻中的主要活性成分）结合相同的受体，通过外周、脊柱和大脑中大麻素受体的联合作用产生镇痛作用。在小型临床研究中，大麻素也显示出可有效阻断瘙痒感，但大麻素在瘙痒中的作用机制尚未得到很好的表征。细胞膜内磷脂衍生的大麻素受体内源性配体（例如 anandamide 和 2-AG）的发现，引起了人们对内源性大麻素系统和控制内源性大麻素张力的酶调节剂的日益浓厚的兴趣。该项目的目标是使用瘙痒行为小鼠模型来研究内源性大麻素系统对抓挠反应的改变。用肥大细胞脱粒剂化合物 48/80 或其他致痒介质治疗小鼠，以诱导稳定水平的抓挠行为。方法将结合遗传模型（即转基因小鼠）和药理学工具（例如受体拮抗剂和酶抑制剂）来研究内源性大麻素在瘙痒治疗中的受体机制、解剖位点和生理反应。最后，LC-MS 定量关键解剖组织中的大麻素和其他脂肪酸酰胺的水平将允许检查内源性大麻素系统在瘙痒应激条件下的生理反应。这些研究将进一步了解内源性大麻素系统的生理功能，并阐明内源性大麻素系统介导的瘙痒的潜在靶点和治疗方法。