Cannabinoid-based therapy and approaches to quantify pain in sickle cell disease

基于大麻素的疗法和量化镰状细胞病疼痛的方法

基本信息

批准号：
8722605
负责人：
Kalpna Gupta
金额：
$ 185.53万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8722605
关键词：
Absence of pain sensation Agonist Analgesics Area Attenuated Behavior Biochemistry Biomedical Engineering Blood Blood Vessels Cannabinoids Cannabis Cells Chronic Collaborations Commit Complex Data Disease Dyes Electroencephalography Evans blue stain Extravasation Functional Magnetic Resonance Imaging Functional disorder Human Hyperalgesia Hypoxia Image Individual Inherited Injury Intercept Ions Laboratories Measures Mus Neuraxis Neurogenic Inflammation Neurons Neuropeptides Neurosciences Nociceptors Outcome PAR-2 Receptor Pain Patients Peripheral Peripheral Nervous System Pharmacology Phenotype Publishing Receptor Signaling Reperfusion Injury Reperfusion Therapy Research Research Personnel Sensory Nerve Endings Sickle Cell Anemia Signal Pathway Skin Systemic disease Testing Transgenic Organisms Tryptase abstracting afferent nerve base cannabinoid receptor central sensitization human subject innovation interdisciplinary approach mast cell mouse model neuroimaging neuroinflammation neurophysiology new technology novel therapeutics prevent sickling success therapy development translational approach translational study vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is an inherited hematologic disorder accompanied by severe pain, inflammation and vascular injury. We propose that nociceptor activation by ongoing hypoxia/reperfusion (H/R) injury leads to the release of neuropeptides by sensory nerves in the skin, stimulating vascular insult and mast cell activation in SCD. In turn, mast cell tryptase activates protease activated receptor 2 (PAR 2) on sensory nerve endings maintaining nociceptor sensitization and release of SP and CGRP resulting in exaggerated neuroinflammation, vascular injury and central sensitization in SCD. Sickle mice show hyperalgesia which is further elevated by H/R and attenuated by non-selective cannabinoid receptor agonist CP55940. Our preliminary data indicate that mast cell activity and Evans blue dye leakage are increased in the skin of sickle mice Vs control, which are inhibited by CP55940. Our general hypothesis is that neurogenic inflammation contributes to pain in SCD and that cannabinoids offer the unique advantage of providing analgesia by disrupting neurogenic inflammation and nociceptor sensitization, thereby preventing central sensitization. We also hypothesize that objective, non-invasive measures of pain - EEC and functional MRI - can be used to optimize analgesic treatments in SCD. These hypotheses will be tested in the following aims. SA#1. A multicellular repertoire involving mast-, endothelial-, glial and neuronal cells orchestrates neurogenic inflammation and hyperalgesia via distinct cellular receptors and signaling pathways, which will be intercepted by cannabinoids utilizing specific cannabinoid receptors (CBR). SA#2. Cannabinoids will attenuate central sensitization in sickle mice and pain in human subjects. SA#3. Simultaneous non-invasive fMRI/EEG multimodal neuroimaging will provide an effective means to quantify pain. We propose to use transgenic sickle mice, and individual cells involved in evoking pain, to perform this translational study. A proof of principl study in humans will be undertaken to examine the effect of Cannabis ion pain in sickle patients. We expect that the multidisciplinary approach combining biochemistry, neurophysiology, pharmacology, behavior and biomedical engineering will advance the treatment of pain in SCD. (End of Abstract)

描述（由申请人提供）：镰状细胞疾病（SCD）是一种遗传性血液学疾病，伴有严重的疼痛，炎症和血管损伤。我们提出，持续的缺氧/再灌注（H/R）损伤会激活伤害感受器，从而导致皮肤中感觉神经释放神经肽，从而刺激SCD中的血管损伤和肥大细胞激活。反过来，肥大细胞胰蛋白酶激活蛋白酶激活的受体2（PAR 2）在维持伤害感受器敏化并释放SP和CGRP的感觉神经末端，从而导致SCD中夸张的神经炎症，血管损伤和中枢敏化。镰状小鼠表现出痛痛，H/R进一步升高，并被非选择性的大麻素受体激动剂CP55940减弱。我们的初步数据表明，在CP55940抑制的镰状小鼠皮肤与对照的皮肤中，肥大细胞活性和Evans蓝色染料泄漏增加了。我们的总体假设是神经源性炎症会导致SCD疼痛，大麻素可以通过破坏神经源性炎症和伤害感受器敏感性来提供镇痛的独特优势，从而防止中心敏化。我们还假设可以使用客观的，非侵入性的疼痛度量 - EEC和功能性MRI-可用于优化SCD中的镇痛处理。这些假设将在以下目的中进行检验。 SA＃1。涉及肥大，内皮，神经胶质和神经元细胞的多细胞曲目可通过不同的细胞受体和信号通路来协调神经源性炎症和痛觉过敏，这将被利用特定大麻素受体（CBR）的大麻素拦截。 SA＃2。大麻素会减弱镰状小鼠的中心敏化和人类受试者的疼痛。 SA＃3。同时非侵入性fMRI/EEG多模式神经影像学将提供有效的疼痛手段。我们建议使用转基因镰刀小鼠，以及参与唤起疼痛的个体细胞进行这项翻译研究。将对人类进行主要研究的证据，以检查大麻离子疼痛对镰状患者的影响。我们预计，将生物化学，神经生理学，药理学，行为和生物医学工程结合在一起的多学科方法将推动SCD疼痛的治疗。（抽象的结尾）