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

描述（由申请人提供）： 镰状细胞病（SCD）是一种遗传性血液病，伴有严重的疼痛，炎症和血管损伤。我们提出，持续缺氧/再灌注（H/R）损伤的伤害感受器激活导致皮肤中感觉神经释放神经肽，刺激SCD中的血管损伤和肥大细胞激活。反过来，肥大细胞类胰蛋白酶激活感觉神经末梢上的蛋白酶激活受体2（PAR 2），维持伤害感受器敏化和SP和CGRP的释放，导致SCD中的过度神经炎症、血管损伤和中枢敏化。镰状小鼠表现出痛觉过敏，其通过H/R进一步升高并通过非选择性大麻素受体激动剂CP 55940减弱。我们的初步数据表明，肥大细胞活性和伊文思蓝染料泄漏增加镰刀小鼠皮肤与对照，这是抑制CP 55940。我们的一般假设是，神经源性炎症有助于SCD疼痛，大麻素提供了独特的优势，通过破坏神经源性炎症和伤害感受器敏化，从而防止中枢敏化提供镇痛。我们还假设，客观的，非侵入性的疼痛措施- EEC和功能性MRI -可用于优化SCD的镇痛治疗。这些假设将在以下目标中进行检验。SA #1。涉及肥大细胞、内皮细胞、神经胶质细胞和神经元细胞的多细胞库通过不同的细胞受体和信号传导途径协调神经源性炎症和痛觉过敏，这将被利用特异性大麻素受体（CBR）的大麻素拦截。SA #2。大麻素将减弱镰状小鼠的中枢致敏作用和人类受试者的疼痛。SA #3。同时非侵入性fMRI/EEG多模态神经成像将提供一种有效的手段来量化疼痛。我们建议使用转基因镰状小鼠，和个别细胞参与唤起疼痛，进行这项翻译研究。将在人类中进行一项主要研究的证据，以检查大麻对镰刀患者疼痛的影响。我们期望生物化学、神经生理学、药理学、行为学和生物医学工程相结合的多学科方法将促进SCD疼痛的治疗。(End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)