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

描述(由申请人提供)： 镰状细胞病是一种遗传性血液病，伴有剧烈的疼痛、炎症和血管损伤。我们认为，持续的缺氧/再灌注(H/R)损伤激活了伤害性感受器，导致皮肤感觉神经释放神经肽，刺激SCD的血管损伤和肥大细胞的激活。反过来，肥大细胞类胰蛋白酶激活感觉神经末梢上的蛋白水解酶激活受体2(PAR 2)，维持伤害性感受器的敏化和SP、CGRP的释放，导致SCD加重的神经炎症、血管损伤和中枢敏化。镰刀鼠表现出痛觉过敏，H/R进一步增强，非选择性大麻素受体激动剂CP55940减弱。我们的初步数据表明，与对照组相比，镰刀鼠皮肤肥大细胞活性和伊文思蓝渗漏增加，而CP55940抑制了肥大细胞活性和伊文思蓝渗漏。我们的一般假设是神经源性炎症导致SCD疼痛，而大麻类化合物通过破坏神经源性炎症和伤害性感受器敏化而提供镇痛的独特优势，从而防止中枢敏化。我们还假设，客观的、非侵入性的疼痛测量--脑电地形图和功能磁共振成像--可用于优化SCD的止痛治疗。这些假设将在以下目标中得到检验。SA#1.涉及肥大细胞、内皮细胞、神经胶质细胞和神经细胞的多细胞谱系通过不同的细胞受体和信号通路协调神经源性炎症和痛觉过敏，这些细胞受体和信号通路将被利用特定大麻素受体(CBR)的大麻素拦截。大麻素将减弱镰状小鼠的中枢敏感化和人类受试者的疼痛。同时无创功能磁共振成像/脑电多模式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刀鼠和参与引起疼痛的单个细胞来进行这项翻译研究。将在人体上进行一项原则性研究的证据，以检验大麻离子疼痛对镰刀患者的影响。我们期望将生物化学、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推动SCD疼痛的治疗。(摘要结束)

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)