Endocannabinoid signaling in a model of cancer pain

癌痛模型中的内源性大麻素信号传导

基本信息

批准号：
8588291
负责人：
Virginia S Seybold
金额：
$ 31.56万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2009-12-16 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8588291
关键词：
2-arachidonylglycerol Accounting Address Advanced Malignant Neoplasm Afferent Neurons Analgesics Attenuated Behavior assessment Biochemical Biological Assay Bone Pain CNR1 gene CNR2 gene Calcium Signaling Cancer Pain Management Cancer Patient Cannabinoids Cannabis sativa plant Catabolism Cells Coculture Techniques Cutaneous Data Development Dose Endocannabinoids Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epidermis Esthesia Hyperalgesia Hypersensitivity In Vitro Inflammation Ipsilateral Malignant Bone Neoplasm Malignant Neoplasms Mechanics Mediating Membrane Messenger RNA Metabolism Modeling Monoacylglycerol Lipases Mus Neoplasm Metastasis Neurons Opioid Pain Patients Phospholipids Play Property Proteins Publishing Relative (related person)Role Sampling Shapes Signal Transduction Skin Source Spinal Ganglia Stimulus Syndrome Testing Tissues United States anandamide base bone cancer cell cancer pain cannabinoid receptor chronic pain coping enzyme activity fatty acid amide hydrolase fibrosarcoma gene therapy immunoreactivity in vivo inhibitor/antagonist insight keratinocyte mu opioid receptors neoplastic cell novel novel strategies novel therapeutics protein degradation protein expression public health relevance receptor receptor expression response somatosensory tumor tumor progression voltage

项目摘要

DESCRIPTION (provided by applicant): As cancer progresses, pain is increasingly associated with destruction of tissue, and severe pain occurs with bone destruction. Derivatives of Cannabis sativa (cannabinoids) are potent analgesics, and endogenous cannabinoids share this property. Anandamide (AEA) and 2-arachidonoylglycerol (2AG) are two endocannabinoids that are synthesized on demand from membrane phospholipids, and they may play fundamental roles in modulating our sensitivity to noxious stimuli. Indeed, we have generated evidence that increased degradation of AEA in skin is associated with mechanical hyperalgesia in a murine model of bone cancer pain. Cannabinoid-1 receptors mediate the inhibitory effects of AEA on somatosensory neurons, and expression of these receptors is increased in dorsal root ganglion neurons ipsilateral to tumors in tumor bearing mice. Activation of the increased pool of receptors by endogenous AEA can be manipulated by decreasing AEA degradation, resulting in prolonged anti-hyperalgesia in tumor-bearing mice. These data provide evidence to support the hypothesis that the local inhibition of endocannabinoid degradation in the periphery reduces mechanical hypersensitivity in a murine model of bone cancer pain through CB1 and CB2 receptor-dependent mechanisms. Studies outlined in this proposal will test this hypothesis further and address specific aims that explore 2AG metabolism in the same model of bone cancer pain. Specific aim 1 addresses whether inhibition of 2AG degradation is more effective than inhibition of AEA degradation in attenuating mechanical hypersensitivity in tumor-bearing mice. Monoglyceride lipase (MGL) degrades 2AG in vivo. Specific aim 2 examines the sources of MGL and cannabinoid receptors that underlie the anti- hyperalgesic effect of MGL inhibition in the periphery and whether expression of these proteins changes in tumor-bearing mice. Specific aim 3 examines the capacities of cells relevant to cutaneous mechanosensation to synthesize AEA and 2AG and whether the capacity for synthesis is changed in the cancer condition. Specific aim 4 addresses whether an MGL inhibitor acts directly on sensory neurons to reduce a depolarization-evoked calcium signal. Together with parallel data generated for AEA signaling, the data generated under specific aims 1-4 will provide extensive information on the cellular mechanisms through which inhibitors of AEA and 2AG degradation reduce mechanical hyperalgesia in cancer pain. The data will provide a rationale for the manipulation of endocannabinoids as a novel therapeutic strategy in the treatment of cancer pain.

描述（由申请人提供）：随着癌症的进展，疼痛越来越多地与组织破坏相关，并且随着骨骼破坏而发生剧烈疼痛。大麻（大麻素）的衍生物是有效的镇痛药，内源性大麻素也具有这种特性。 Anandamide (AEA) 和 2-arachidonoylglycerol (2AG) 是两种内源性大麻素，它们是根据膜磷脂的需要合成的，它们可能在调节我们对有害刺激的敏感性方面发挥重要作用。事实上，我们已经获得证据表明，皮肤中 AEA 降解的增加与骨癌疼痛小鼠模型中的机械性痛觉过敏有关。 Cannabinoid-1 受体介导 AEA 对体感神经元的抑制作用，并且这些受体的表达在荷瘤小鼠肿瘤同侧的背根神经节神经元中增加。内源性 AEA 对增加的受体库的激活可以通过减少 AEA 降解来控制，从而在荷瘤小鼠中产生长期的抗痛觉过敏。这些数据提供了支持以下假设的证据：外周内源性大麻素降解的局部抑制通过 CB1 和 CB2 受体依赖性机制降低骨癌疼痛小鼠模型中的机械超敏性。该提案中概述的研究将进一步检验这一假设，并解决在同一骨癌疼痛模型中探索 2AG 代谢的具体目标。具体目标 1 探讨在减轻荷瘤小鼠的机械过敏方面，抑制 2AG 降解是否比抑制 AEA 降解更有效。单甘油酯脂肪酶 (MGL) 在体内降解 2AG。具体目标 2 检查 MGL 和大麻素受体的来源，这些受体是外周 MGL 抑制的抗痛觉过敏作用的基础，以及这些蛋白质的表达在荷瘤小鼠中是否发生变化。具体目标 3 检查与皮肤机械感觉相关的细胞合成 AEA 和 2AG 的能力，以及合成能力在癌症条件下是否发生变化。具体目标 4 解决 MGL 抑制剂是否直接作用于感觉神经元以减少去极化诱发的钙信号。与 AEA 信号传导生成的并行数据一起，在特定目标 1-4 下生成的数据将提供有关 AEA 和 2AG 降解抑制剂减少癌痛中机械性痛觉过敏的细胞机制的广泛信息。这些数据将为操纵内源性大麻素作为治疗癌性疼痛的新型治疗策略提供依据。