Characterization of a novel spinal astrocyte-neuron signaling system in chronic pain

慢性疼痛中新型脊髓星形胶质细胞-神经元信号系统的表征

• 批准号: 10216697
• 负责人: Alonso Guedes
• 金额: $ 19.34万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216697
• 关键词: Adenosine; Adenosine Diphosphate Ribose; Affect; Agonist; Analgesics; Area; Astrocytes; Behavior; Calcium; Calcium Signaling; Cell Culture Techniques; Cells; Chemicals; Coculture Techniques; Communication; Cues; Cyclic ADP-Ribose; Data; Development; Enzymes; Freund' s Adjuvant; Generations; Genetic; Goals; Hippocampus (Brain); Hypersensitivity; Immune; Inflammation; Injections; Knock-out; Knockout Mice; Knowledge; Lead; Loperamide; Mechanics; Mediating; Mediator of activation protein; Medical; Metabolism; Methods; Mission; Modeling; Morphine; Mus; NAADP; Nature; Neuraxis; Neurons; Nicotinamide adenine dinucleotide; Nociception; Opiate Addiction; Opioid; Organism; Pain management; Peripheral; Peripheral nerve injury; Pharmacologic Substance; Pharmacology; Population; Production; Property; Public Health; Research; Rewards; Role; Signal Transduction; Spinal; Spinal Cord; System; Testing; United States National Institutes of Health; Wild Type Mouse; base; chronic neuropathic pain; chronic pain; chronic painful condition; cost; design; disability; evidence base; experimental study; improved; inflammatory pain; inhibitor/antagonist; innovation; mouse model; mu opioid receptors; nerve injury; novel; novel therapeutics; opioid epidemic; pain model; painful neuropathy; pre-clinical; response; socioeconomics; spared nerve; therapeutic development; therapeutic target; tool; treatment strategy

Project Summary/Abstract Chronic pain affects 20% of the U.S. population, poses an enormous socioeconomical cost and remains an area of considerable unmet medical need. The opioid epidemics added urgency to develop novel and actionable therapeutic targets. We have identified a novel intercellular signaling system in spinal cord involving the multifunctional enzyme CD38 that may inform the development of new-generation analgesics and help solve this critical void. CD38 was first identified as an immune cell marker and is now widely recognized as a multifunctional enzyme that regulates cellular responses to chemical cues via the metabolism of nicotinamide adenine dinucleotide (NAD) into multiple mediators of calcium signaling. Using genetic and pharmacologic methods in mouse models of neuropathic and inflammatory pains, we generated evidence suggesting that CD38 expressed in astrocytes is part of an endogenous anti-nociceptive system in the spinal cord that is relevant to chronic pain. There is, therefore, a critical need to fully characterize and validate the role of CD38 and its metabolites in reducing hypersensitivity associated with peripheral nerve injury and inflammation. Our long-term goal is to understand the mechanism by which CD38 influences nociceptive signaling to develop novel pain therapies. Our overall objective in this application is to characterize how CD38 expression in the spinal cord mediates anti-nociception in mouse models of neuropathic and inflammatory pains. Our central hypothesis is that CD38-dependent signaling in the spinal cord can decrease hypersensitivity associated with peripheral nerve injury and inflammation. The rationale for the proposed studies is that characterizing the CD38 anti-nociceptive signaling could lead to novel therapeutic developments for chronic pain. In the absence of such knowledge, the realization of a CD38-centered strategy to treat chronic pain will remain uncertain. The following two specific aims will be pursued: 1) Validate CD38 as a target for opioid signaling in neuropathic and inflammatory pain models. 2) Characterize the anti-nociceptive properties, tolerance and reward liability of CD38-generated metabolites in neuropathic and inflammatory pains. For the first aim, we will use an integrated genetic and pharmacologic strategy in distinct pain models (spared nerve injury, SNI; complete Freund’s Adjuvant, CFA) to understand the role of CD38 in opioid signaling in the spinal cord. Under the second aim, we will use CD38-generated metabolites alone or in combination with opioids in the CFA and SNI pain models to determine the anti-nociceptive properties of the metabolites. The proposed exploratory research is innovative because it focuses on a novel endogenous antinociceptive spinal mechanism relevant to chronic pain with the advantage of improved authentication of pharmacological tools. The research is significant because it is expected to advance the mechanism-based understanding of spinal opioid signaling in neuropathic and inflammatory pains, and provide strong evidence-based proof of principle for further developments of CD38- based strategies for the treatment of chronic pain.

项目摘要/摘要 慢性疼痛影响美国20％的人口，构成巨大的社会经济成本，并且仍然是 考虑面积未满足的医疗需求。阿片类药物发作增加了发展新颖的紧迫性 可操作的治疗靶标。我们已经确定了涉及的脊髓中的新型细胞间信号系统 多功能酶CD38可能会为新一代镇痛药的发展提供帮助并有助于 解决这个关键空隙。 CD38首先被识别为免疫细胞标记物，现在被广泛认为是 多功能酶通过烟酰胺的代谢来调节细胞对化学提示的反应 腺嘌呤二核苷酸（NAD）成多个钙信号传导的介体。使用遗传学和药理学 神经性和炎症性疼痛的小鼠模型中的方法，我们产生了证据表明 在星形胶质细胞中表达的CD38是脊髓中内源性抗伤害性系统的一部分 与慢性疼痛有关。因此，迫切需要充分表征和验证CD38的作用 及其代谢物在减少与周围神经损伤和炎症相关的超敏反应方面。我们的 长期目标是了解CD38影响伤害性信号的机制 新颖的疼痛疗法。我们在此应用中的总体目标是表征CD38在 脊髓介导神经性和炎症性疼痛的小鼠模型中的抗伤害感受。我们的中心 假设是脊髓中的CD38依赖性信号传导可以降低与 周围神经损伤和炎症。拟议研究的理由是表征 CD38抗伤害感受信号传导可能会导致慢性疼痛的新型热发展。在缺席的情况下 在这种知识中，以CD38为中心的治疗慢性疼痛的策略的实现将不确定。 以下两个具体目标将被追求：1）验证CD38作为神经性疗法中阿片类药物信号的目标 炎症性疼痛模型。 2）表征反伤害性特性，公差和奖励责任 CD38产生的神经性和炎症性疼痛中的代谢产物。为了第一个目标，我们将使用集成的 不同疼痛模型中的遗传和药物科学（幸运的神经损伤，SNI；完整的弗洛德 辅助，CFA）了解CD38在脊髓中阿片类药物信号传导中的作用。在第二个目标下，我们 将单独使用CD38生成的代谢物，或与CFA和SNI疼痛模型中的阿片类药物结合使用 确定代谢产物的抗伤害性特性。拟议的探索性研究是创新的 因为它专注于一种与慢性疼痛有关 改善药品工具身份验证的优势。这项研究很重要，因为它是 预计将在神经性疗法和 炎症性疼痛，并为CD38-的进一步发展提供了强大的基于证据的原理证明 基于慢性疼痛治疗的策略。