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: 10382365
• 负责人: Alonso Guedes
• 金额: $ 23.25万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382365
• 关键词: Adenosine; Adenosine Diphosphate Ribose; Affect; Agonist; Analgesics; Area; Astrocytes; Behavior; Calcium; Calcium Signaling; 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 pain management; chronic painful condition; cost; design; disability; evidence base; experimental study; improved; inflammatory pain; inhibitor; 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.

项目概要/摘要 慢性疼痛影响着 20% 的美国人口，造成了巨大的社会经济成本，并且仍然是一个严重的问题 阿片类药物的流行增加了开发新的和未满足的医疗需求的紧迫性。 我们已经确定了一种涉及脊髓的新型细胞间信号系统。 多功能酶 CD38 可能为新一代镇痛药的开发提供信息并帮助 解决这一关键空白 CD38 最初被确定为免疫细胞标记物，现在被广泛认为是一种免疫细胞标记物。 通过烟酰胺代谢调节细胞对化学信号的反应的多功能酶 利用遗传和药理学将腺嘌呤二核苷酸 (NAD) 转化为多种钙信号传导介质。 在神经性疼痛和炎症性疼痛的小鼠模型中使用方法，我们产生的证据表明 星形胶质细胞中表达的 CD38 是脊髓内源性抗伤害系统的一部分 因此，迫切需要充分表征和验证 CD38 的作用。 及其代谢物可减少与周围神经损伤和炎症相关的超敏反应。 长期目标是了解 CD38 影响伤害性信号传导的机制 我们在此应用中的总体目标是表征 CD38 在疼痛中的表达方式。 脊髓在神经性疼痛和炎症性疼痛的小鼠模型中介导抗伤害感受。 假设脊髓中的 CD38 依赖性信号传导可以减少与以下疾病相关的超敏反应： 所提出的研究的基本原理是描述周围神经损伤和炎症。 CD38 抗伤害信号传导可能会导致慢性疼痛的新治疗发展。 基于这些知识，以 CD38 为中心的治疗慢性疼痛策略的实现仍不确定。 我们将追求以下两个具体目标： 1) 验证 CD38 作为神经病理性和慢性疾病中阿片类药物信号传导的靶点 2) 表征炎性疼痛模型的抗伤害特性、耐受性和奖励责任。 CD38 生成的代谢物在神经性疼痛和炎症性疼痛中的作用 对于第一个目标，我们将使用综合的方法。 不同疼痛模型中的遗传和药理学策略（幸存神经损伤，SNI；完全弗氏疼痛模型） 辅助，CFA）了解 CD38 在脊髓阿片类信号传导中的作用 根据第二个目标，我们。 将在 CFA 和 SNI 疼痛模型中单独使用 CD38 生成的代谢物或与阿片类药物联合使用 确定代谢物的抗伤害特性所提出的探索性研究具有创新性。 因为它关注的是一种与慢性疼痛相关的新型内源性脊髓镇痛机制 改进药理学工具验证的优点这项研究意义重大，因为它是 预计将促进对神经病理性和脊髓阿片类药物信号传导基于机制的理解 炎症疼痛，并为 CD38- 的进一步发展提供强有力的基于证据的原理证明 治疗慢性疼痛的基础策略。