Mechanistic Bases for the Adverse Interaction of Nicotine and Chronic Pain

尼古丁与慢性疼痛不良相互作用的机制基础

基本信息

批准号：
8646010
负责人：
Francis Josef Jareczek
金额：
$ 2.93万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-09 至 2018-04-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646010
关键词：
Abbreviations Accounting Acute Pain Address Affect Affinity Agonist Analgesics Behavioral Binding Brain Stem Cell Nucleus Cells Cessation of life Chronic Chronic inflammatory pain Clinical Communities Conscious Data Development Dose Drug effect disorder Ductal Environment Expenditure Exposure to Feedback Freund&apos s Adjuvant Future General Population Genes Goals Gray unit of radiation dose Health Healthcare Heating Hyperalgesia Individual Inflammatory Infusion procedures Injection of therapeutic agent Intervention Investigation Iowa Label Link Measurement Methods Microinjections Modeling Molecular Biology Morbidity - disease rate Nature Neurons Nicotine Nicotinic Receptors Nociception Pain Pain Research Pain management Pathway interactions Patients Persistent pain Persons Pharmaceutical Preparations Pharmacology Phosphate Buffer Physicians Polymerase Chain Reaction Population Prevalence Property Public Health Rattus Reporting Role Saline Scientist Smoke Smoker Smoking Societies Synaptic Transmission System Testing Therapeutic Intervention Time Tissues Training Universities Up-Regulation Virus Withdrawal Work acetylcholine receptor agonist base behavioral pharmacology chronic pain clinically relevant cost epibatidine inflammatory pain innovation insight investigator training midbrain central gray substance mortality multidisciplinary neurochemistry non-smoker optogenetics pain behavior patch clamp postsynaptic pre-clinical presynaptic programs public health relevance radioligand receptor response smoking prevalence success

项目摘要

DESCRIPTION (provided by applicant): Smoking is the leading preventable cause of mortality, accounting for ~5 million deaths per year and up to 15% of healthcare expenditures worldwide. Chronic pain exacts a similarly high toll on individuals and society. In the U.S., chronic pain affects ~116 million persons and generates $635 billion in costs yearly. The interplay between chronic pain and smoking has been evident for decades - it appears that a positive feedback loop exists in which individuals smoke to relieve their pain, smoking exacerbates the pain, and individuals smoke more in response. Understanding the mechanistic underpinnings of this relationship will provide insights into new behavioral or pharmacological therapeutic interventions. Little is known about CNS mechanisms that may contribute to the adverse relationship between smoking and chronic pain. We recently determined that activation of ¿4¿2 nicotinic acetylcholine receptors (nAChR) by microinjection of the prototypic agonist epibatidine in the rostral ventromedial medulla (RVM), a critical brainstem relay for bulbospinal pain modulation, produces antinociception. However, the efficacy of epibatidine is greatly diminished under conditions of persistent inflammatory pain produced by intraplantar injection of complete Freund's adjuvant (CFA) in the hind paw. The mechanistic reason for this decrease is unknown. The overall goal of this proposal is to investigate the mechanistic intersection of smoking (nicotine use) and chronic pain. Having established that persistent inflammatory nociception decreases the antinociceptive efficacy of epibatidine in the RVM, SA 1 tests the "mirror" hypothesis that chronic exposure of the RVM to an ¿4¿2AChR agonist enhances the heat hyperalgesia induced by CFA. SA 2 tests the hypothesis that persistent inflammatory nociception decreases the number or affinity of ¿4¿2AChRs in the RVM, determines whether this decrease is transcriptional or translational in nature, and confirms that intra-RVM infusion o epibatidine produces the expected upregulation of ¿4¿2AChRs. SA 3 determines whether persistent inflammatory nociception decreases the presynaptic or postsynaptic actions of epibatidine in specific populations of spinally-projecting RVM neurons. This proposal is innovative in that it 1) examines the intersection of smoking and chronic pain at a mechanistic level, and 2) focuses on the role of bulbospinal pain modulatory pathways as a contributing mechanism. The hypotheses and methods address my desire to develop as a pharmacologist and neuroscientist, and will provide me multidisciplinary training in cutting-edge methods and quantitative approaches ranging from system to cellular levels. My professional development will be further augmented by the training environment provided by the University of Iowa Pain Research Program. I will gain valuable feedback through weekly interactions with broadly-trained investigators, as well as presentation of my work to the local and larger scientific communities and to my thesis committee, which includes 3 physician-scientists. As a whole, this proposal outlines the investigation of a critical clinically-based question conducted in an outstanding environment and will facilitate my future success as a physician-scientist.

描述（由申请人提供）：吸烟是导致死亡的主要可预防原因，每年导致约 500 万人死亡，占全球医疗保健支出的 15%。在美国，慢性疼痛对个人和社会造成的损失同样很高。慢性疼痛影响约 1.16 亿人，每年产生 6,350 亿美元的费用。慢性疼痛与吸烟之间的相互作用几十年来一直很明显 - 似乎存在一个积极的反馈循环，其中个人吸烟。吸烟会减轻疼痛，而吸烟会加剧疼痛，而了解这种关系的机制基础将为新的行为或药物治疗干预措施提供见解，而人们对可能导致吸烟与疼痛之间的不利关系的中枢神经系统机制知之甚少。我们最近确定了 ¿ 的激活。 4¿2 烟碱乙酰胆碱受体 (nAChR) 通过在头端腹内侧延髓 (RVM) 中显微注射原型激动剂皮巴替丁 (RVM) 来产生抗镇痛作用，这是球脊髓疼痛调节的关键脑干中继，但在持续的情况下，皮巴替丁的功效会大大减弱。足底注射弗氏完全佐剂产生的炎性疼痛(CFA) 这种减少的机制尚不清楚，该提案的总体目标是研究吸烟（尼古丁使用）和慢性疼痛的机制交叉点。 RVM 中的 Epibatidine，SA 1 测试了“镜像”假设，即 RVM 长期暴露于 ¿ 4¿2AChR 激动剂增强CFA 诱导的热痛觉过敏 SA 2 测试了持续炎症伤害感受降低了Ф2AChR 激动剂增强CFA 诱导的热痛觉过敏的数量或亲和力的假设。 RVM 中的 4¿2AChR，确定这种减少本质上是转录还是翻译，并确认 RVM 内输注 o Epibatidine 会产生预期的 ¿2 上调4¿2AChRs.SA 3 确定持续性炎症伤害感受是否会降低特定脊髓投射 RVM 神经元群中皮巴替丁的突触前或突触后作用。该提议的创新之处在于 1) 在机制水平上研究了吸烟与慢性疼痛的交叉点。，2）重点关注球脊髓疼痛调节途径作为贡献机制的作用，这些假设和方法满足了我发展为药理学家的愿望和神经科学家，将为我提供从系统到细胞水平的尖端方法和定量方法的多学科培训，爱荷华大学疼痛研究项目提供的培训环境将进一步增强我的专业发展，我将通过该项目获得宝贵的反馈。每周与训练有素的研究人员进行互动，并向当地和更大的科学界以及我的论文委员会（包括 3 名医师科学家）介绍我的工作。总的来说，该提案概述了一项基于临床的关键调查。问题在良好的环境中进行，并且将促进我未来作为一名医生科学家的成功。