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

• 批准号: 9060914
• 负责人: Francis Josef Jareczek
• 金额: $ 3.01万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 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/9060914
• 关键词: 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; Electrophysiology (science); Environment; Expenditure; Exposure to; Feedback; Freund' s Adjuvant; Future; General Population; Genes; Goals; 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; Physicians; 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; radioligand; receptor; response; smoking prevalence; success

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 α4β2 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 α4β2 AChR agonist enhances the heat hyperalgesia induced by CFA. SA 2 tests the hypothesis that persistent inflammatory nociception decreases the number or affinity of α4β2 AChRs 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 α4β2 AChRs. 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（由适用提供）：吸烟是死亡率的主要预防原因，每年约500万人死亡，最多可占全球医疗支出的15％。慢性疼痛对个人和社会造成了同样的巨大损失。在美国，慢性疼痛影响约1.16亿人，每年产生6350亿美元的成本。数十年来，慢性疼痛和吸烟之间的相互作用一直是证据 - 似乎存在一个积极的反馈回路，其中个体吸烟以减轻疼痛，吸烟加剧了疼痛，并且个人对痛苦的反应更多。了解这种关系的机械基础将提供有关新行为或药物治疗干预措施的见解。对于可能导致吸烟与慢性疼痛之间不良关系的中枢神经系统机制知之甚少。我们最近确定，通过对尾腹腹膜髓质（RVM）中的原型激动剂表皮定氨酸对α4β2烟碱乙酰胆碱受体（NACHR）的激活，这是一个关键的脑杆菌伴有，用于球形疼痛调节的关键脑干相关。然而，在持续的炎症性疼痛的条件下，由于持续的炎症性疼痛，在后爪中注射了完整的弗朗德可调节（CFA），因此表皮丁胺的效率大大降低。这种减少的机械原因尚不清楚。该提案的总体目标是研究吸烟（尼古丁使用）和慢性疼痛的机械交集。 SA 1确定持续性炎症性肿瘤可降低Epibatidine在RVM中的抗障碍有效性，SA 1检验了RVM慢性暴露于α4β2ACHR激动剂的“镜像”假设增强了CFA诱导的热触及过敏。 SA 2检验了以下假设：持续性炎症性肿瘤降低了RVM中α4β2ACHR的数量或亲和力，确定这种降低是本质上的转录还是转化，并确认Intra-RVM输注O epibatidine o epibatidine会产生α4β2ACHR的预期上调。 SA 3确定持续性炎症性肿瘤是否会降低深度注射RVM神经元特定群体中表皮胺的突触前或突触后作用。该提议具有创新性，因为它1）研究了在机械水平上检查吸烟和慢性疼痛的相交，而2）侧重于球囊疼痛调节途径的作用，作为一种促进机制。这些假设和方法解决了我发展为药物学家和神经科学家的愿望，并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计划提供的培训环境将进一步增强我的专业发展。我将通过与广泛训练的研究人员进行每周互动，以及向当地和更大的科学社区以及我的论文委员会（包括3个物理科学家）的作品介绍，从而获得宝贵的反馈。总体而言，该提案概述了在杰出的环境中进行的基于临床的临床问题的投资，并将促进我作为医师科学家的未来成功。