Mechanistic Bases for the Adverse Interaction of Nicotine and Chronic Pain

描述（由申请人提供）：吸烟是导致死亡的主要可预防原因，每年造成约500万人死亡，占全球医疗保健支出的15%。慢性疼痛对个人和社会造成了同样高的损失。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。几十年来，慢性疼痛和吸烟之间的相互作用已经很明显了——似乎存在一个积极的反馈循环，在这个循环中，个人吸烟减轻疼痛，吸烟加剧疼痛，而个人则更多地吸烟作为回应。了解这种关系的机制基础将为新的行为或药物治疗干预提供见解。关于中枢神经系统机制，吸烟和慢性疼痛之间的不良关系知之甚少。我们最近发现，通过显微注射原型激动剂epibatidine，在吻侧腹内侧髓质（RVM）中激活α4β2烟碱乙酰胆碱受体（nAChR），产生抗痛觉作用，RVM是调节球脊髓疼痛的关键脑干转接站。然而，在后爪足底注射完全弗氏佐剂（CFA）产生持续炎症性疼痛的情况下，依比替丁的疗效大大降低。这种减少的机制原因尚不清楚。这项提议的总体目标是调查吸烟（尼古丁使用）和慢性疼痛的机制交叉。在证实持续的炎症性痛觉会降低epibatidine在RVM中的抗痛觉效果后，SA 1验证了“镜像”假说，即RVM长期暴露于α4β2 AChR激动剂会增强CFA诱导的热痛觉过敏。SA 2验证了持续的炎症伤害性降低RVM中α4β2 achr的数量或亲和力的假设，确定了这种降低是转录性的还是翻译性的，并证实了RVM内注入依比替丁会产生预期的α4β2 achr的上调。sa3决定了持续的炎性伤害感觉是否会降低依比替丁在特定脊髓突起RVM神经元群中的突触前或突触后作用。这一建议的创新之处在于：1)在机制水平上研究吸烟和慢性疼痛的交叉关系；2)关注球脊髓疼痛调节通路作为一种促进机制的作用。这些假设和方法满足了我作为一名药理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前沿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促进我的专业发展。我将通过每周与受过广泛训练的研究人员的互动，以及向当地和更大的科学界以及我的论文委员会（其中包括3名内科科学家）展示我的工作，获得有价值的反馈。总的来说，这个提案概述了在一个优秀的环境中进行的一个关键的临床基础问题的调查，这将有助于我未来作为一名内科科学家的成功。

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.