Mechanistic Bases for the Adverse Interaction of Nicotine and Chronic Pain

描述(由申请人提供)：吸烟是主要的可预防的死亡原因，每年导致约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也造成了同样高的损失。在美国，慢性疼痛影响着约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--似乎存在一个正反馈回路，在这个回路中，个人吸烟以缓解疼痛，吸烟加剧疼痛，个人吸烟作为回应。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。吸烟和慢性疼痛之间的不良关系可能与中枢神经系统机制有关，但人们对此知之甚少。我们最近发现，在延髓头端腹内侧区(RVM)微量注射典型激动剂表巴替丁，激活烟碱型乙酰胆碱受体(NAChR)，产生抗伤害性感受。然而，在足底注射完全弗氏佐剂(CFA)所产生的持续性炎性疼痛的情况下，表巴替丁的疗效会大大降低。造成这一下降的机制原因尚不清楚。这项提案的总体目标是调查吸烟(尼古丁使用)和慢性疼痛之间的机械交叉。在确定持续的炎性伤害性感觉降低了依巴替丁在RVM中的抗伤害性效应后，SA 1测试了“镜像”假说，即RVM长期暴露于2AChR激动剂会增强CFA诱导的热痛觉过敏。SA 2验证了持续炎性伤害性感觉降低RVM中2AChRs的数量或亲和力的假设，确定这种下降是转录还是翻译性质的，并证实RVM内注射表巴替丁可产生预期的2AChRs上调。Sa-3决定了持续的炎性伤害性感觉是否降低了特定群体的脊髓投射的RVM神经元中依巴替丁的突触前或突触后的作用。这一建议的创新之处在于：1)在机械水平上研究了吸烟和慢性疼痛的交集；2)重点研究了球脊髓疼痛调节通路作为一种贡献机制的作用。这些假设和方法满足了我作为药理学家和神经学家的发展愿望，并将在从系统到细胞水平的尖端方法和量化方法方面为我提供多学科培训。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。我将通过每周与训练有素的研究人员的互动，以及向当地和更大的科学界以及我的论文委员会(包括3名内科科学家)介绍我的工作，获得有价值的反馈。作为一个整体，这项建议概述了在一个突出的环境中进行的基于临床的关键问题的调查，并将促进我作为一名内科科学家未来的成功。

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 ¿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.