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.

Public Health Relevance

Smoking and chronic pain are significant public health problems, each exacting a huge toll on both individuals and society, and their co-occurrence is not uncommon. Furthermore, smoking exacerbates chronic pain, and chronic pain leads individuals to smoke more. This project seeks to identify and characterize the central mechanisms underpinning this adverse interaction. A better understanding of these mechanisms would be a boon to society, facilitating the development of more efficacious behavioral and pharmacological interventions for the management of chronic pain in smokers and nonsmokers alike.

National Institute of Health (NIH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Babecki, Beth
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University of Iowa
Schools of Medicine
Iowa City
United States
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