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Targeting Primary Afferent Nerves for Novel Antitussive Therapy

Bradley J. Undem, PhD; Michael J. Carr, PhD
Author and Funding Information

From the Division of Allergy and Clinical Immunology, Department of Medicine (Dr Undem), Johns Hopkins University, Baltimore, MD; and Respiratory Drug Discovery (Dr Carr), GlaxoSmithKline, King of Prussia, PA.

Correspondence to: Bradley J. Undem, PhD, Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224; e-mail: bundem@jhmi.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(1):177-184. doi:10.1378/chest.09-1960
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The best available data support the hypothesis that there are at least two types of vagal nerves responsible for initiating coughing reflexes. One type of nerve conducts action potentials in the A-range and is characterized by rapidly adapting responses to mechanical probing or acidification of the large airway epithelium. Stimulation of these nerves can evoke cough in unconscious experimental animals and humans. These nerves are important in immediate cough evoked by aspiration and as such perform a critical role in airway defense. The other type of primary afferent nerve involved in cough is the vagal C-fiber. Inhalation of selective C-fiber stimulants leads to cough only in conscious animals. In clinical studies, inhalation of a low concentration of a C-fiber stimulant causes an irritating, itchy urge-to-cough sensation that mimics the urge-to-cough sensations associated with respiratory tract infection, post-infection, gastroesophageal reflux disorders, and inflammatory airway diseases. Here we discuss the recent advances in sensory neurobiology that allow for the targeting of vagal C-fibers for novel antitussive therapy. No attempts are made to be all-inclusive with respect to the numerous possible molecular targets being considered to accomplish this goal. Rather, two general strategies are discussed: decreasing generator potential amplitude and decreasing the efficiency by which a generator potential evokes action-potential discharge. For the first category we focus on two targets, transient receptor potential vanilloid 1 and transient receptor potential A1. For the latter category we focus on recent advances in voltage-gated sodium (NaV) channel biology.

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