Abstract
Topical application of nicotine, as used in nicotine replacement therapies, causes irritation of the mucosa and skin. This reaction has been attributed to activation of nicotinic acetylcholine receptors (nAChRs) in chemosensory neurons. In contrast with this view, we found that the chemosensory cation channel transient receptor potential A1 (TRPA1) is crucially involved in nicotine-induced irritation. We found that micromolar concentrations of nicotine activated heterologously expressed mouse and human TRPA1. Nicotine acted in a membrane-delimited manner, stabilizing the open state(s) and destabilizing the closed state(s) of the channel. In the presence of the general nAChR blocker hexamethonium, nociceptive neurons showed nicotine-induced responses that were strongly reduced in TRPA1-deficient mice. Finally, TRPA1 mediated the mouse airway constriction reflex to nasal instillation of nicotine. The identification of TRPA1 as a nicotine target suggests that existing models of nicotine-induced irritation should be revised and may facilitate the development of smoking cessation therapies with less adverse effects.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Airway Resistance / drug effects
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Airway Resistance / genetics
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Animals
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Antipruritics / pharmacology
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Biophysics
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CHO Cells
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Calcium
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Calcium Channels / genetics
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Cells, Cultured
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Cricetinae
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Cricetulus
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Electric Stimulation
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Extracellular Fluid / drug effects
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Extracellular Fluid / metabolism
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Humans
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Mecamylamine / pharmacology
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Menthol / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mustard Plant
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Nerve Tissue Proteins / genetics
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Nicotine / pharmacology*
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Nicotinic Agonists / pharmacology*
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Nicotinic Antagonists / pharmacology
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Patch-Clamp Techniques / methods
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Plant Oils / pharmacology
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Plethysmography, Whole Body / methods
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Sensory Receptor Cells / cytology
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Sensory Receptor Cells / drug effects*
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Sensory Receptor Cells / metabolism*
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TRPA1 Cation Channel
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Time Factors
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Transfection / methods
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Transient Receptor Potential Channels / genetics
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Trigeminal Ganglion / cytology
Substances
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Antipruritics
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Calcium Channels
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Nerve Tissue Proteins
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Nicotinic Agonists
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Nicotinic Antagonists
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Plant Oils
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TRPA1 Cation Channel
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TRPA1 protein, human
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Transient Receptor Potential Channels
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Menthol
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Mecamylamine
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Nicotine
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Calcium
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mustard oil