Smokers who use nicotine replacement products to help them quit smoking can experience local irritation at the site of application. It had been generally assumed that the irritation was caused by nicotine stimulation of nicotinic acetylcholine receptors (nAChRs) in sensory neurons, but new research by scientists in Belgium and Spain has shown that the irritation is caused instead by activation of the transient receptor potential cation channel, TRPA1. TRP cation channels are an ancient family of receptors that act as diverse cellular sensors, responding to temperature, taste, touch, pain and other stimuli, both at the level of the entire multicellular organism and also at the level of single cells. TRPA1 is expressed in nociceptive neurons and is activated by a variety of noxious stimuli, including extreme cold and pungent compounds such as mustard oil, as well as playing a role in inflammatory pain.
In the present study, the researchers showed that nicotine activates both human and mouse TRPA1 channels expressed in Chinese hamster ovary cells. In contrast to TRPA1 activation by electrophiles such as mustard oil, during which N-terminal cysteine residues are covalently modified, activation by nicotine does not involve covalent modification (as would be expected from the structure of nicotine). A significantly lower proportion of nociceptive mouse trigeminal neurons from Trpa1 knockout mice responded to nicotine exposure than did neurons from wild-type mice. In neurons from wild-type mice, nicotine was found to evoke two separate responses: rapid and quickly desensitising responses mediated by nAChRs and slower, more sustained responses mediated by TRPA1. To test whether TRPA1 contributes to irritant effects of nicotine in vivo, the team compared the airway constriction reflexes of wild-type and Trpa1 knockout mice to stimulation of the nasal mucosa. Airway constriction increased significantly after nicotine application in wild-type but not Trpa1 knockout mice.
The study, which is published in the journal Nature Neuroscience, suggests that inhibitors of TRPA1 could be used to develop smoking cessation therapies with fewer side effects and better compliance. Although relatively high nicotine concentrations are needed to activate TRPA1, the concentrations needed are within the range delivered by nicotine nasal sprays, the most effective form of nicotine replacement therapy, but also the one with the highest dropout rate because of local irritation.