The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol

Abstract

The cold-sensitive cation channel TRPM8 is a target for menthol, which is used routinely as a cough suppressant and as an additive to tobacco and food products. Given that cold temperatures and menthol activate neurons through gating of TRPM8, it is unclear how menthol actively suppresses cough. In this study we describe the antitussive effects of (-)-menthol in conscious and anesthetized guinea pigs. In anesthetized guinea pigs, cough evoked by citric acid applied topically to the tracheal mucosa was suppressed by menthol only when it was selectively administered as vapors to the upper airways. Menthol applied topically to the tracheal mucosa prior to and during citric acid application or administered continuously as vapors or as an aerosol to the lower airways was without effect on cough. These actions of upper airway menthol treatment were mimicked by cold air delivered to the upper airways but not by (+)-menthol, the inactive isomer of menthol, or by the TRPM8/TRPA1 agonist icilin administered directly to the trachea. Subsequent molecular analyses confirmed the expression of TRPM8 in a subset of nasal trigeminal afferent neurons that do not coincidently express TRPA1 or TRPV1. We conclude that menthol suppresses cough evoked in the lower airways primarily through a reflex initiated from the nose.

Expert opinion on the cough hypersensitivity syndrome in respiratory medicine

“…The question as to how disease in the upper airway (largely innervated by the trigeminal nerve) can modulate the cough reflex, the afferent component of which is served by the vagus nerve, is not clear. It is possible that cough is due to mechanical stimulation of the laryngopharyngeal region by mucus, although, as already suggested, a more plausible explanation is that disease is not confined to the upper airway but that inflammation of the entire airway is present [78]. Most opinion leaders agreed with reservations that genetic studies are only useful in cough associated with neurological conditions.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Indeed, the menthol receptor TRPM8 is expressed in trigeminal ganglion neurons (McKemy et al, 2002) (Xing et al, 2008). Using a combination of functional and neurochemical (immunostaining and single-cell RT-PCR) studies, it was shown that menthol exerts its antitussive effect in the guinea pig by interacting at TRPM8-expressing (and TRPV1 negative) trigeminal afferents (Plevkova et al, 2013). Cough is believed to be "plastic": Up-and downregulation of the cough reflex may be mediated by distinct sensory afferents.…”

The emerging role of transient receptor potential channels in chronic lung disease

“…In fact, TRPM8 is thought to be the target responsible for cough and bronchoconstriction caused by inhalation of cold air [86,87]. In contrast, menthol, which is thought to exert its actions through the TRPM8 channel, has been shown to inhibit citric acid-induced cough in guinea pigs [88,89] and humans [90] and causes a short-lasting decrease in capsaicin cough in normal subjects [91]. Furthermore, it has been used as an OTC medication for a number of years for its antitussive properties, and is often added to cigarettes to inhibit irritancy [73].…”