title: Menthol suppresses laryngeal C-fiber hypersensitivity to cigarette smoke in a rat model of gastroesophageal reflux disease: the role of TRPM8.
abstract: Patients with gastroesophageal reflux disease (GERD) display enhanced laryngeal reflex reactivity to stimuli that may be due to sensitization of the laryngeal C-fibers by acid and pepsin. Menthol, a ligand of transient receptor potential melastatin-8 (TRPM8), relieves throat irritation. However, the possibility that GERD induces laryngeal C-fiber hypersensitivity to cigarette smoke (CS) and that menthol suppresses this event has not been investigated. We delivered CS into functionally isolated larynxes of 160 anesthetized rats. Laryngeal pH 5-pepsin treatment, but not pH 5-denatured pepsin, augmented the apneic response to CS, which was blocked by denervation or perineural capsaicin treatment (a procedure that blocks the conduction of C fibers) of the superior laryngeal nerves. This augmented apnea was partially attenuated by capsazepine [an transient receptor potential vanilloid 1 (TRPV1) antagonist], SB-366791 (a TRPV1 antagonist), and HC030031 [a transient receptor potential ankyrin 1 (TRPA1) antagonist] and was completely prevented by a combination of TRPV1 and TRPA1 antagonists. Local application of menthol significantly suppressed the augmented apnea and this effect was reversed by pretreatment with AMTB (a TRPM8 antagonist). Our electrophysiological studies consistently revealed that laryngeal pH 5-pepsin treatment increased the sensitivity of laryngeal C-fibers to CS. Likewise, menthol suppressed this laryngeal C-fiber hypersensitivity and its effect could be reversed by pretreatment with AMTB. Our results suggest that laryngeal pH 5-pepsin treatment increases sensitivity to CS of both TRPV1 and TRPA1, which are presumably located at the terminals of laryngeal C-fibers. This sensory sensitization leads to enhanced laryngeal reflex reactivity and augmentation of the laryngeal C-fiber responses to CS, which can be suppressed by menthol acting via TRPM8.
authors.affiliation: Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan;
authors.forename: Bi-Yu
authors.initials: BY
authors.lastname: Liu
authors.affiliation: Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan;
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, Cheng Hsin General Hospital, Taipei, Taiwan;
authors.forename: Hung-Fu
authors.initials: HF
authors.lastname: Lee
authors.affiliation: Department of Otolaryngology, Taipei Veteran General Hospital, Taipei, Taiwan; Department of Otolaryngology, National Yang-Ming University, Taipei, Taiwan; and.
authors.forename: Ching-Yin
authors.initials: CY
authors.lastname: Ho
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Ting
authors.initials: T
authors.lastname: Ruan
authors.affiliation: Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; yrkou@ym.edu.tw tingruan@hotmail.com.
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
mesh_terms: D000818:Animals; D001049:Apnea / Q000188:drug therapy / Q000378:metabolism; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006967:Hypersensitivity / Q000378:metabolism / Q000503:physiopathology*; D007823:Laryngeal Nerves / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007830:Larynx / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008610:Menthol / Q000494:pharmacology*; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D050053:TRPM Cation Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D062789:Tobacco Products / Q000009:adverse effects*; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; C498947:Trpm8 protein, rat; C493922:Trpv1 protein, rat; D008610:Menthol
keywords: TRPM8; cigarette smoke; laryngeal C-fibers; laryngeal hypersensitivity; menthol