title: 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.
authors: Department of Pathophysiology, Jessenius School of Medicine, Comenius University, Bratislava, Slovak Republic.
authors: J
authors: J
authors: Plevkova
authors: M
authors: M
authors: Kollarik
authors: I
authors: I
authors: Poliacek
authors: M
authors: M
authors: Brozmanova
authors: L
authors: L
authors: Surdenikova
authors: M
authors: M
authors: Tatar
authors: N
authors: N
authors: Mori
authors: B J
authors: BJ
authors: Canning
mesh_terms: D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D003080:Cold Temperature / Q000009:adverse effects; D003371:Cough / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D008610:Menthol / Q000494:pharmacology*; D009297:Nasal Mucosa / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D009666:Nose / Q000187:drug effects / Q000294:innervation*; D012018:Reflex / Q000187:drug effects / Q000235:genetics; D012119:Respiration / Q000187:drug effects / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D014276:Trigeminal Nerve / Q000187:drug effects / Q000378:metabolism
chemical_list: D000996:Antitussive Agents; D050053:TRPM Cation Channels; D008610:Menthol
keywords: cough; turbinate; vagal
references: Pulm Pharmacol Ther. 2012 Jun;25(3):236-41
references: 22465565
references: J Physiol. 2005 Dec 1;569(Pt 2):559-73
references: 16051625
references: Bioorg Med Chem Lett. 2012 Apr 15;22(8):2922-6
references: 22421018
references: J Neurophysiol. 2006 Feb;95(2):1221-30
references: 16424459
references: Tob Induc Dis. 2011 May 23;9 Suppl 1:S7
references: 21624153
references: Am J Physiol Regul Integr Comp Physiol. 2006 Aug;291(2):R454-63
references: 16914432
references: Thorax. 1994 Oct;49(10):1024-6
references: 7974298
references: J Appl Physiol (1985). 1991 May;70(5):2080-6
references: 1864790
references: Curr Opin Pharmacol. 2011 Jun;11(3):218-23
references: 21723782
references: Pediatr Pulmonol. 2008 Jun;43(6):532-7
references: 18435479
references: Cell. 2003 Mar 21;112(6):819-29
references: 12654248
references: Nature. 2007 Jul 12;448(7150):204-8
references: 17538622
references: FASEB J. 2011 Dec;25(12):4434-44
references: 21903934
references: J Physiol. 1988 Aug;402:411-20
references: 3236245
references: Am J Public Health. 2011 Jul;101(7):1234-6
references: 21566038
references: J Laryngol Otol. 1988 Jun;102(6):506-8
references: 3397650
references: Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G212-21
references: 19959819
references: Rhinology. 2010 Mar 02;48(1):7-10
references: 20502728
references: Am J Physiol Lung Cell Mol Physiol. 2008 Nov;295(5):L858-65
references: 18689601
references: Pneumologie. 2001 Mar;55(3):115-9
references: 11303537
references: J Neurophysiol. 2007 Feb;97(2):966-78
references: 17151223
references: PLoS One. 2011;6(9):e25894
references: 21984952
references: Am J Health Syst Pharm. 2003 Aug 15;60(16):1657-9
references: 12966910
references: Cough. 2012 Dec 03;8(1):11
references: 23199233
references: Respir Physiol. 1996 Mar;103(3):211-9
references: 8738897
references: J Physiol. 2008 Mar 15;586(6):1595-604
references: 18218683
references: J Neurosci. 2007 Sep 12;27(37):9874-84
references: 17855602
references: Am J Respir Crit Care Med. 1997 Jul;156(1):309-13
references: 9230767
references: Am J Physiol Regul Integr Comp Physiol. 2013 Jun 1;304(11):R1017-23
references: 23576611
references: J Physiol Pharmacol. 2004 Sep;55 Suppl 3:101-6
references: 15611600
references: J Investig Allergol Clin Immunol. 2001;11(1):56-8
references: 11436974
references: Respir Physiol Neurobiol. 2011 Aug 15;177(3):327-32
references: 21621010
references: Am J Respir Crit Care Med. 1998 Jul;158(1):42-8
references: 9655705
references: Handb Exp Pharmacol. 2007;(179):329-44
references: 17217067
references: Respir Physiol Neurobiol. 2010 Aug 31;173(1):11-5
references: 20580681
references: Pulm Pharmacol. 1994 Jun;7(3):179-84
references: 7827436
references: Nicotine Tob Res. 2011 Oct;13(10):989-97
references: 21652736
references: Brain Res Mol Brain Res. 2005 May 20;136(1-2):91-8
references: 15893591
references: Pediatrics. 2010 Dec;126(6):1092-9
references: 21059712
references: J Physiol Pharmacol. 2008 Dec;59 Suppl 6:153-61
references: 19218639
references: Eur Respir J. 2005 Dec;26(6):1097-103
references: 16319342
references: Mol Pain. 2008 Jun 05;4:22
references: 18534015
references: Eur Respir J. 1995 Jul;8(7):1110-4
references: 7589394
references: Brain Res. 2010 Mar 10;1319:60-9
references: 20079339
references: J Neurosci. 2012 Feb 8;32(6):2086-99
references: 22323721
references: J Allergy Clin Immunol. 2005 Dec;116(6):1282-8
references: 16337460
references: Annu Rev Public Health. 2000;21:309-33
references: 10884956
references: Respir Physiol Neurobiol. 2004 Sep 15;142(2-3):225-35
references: 15450482
references: J Appl Physiol (1985). 1994 Jun;76(6):2672-9
references: 7928899
references: J Comp Neurol. 2005 Dec 26;493(4):596-606
references: 16304633
references: J Neurosci. 2009 Oct 28;29(43):13662-71
references: 19864578
references: Am J Physiol Regul Integr Comp Physiol. 2011 Jun;300(6):R1278-87
references: 21411765
references: Curr Allergy Asthma Rep. 2003 May;3(3):210-4
references: 12662469
references: Thorax. 2004 Sep;59(9):769-72
references: 15333853
references: Respir Med. 2013 Mar;107(3):433-8
references: 23266255
references: Neuroreport. 2005 Jun 21;16(9):955-9
references: 15931068
references: J Physiol. 2010 Dec 1;588(Pt 23):4769-83
references: 20937710