Chemosensory Perception

, Volume 3, Issue 3–4, pp 190–199 | Cite as

Four Irritating Odorants Target the Trigeminal Chemoreceptor TRPA1

  • Paige M. Richards
  • Erik C. Johnson
  • Wayne L. Silver


The trigeminal nerve responds to a variety of nociceptive stimuli, including many chemicals that activate the olfactory system at lower concentrations. However, the mechanisms by which specific odorants activate the trigeminal nerve are largely undetermined. We used an integrative approach to determine whether TRPA1 channels were the target of eight olfactory stimuli known to activate the trigeminal nerve. In a mammalian cell line stably expressing the human TRPA1 channel, we observed significant increases in intracellular calcium levels upon application of α-terpineol, amyl acetate, benzaldehyde, and toluene. Notably, these responses were greatly reduced when these chemicals were applied in conjunction with the TRPA1 inhibitor HC-030031. To determine whether TRPA1 is required for detecting these odorants as irritants in vivo, we evaluated physiological and behavioral responses to these stimuli in mice lacking the TRPA1 channel. A decline in respiration was seen in wild-type but not TRPA1 knockout mice upon exposure to α-terpineol, benzaldehyde, and toluene. Furthermore, we observed either attenuated or absent avoidance behaviors in TRPA1 knockout mice compared to wild-type mice when exposed to α-terpineol, amyl acetate, and benzaldehyde. Our results show that TRPA1 is a molecular target for four different odorants—α-terpineol, amyl acetate, benzaldehyde, and toluene. Additionally, this study suggests that TRPA1 is required for detection of α-terpineol, benzaldehyde, and toluene as trigeminal irritants. However, TRPA1 is likely only one of multiple trigeminal receptors detecting amyl acetate.


Behavioral aversion Intracellular calcium Irritant Respiratory pause Trigeminal nerve TRPA1 


  1. Alarie YY (1973) Sensory irritation by airborne chemicals. CRC Crit Rev Toxicol 2:299–363CrossRefGoogle Scholar
  2. Alimohammadi H (2004) Trigeminal nerve-mediated nasal chemesthesis: chemosensory mechanisms of the Vth cranial nerve. Dissertation, Wake Forest UniversityGoogle Scholar
  3. Alimohammadi H, Silver WL (2000) Evidence for nicotinic acetylcholine receptors on nasal trigeminal nerve endings of the rat. Chem Senses 25:61–66CrossRefGoogle Scholar
  4. Bandell M, Story GM, Hwang SW et al (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849–857CrossRefGoogle Scholar
  5. Bautista DM, Sigal YM, Milstein AD et al (2008) Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nat Neurosci 7:772–779CrossRefGoogle Scholar
  6. Bhattacharya MR, Bautista DM, Wu K et al (2008) Radial stretch reveals distinct populations of mechanosensitive mammalian somatosensory neurons. Proc Natl Acad Sci USA 105:20015–20020CrossRefGoogle Scholar
  7. Birse RT, Johnson EC, Taghert PH et al (2006) Widely distributed Drosophila G-protein coupled receptor (CG7887) is activated by endogenous tachykinin-related peptides. J Neurobiol 66:33–46CrossRefGoogle Scholar
  8. Brand G (2006) Olfactory/trigeminal interactions in nasal chemoreception. Neurosci Biobehav Rev 30:908–917CrossRefGoogle Scholar
  9. Bryant B, Silver WL (2000) Chemesthesis: the common chemical sense. In: Finger TE, Silver WL, Restrepo D (eds) The neurobiology of taste and smell. Wiley-Liss, New YorkGoogle Scholar
  10. Caterina MJ, Schumacher MA, Tominaga M et al (1997) The capsaicin receptor: a heat-activated channel in the pain pathway. Nature 389:816–824CrossRefGoogle Scholar
  11. Chen J, Kym PR (2009) TRPA1: the species difference. J Gen Physiol 133:623–625CrossRefGoogle Scholar
  12. Cometto-Muñiz JE, Cain WS (1990) Thresholds for odor and nasal pungency. Physiol Behav 48:719–725CrossRefGoogle Scholar
  13. Cometto-Muñiz JE, Cain WS (1995) Relative sensitivity of the ocular trigeminal, nasal trigeminal and olfactory systems to airborne chemicals. Chem Senses 20:191–198CrossRefGoogle Scholar
  14. Cometto-Muñiz JE, Cain WS, Abraham MH et al (2002) Psychometric functions for the olfactory and trigeminal detectability of butyl acetate and toluene. J Appl Toxicol 22:25–30CrossRefGoogle Scholar
  15. Devos M, Patte F, Rouault J et al (1990) Standardized human olfactory thresholds. Oxford University Press, New YorkGoogle Scholar
  16. Doerner JF, Gisselmann G, Hatt H et al (2007) Transient receptor potential channel A1 is directly gated by calcium ions. J Biol Chem 282:13180–13189CrossRefGoogle Scholar
  17. Finger TE, Bottger B, Hansen A et al (2003) Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration. Proc Natl Acad Sci USA 100:8981–8986CrossRefGoogle Scholar
  18. Frasnelli J, Hummel T (2007) Interactions between the chemical senses: trigeminal function in patients with olfactory loss. Int J Psychophysiol 65:177–181CrossRefGoogle Scholar
  19. Hinman A, Chuang H, Bautista DM et al (2006) TRP channel activation by reversible covalent modification. Proc Natl Acad Sci USA 103:19564–19568CrossRefGoogle Scholar
  20. Hummel T, Barz S, Lotsch J et al (1996) Loss of olfactory function leads to a decrease of trigeminal sensitivity. Chem Senses 21:75–79CrossRefGoogle Scholar
  21. Ichikawa H, Sugimoto T (2002) The co-expression of ASIC3 with calcitonin gene-related peptide and parvalbumin in the rat trigeminal ganglion. Brain Res 943:287–291CrossRefGoogle Scholar
  22. Iwasaki Y, Tanabe M, Kayama Y et al (2009) Miogadial and miogatrial with alpha, beta-unsaturated 1, 4-dialdehyde moieties—novel and potent TRPA1 agonists. Life Sci 85:60–69CrossRefGoogle Scholar
  23. Jacquot L, Monnin J, Brand G (2004a) Influence of trigeminal stimuli on olfactory sensitivity. C R Biol 327:305–311CrossRefGoogle Scholar
  24. Jacquot L, Monnin J, Brand G (2004b) Unconcious odor detection could not be due to odor itself. Brain Res 1002:51–54CrossRefGoogle Scholar
  25. Johnson EC, Garczynski SF, Park D et al (2003) Identification and characterization of a G protein-coupled receptor for the neuropeptide proctolin in Drosophila melanogaster. Proc Natl Acad Sci USA 100:6198–6203CrossRefGoogle Scholar
  26. Jordt SE, Bautista DM, Chuang HH et al (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265CrossRefGoogle Scholar
  27. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210CrossRefGoogle Scholar
  28. Kobal G, van Toller S, Hummel T (1989) Is there directional smelling? Experientia 45:130–132CrossRefGoogle Scholar
  29. Kobayashi H, Yoshiyama M, Zakoji H et al (2009) Sex differences in the expression profile of acid-sensing ion channels in the mouse urinary bladder: a possible involvement of irritative bladder symptoms. BJU Int 104:1746–1751CrossRefGoogle Scholar
  30. MacPherson LJ, Dubin AE, Evans MJ et al (2007) Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541–545CrossRefGoogle Scholar
  31. Matta JA, Cornett PM, Miyares RL et al (2008) General anesthetics activate a nociceptive ion channel to enhance pain and inflammation. Proc Natl Acad Sci USA 105:8784–8789CrossRefGoogle Scholar
  32. McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58CrossRefGoogle Scholar
  33. McNamara CR, Mandel-Brehm J, Bautista DM et al (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci USA 104:13525–13530CrossRefGoogle Scholar
  34. Peier AM, Moqrich A, Hergarden AC et al (2002) A TRP channel that senses cold stimuli and menthol. Cell 108:705–715CrossRefGoogle Scholar
  35. Peterlin Z, Chesler A, Firestein S (2007) A painful TRP can be a bonding experience. Neuron 53:635–638CrossRefGoogle Scholar
  36. Radil T, Wysocki CJ (1998) Spatiotemporal masking in pure olfaction. Ann NY Acad Sci 855:641–644CrossRefGoogle Scholar
  37. Schaper M (1993) Development of a database for sensory irritants and its use in establishing occupational exposure limits. Am Ind Hyg Assoc J 54:488–544Google Scholar
  38. Silver WL, Clapp TR, Stone LM et al (2006) TRPV1 receptors and nasal trigeminal chemesthesis. Chem Senses 31:807–812CrossRefGoogle Scholar
  39. Spehr J, Spehr M, Hatt H et al (2004) Subunit-specific P2X-receptor expression defines chemosensory properties of trigeminal neurons. Eur J Neurosci 19:2497–2510CrossRefGoogle Scholar
  40. Story GM, Peier AM, Reeve AJ et al (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829CrossRefGoogle Scholar
  41. Symanowicz PT, Gianutsos G, Morris JB (2004) Lack of role for the vanilloid receptor in response to several inspired irritant air pollutants in the C57Bl/6J mouse. Neurosci Lett 362:150–153CrossRefGoogle Scholar
  42. Talavera K, Maarten G, Karashima Y et al (2009) Nicotine activates the chemosensory cation channel TRPA1. Nat Neurosci 12:1293–1299CrossRefGoogle Scholar
  43. Tizzano M, Gulbransen BD, Vandenbeuch AV et al (2010) Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci USA 107:3210–3215CrossRefGoogle Scholar
  44. Tucker D (1971) Nonolfactory responses from the nasal cavity: Jacobson’s organ and the trigeminal system. In: Beidler LM (ed) Handbook of sensory physiology, vol IV. Chemical senses. Springer-Verlag, BerlinGoogle Scholar
  45. van Thriel C, Schaper M, Kiesswetter E et al (2006) From chemosensory thresholds to whole body exposures—experimental approaches evaluating chemosensory effects of chemicals. Int Arch Occup Environ Health 79:308–321CrossRefGoogle Scholar
  46. Vijayaraghavan R (1993) Characteristic modifications of the breathing pattern of mice to evaluate the effects of airborne chemicals on the respiratory tract. Arch Toxicol 67:478–490CrossRefGoogle Scholar
  47. Wang YY, Chang RB, Liman ER (2010) TRPA1 dependent detection of CO2 by nociceptors: CO2 sensing by TRPA1. J Neurosci (in press)Google Scholar
  48. Xiao B, Dubin AE, Bursulaya B et al (2008) Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels. J Neurosci 28:9640–9651CrossRefGoogle Scholar
  49. Yang BH, Piao ZG, Kim YB et al (2003) Activation of vanilloid receptor 1 (VR1) by eugenol. J Dent Res 82:781–785CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2010

Authors and Affiliations

  • Paige M. Richards
    • 1
  • Erik C. Johnson
    • 1
  • Wayne L. Silver
    • 1
  1. 1.Department of BiologyWake Forest UniversityWinston-SalemUSA

Personalised recommendations