Chemical Senses Advance Access published online on June 14, 2007
Chemical Senses, doi:10.1093/chemse/bjm038
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A Quantitative Structure–Activity Analysis on the Relative Sensitivity of the Olfactory and the Nasal Trigeminal Chemosensory Systems
1 Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK 2 Chemosensory Perception Laboratory, Department of Surgery (Otolaryngology), University of California, San Diego, La Jolla, CA 92093-0957, USA
Correspondence to be sent to: Michael H. Abraham, Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK. e-mail: m.h.abraham{at}ucl.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResults and discussionConclusionFundingReferences |
|---|
We have applied a quantitative structure–activity relationship (QSAR) approach to analyze the chemical parameters that determine the relative sensitivity of olfaction and nasal chemesthesis to a common set of volatile organic compounds (VOCs). We used previously reported data on odor detection thresholds (ODTs) and nasal pungency thresholds (NPTs) from 64 VOCs belonging to 7 chemical series (acetate esters, carboxylic acids, alcohols, aliphatic aldehydes, alkylbenzenes, ketones, and terpenes). The analysis tested whether NPTs could be used to separate out "selective" chemosensory effects (i.e., those resting on the transfer of VOCs from the gas phase to the receptor phase) from "specific" chemosensory effects in ODTs. Previous work showed that selective effects overwhelmingly dominate chemesthetic potency whereas both selective and specific effects control olfactory potency. We conclude that it is indeed possible to use NPTs to separate out selective from specific effects in ODTs. Among the series studied, aldehydes and acids, except for formic acid, show clear specific effects in their olfactory potency. Furthermore, for VOCs whose odor potency rests mainly on selective effects, we have developed a QSAR equation that can predict their ODTs based on their NPTs.
Key words: chemesthetic QSAR, mechanism of biological activity, nasal chemosensory sensitivity, nasal irritation thresholds, odor detection thresholds, olfactory QSAR, VOCs
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionConclusionFundingReferences |
|---|
Humans rely principally on 2 chemosensory systems to detect airborne chemicals: olfaction and chemesthesis. The sense of smell is restricted to the nasal cavity and mediated by the olfactory nerve. In contrast, chemesthesis (Bryant and Silver 2000
), or chemical feel, is present in all mucosae, also in the skin under the epidermis (Keele 1962), and is mediated by a variety of nerves, depending on the location of stimulation. Due to their direct exposure to the air, we breathe and that surrounds us, the nasal and the ocular mucosa are common sites of chemesthetic stimulation (Doty et al. 2004). Nasal chemesthesis includes sensations such as stinging, freshness, prickling, piquancy, tingling, irritation, burning and the like, which, due to their sharp nature, we group together under the term nasal pungency. Chemesthesis in both sites is mediated by the trigeminal nerve, see review in Doty and Cometto-Muñiz (2003). In the present paper, we will focus on the comparative sensitivity of olfaction and nasal chemesthesis toward volatile organic compounds (VOCs), using a quantitative structure–activity relationship (QSAR) approach.
Odorants reaching the lumen above the olfactory epithelium transfer from the gas phase into the mucus phase and they continue to be distributed among the various biophases until they reach the olfactory receptors (ORs) (Rawson and Yee 2006) in the membrane of the cilia of olfactory sensory neurons (Schwarzenbacher et al. 2005; Flannery et al. 2006). ORs belong to the large family of G-protein–coupled receptors (Breer 2003; Liman 2006). In humans, there are about 388 genes coding for functional ORs and about 414 pseudogenes that do not code for functional ORs (Niimura and Nei 2006). Each odorant is believed to activate a specific pattern of ORs (Malnic et al. 1999).
Irritants entering the nasal cavity also transfer from the gas phase into the mucus and other biophases until they reach chemesthetic receptors in free nerve endings of the trigeminal nerve (Finger et al. 1990), particularly from C and Adelta fibers. Trigeminal chemoreceptors include vanilloid (Tominaga M and Tominaga T 2005; Silver et al. 2006), nicotinic acetylcholine (Thuerauf et al. 1999, 2006; Alimohammadi and Silver 2000), and menthol (Kobayashi et al. 2005; Damann et al. 2006) receptors. Capsaicin, menthol, and a variety of pungent compounds stimulate sensory nerve fibers via activation of members of a family of transient receptor potential channels (Trevisani et al. 2002; Jordt et al. 2004; Macpherson et al. 2005, 2006) that includes about 30 members (Montell 2005; Ramsey et al. 2006). These and other receptors and mechanisms (Inoue and Bryant 2005), including cell damage by reactive VOCs and consequent release of nociception mediators (Sutherland et al. 2000), could play a role in nasal chemesthesis as evoked by common VOCs, including alcohols, esters, ketones, alkylbenzenes, aldehydes, etc. (Cometto-Muñiz 2001).
In the main, VOCs that can evoke irritation can also evoke odor. A previous separate QSAR analysis on nasal pungency thresholds (NPTs) (Abraham et al. 1998) and odor detection thresholds (ODTs) (Abraham et al. 2002) revealed that "selective" processes (e.g., transfer driven effects in which small structural changes in the VOC evoke predictable, and rather small, changes in biological activity) overwhelmingly dominate chemesthetic detection, whereas both selective and "specific" processes (e.g., effects in which small structural changes in the VOC may evoke less predictable, and often large, changes in biological activity) control olfactory potency. To understand further the nature of the chemical factors that influence ODT values, we have explored here the possibility that NPT values could be used to estimate selective effects in ODTs, thus producing a tool to assess the weight of the remaining specific (VOC-receptor) effects. The topic opens the window to ponder why certain chemical families or particular compounds (and which ones) could have driven the need for a more specialized and sensitive chemoreception in humans. The present study involves data on 64 VOCs from various chemical series. The compounds are listed in our previous separate QSAR analysis of odor (Abraham et al. 2002) and nasal pungency (Abraham et al. 1998) thresholds. However, we give in Table 1 an updated list. In the next section, we describe the QSAR model and illustrate further the meaning of the terms selective and specific within the present context.
|
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionConclusionFundingReferences |
|---|
Both odor and nasal pungency involve the transfer of a compound, for example, a VOC, from an air stream through a mucus layer into a receptor or receptor area. This environment is likely to be inhomogeneous, being partly a hydrophobic lipid-like area and partly a hydrophilic aqueous-like area. We have previously developed an equation, equation (1), that seems to be very satisfactory for the correlation and explanation of the transfer of VOCs from the gaseous phase to a large number of solvents or other condensed phases, including biophases (Abraham 1993
; Abraham et al. 2006a, 2006b, 2007).
 | (1) |
). Briefly, E is the excess molar refraction, S is the dipolarity/polarizability, and A and B are the overall or effective hydrogen bond acidity and basicity, respectively, of the VOC. L(log L16) is defined through L16, the VOC gas-hexadecane partition coefficient at 298 K, and is a measure of the lipophilicity of the VOC. In turn, the regression coefficients are not merely fitted coefficients because they define the complementary physicochemical properties that characterize the receptor environment or biophase most receptive to the VOC (Abraham 1996). SP is either a physicochemical property of a VOC, such as log K where K is the gas to solvent partition coefficient for a series of VOCs into a given solvent or condensed phase, or a biological property of a VOC, such as an odor or NPT for a series of VOCs (Abraham et al. 2001).
When equation (1) was applied to NPTs, as log(1/NPT), a very good correlation that accounted for more than 95% of the total effect was obtained (Abraham et al. 1998). This strongly suggests that the factors that influence NPTs are those that influence the transfer of VOCs from the gas phase to condensed phases, that is from the gas phase to the receptor phase, and that other effects are of secondary importance. However, when equation (1) was applied to ODTs, as log(1/ODT), a much poorer correlation was found (Abraham et al. 2002). Only by excluding families of compounds such as the aldehydes and carboxylic acids or by assigning a special descriptor to these families could a satisfactory correlation be obtained. Structural effects in transfer-type processes are invariably selective, in that different VOCs are transported from the gas phase to condensed phases with different equilibrium constants that do not vary greatly with small changes in structure. The poor correlation observed for log(1/ODT) values suggests that they are partly influenced by transfer from the gas phase to the receptor phase and are partly influenced by some type of specific effects.
In order to obtain more information on the factors that influence ODT values, we now explore the possibility that NPT values could be used to estimate the selective factors, that is to separate out the selective transport-related effects and to leave only the specific effects. The present study involves data on 64 VOCs from various chemical series. The compounds are listed in our previous separate QSAR analysis of odor (Abraham et al. 2002) and nasal pungency (Abraham et al. 1998) thresholds.
|
Results and discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionConclusionFundingReferences |
|---|
ODTs and NPTs were correlated against Abraham's descriptors, using equation (1). The aim was to obtain a similar equation for both sets of data to make possible a comparison between them. To do so, compounds that were outliers in the equation for ODT, that is aldehydes and carboxylic acids, were left out in both cases. In addition, 4 compounds that were outliers in the ODT equation and which might act through specific effects were omitted, viz: propanone, methyl acetate, tert-butyl acetate, and 1-octanol. Only the Abraham descriptors from equation (1) were used, without including any extra descriptor, or indicator variable. The resulting equations are
 | (2) |
 |
 | (3) |
 |
We then regressed the observed values of log(1/ODT) against Clog(1/NPT) for the VOCs that we suggest act by selective effects only and obtained equation (4).
 | (4) |
If the A descriptor is used as another independent variable, the regression improves slightly, as shown in equation (5).
 | (5) |
Both equations (4) and (5) reproduce the values of log(1/ODT) as well as does the full equation (2), for selectively acting VOCs. We can then use either equation as a "baseline" for selective effects and can identify compounds that yield ODTs through a combination of selective and specific effects. This is illustrated in Figure 1, where we plot log(1/ODT) values for the 50 VOCs used in equations (4) and (5), plus aldehydes and acids, against calculated values from equation (5). The 5 aldehydes are more potent than calculated by an average of 1.7 log units, and the acids (excluding formic acid) by an average of 3.0 log units. These are our estimates of the specific effect of the 2 series of VOCs. In our previous analysis of ODTs (Abraham et al. 2002), we were able to accommodate aldehydes and acids into general equations by adding an indicator variable that increased the potency of these compounds by 1.6 or 2.0 log units, depending on the exact form of the equation; the increased potency was for an average for the aldehydes and acids taken together. The present results for aldehydes and acids taken separately is in line with our previous analysis, but, we suggest, affords a much better estimate of the specific effect on ODTs.
|
and acids 
. The regression line is for the selective compounds.We can be reasonably sure that the aldehydes and acids provoke ODT through extra specific as well as selective effects because we have data for several other series for which we can calculate deviations from equation (5). We give in Table 2 values of the average error (AE), the absolute average error (AAE), and the SD of the observed and calculated values for the various series. The key statistics are AE and AAE. The AE denotes deviation from equation (5), either in a positive or negative sense {AE = (calculated – observed values)/N, where N is the number of data points}. If AE and AAE are compared, it is then possible to deduce whether a given value of AE is due to random deviations or systematic deviations from equation (5). For the first 4 series, the AE values are very small, so that there are no systematic deviations. The numerically larger AAE values then represent random deviations, as do the corresponding SD values. These range from 0.33 to 0.77 log units in accord with the SD value of 0.57 log units in equation (5). However, for the aldehydes and acids, AE is identical to AAE—all the deviations are of the same sign and are then systematic and not random. The SD value for the aldehydes is 3.6 times the SD in equation (5) and for the acids is 6.3 times the SD, so that the deviations from equation (5) are very large indeed. It is these systematic, not random, deviations from equation (5) that lead us to conclude that aldehydes and acids exert effects on ODTs through a combination of specific and selective effects.
|
We have used the term specific effects to describe the observation that aldehydes and acids are much more potent as regard ODTs than we calculate from our QSAR analysis. The nature of these specific effects is not obvious. They may be due to specific VOC-receptor interactions, but other possibilities exist. For example, it has been shown that odor-binding proteins (OBPs) have a high affinity for aldehydes and acids (Tcatchoff et al. 2006
). Although the role of OBPs is not clear, we cannot exclude the possibility that aldehydes and acids are preferentially transported to the odor receptors. For individual VOCs, the position is not that straightforward. Of the 4 outliers that we have identified for ODTs, 1-octanol (2.15 obs, 0.41 calc) and tert-butyl acetate (–0.11 obs, –1.49 calc) are more potent than calculated through equation (5), but whether these effects are due, for example, to specific VOC-receptor interactions, rather than to error in either the ODT determinations or the descriptors is difficult to assess. Both methyl acetate (–3.46 obs, –2.06 calc) and propanone (–4.07 obs, –2.02 calc) are much less potent than calculated through equation (5); this cannot be due to any (extra) specific effect at all and suggests that there are some factors that still need to be accounted for.
Now that we have used Clog(1/NPT) values to determine the specific effect of aldehydes and acids on ODT values, we can revert to log(1/NPT) values themselves in order to obtain a correlation between observed ODT values and observed NPT values for compounds that exert their influence through selective effects.
 | (6) |
 | (7) |
). In addition, knowing the identity of these particularly powerful odorants can provide clues on the evolutionary factors that have driven the sense of smell to carve an enhanced sensitivity toward them (Niimura and Nei 2006).
|
Finally, we can ask why we are able to use nasal pungency thresholds as a base line for selective effects in another biological end point altogether. Possible biological mechanisms of action of VOCs have been set out (Abraham et al. 1994
) and we show in Figure 3 the "2-stage" mechanism that was suggested. In the first stage, the VOC is transferred from the vapor phase to a receptor phase or receptor area, and in the second stage, the VOC activates a receptor. Now transfer from the vapor phase to typical organic phases involves selective effects, not specific effects. Thus if the main step in the mechanism of nasal pungency is the first stage, this would account for structural effects in the VOCs being selective only. We can obtain some information on this by comparing the coefficients in the selective NPT and ODT equations, equations (2) and (3), with those for transfer from the gas phase to various solvents (Hoover et al. 2004; Abraham and Ibrahim 2006b) and biological phases (Abraham 1993; Abraham et al. 2005, 2006a, 2006b, 2007; Abraham and Ibrahim 2006a). Details are in Table 3. The coefficients in these equations for transfer to solvents reflect the chemical properties of the solvent phases, so that the nearer one set of coefficients is to another set, the closer are the chemical properties of the phases. It is rather difficult to assess the closeness of sets of coefficients just by eye, and it is convenient to use principal components analysis. In this method, the 5 columns of coefficients, e to l, are transformed into 5 orthogonal columns of data (5 principal components [PCs]) that contain the same information as the original columns of coefficients. The first 2 PCs contain 80% of the total information, in the present case, and a plot of the scores of PC2 against PC1 will provide a visual estimate of how close are the sets of coefficients. The coefficients for the phases investigated are in Table 3, and the PC plot is shown as Figure 4. The coefficients for the NPT and ODT equations are quite near to each other and to coefficients for transfer from the gas phase to biological phases (brain, muscle, liver) and organic solvents (wet 1-octanol, methanol, ethanol). All these solvents or phases have substantial values of the a and b coefficients. Transfer to all the solvents and biological phases shown in Table 3 involves selective, not specific, structural effects of the VOCs. Hence if the main step in a mechanism involves stage 1, or if only VOCs that act by selective effects are included, it is to be expected that the coefficients in the corresponding equations will be close to some particular solvent or biological phase. This is exactly what we find for the NPT or ODT equations. Of course the mechanism of nasal pungency, or odor, detection thresholds will involve VOCs passing from the gas phase through various layers of materials to the receptor phase (Rawson and Yee 2006). But in an equilibrium situation, the overall equilibrium constant depends only on the concentrations in the initial phase (the gas phase) and the final phase (the receptor phase)—the intermediate phases in this context are irrelevant.
|
|
|
ODT. |
Conclusion |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionConclusionFundingReferences |
|---|
It is possible to separate out specific effects from selective effects in ODTs by the use of NPTs used as an indication of selective chemosensory effects. The main VOCs that show specific effects are the aldehydes and carboxylic acids, except for formic acid. Although this VOC appears "normal," it is possible that this is a fortuitous combination of more than one specific effect. There are other VOCs that appear also to exhibit some specific effects as regard odor thresholds, and we can identify these as follows: 1-octanol, methyl acetate, propanone, and tert-butyl acetate. Whether these VOCs really do exhibit some specific effects, or whether there is some possible experimental error is not clear—these 4 VOCs share no obvious common features. Equation (6) and particularly equation (7) represent excellent predictive methods for ODTs directly from observed nasal pungency detection thresholds. The correlation between NPT and ODT values for compounds that have only selective effects can be explained very satisfactorily by a 2-stage mechanism of biological activity.
|
Funding |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionConclusionFundingReferences |
|---|
National Institute on Deafness and Other Communication Disorders, National Institutes of Health (R01 DC002741, R01 DC005003, and R01 DC05602).
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionConclusionFundingReferences |
|---|
Abraham MH. Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes. Chem Soc Rev (1993) 22:73–83.[CrossRef]
Abraham MH. The potency of gases and vapors: QSARs—anesthesia, sensory irritation, and odor. In: Indoor air and human health—Gammage RB, Berven BA, eds. (1996) 2nd ed. Boca Raton (FL): CRC Lewis Publishers. 67–91.
Abraham MH, Gola JMR, Cometto-Muñiz JE, Cain WS. The correlation and prediction of VOC thresholds for nasal pungency, eye irritation and odour in humans. Indoor Built Environ (2001) 10:252–257.[CrossRef]
Abraham MH, Gola JMR, Cometto-Muñiz JE, Cain WS. A model for odor thresholds. Chem Senses (2002) 27:95–104.
Abraham MH, Ibrahim A. Air to fat and blood to fat distribution of volatile organic compounds and drugs: linear free energy analyses. Eur J Med Chem (2006a) 41:1430–1438.[CrossRef][Web of Science][Medline]
Abraham MH, Ibrahim A. Gas to olive oil partition coefficients: a linear free energy analysis. J Chem Inf Model (2006b) 46:1735–1741.[CrossRef][Web of Science][Medline]
Abraham MH, Ibrahim A, Acree WE Jr. Air to blood distribution of volatile organic compounds: a linear free energy analysis. Chem Res Toxicol (2005) 18:904–911.[CrossRef][Web of Science][Medline]
Abraham MH, Ibrahim A, Acree WE Jr. Air to brain, blood to brain and plasma to brain distribution of volatile organic compounds: linear free energy analyses. Eur J Med Chem (2006a) 41:494–502.[CrossRef][Web of Science][Medline]
Abraham MH, Ibrahim A, Acree WE Jr. Air to muscle and blood/plasma to muscle distribution of volatile organic compounds and drugs: linear free energy analyses. Chem Res Toxicol (2006b) 19:801–808.[CrossRef][Web of Science][Medline]
Abraham MH, Ibrahim A, Acree WE Jr. Air to liver partition coefficients for volatile organic compounds and blood to liver partition coefficients for volatile organic compounds and drugs. Eur J Med Chem (2007) 42:743–751.[CrossRef][Medline]
Abraham MH, Ibrahim A, Zissimos AM. Determination of sets of solute descriptors from chromatographic measurements. J Chromatogr A (2004) 1037:29–47.[CrossRef][Web of Science][Medline]
Abraham MH, Kumarsingh R, Cometto-Muñiz JE, Cain WS. An algorithm for nasal pungency thresholds in man. Arch Toxicol (1998) 72:227–232.[CrossRef][Web of Science][Medline]
Abraham MH, Nielsen GD, Alarie Y. The Ferguson principle and an analysis of biological activity of gases and vapors. J Pharm Sci (1994) 83:680–688.[CrossRef][Web of Science][Medline]
Alimohammadi H, Silver WL. Evidence for nicotinic acetylcholine receptors on nasal trigeminal nerve endings of the rat. Chem Senses (2000) 25:61–66.
Breer H. Olfactory receptors: molecular basis for recognition and discrimination of odors. Anal Bioanal Chem (2003) 377:427–433.[CrossRef][Web of Science][Medline]
Bryant B, Silver WL. Chemesthesis: the common chemical sense. In: The neurobiology of taste and smell—Finger TE, Silver WL, Restrepo D, eds. (2000) 2nd ed. New York: Wiley-Liss. 73–100.
Cometto-Muñiz JE. Physicochemical basis for odor and irritation potency of VOCs. In: Indoor air quality handbook—Spengler JD, Samet J, McCarthy JF, eds. (2001) New York: McGraw-Hill. 20.1–20.21.
Damann N, Rothermel M, Klupp BG, Mettenleiter TC, Hatt H, Wetzel CH. Chemosensory properties of murine nasal and cutaneous trigeminal neurons identified by viral tracing. BMC Neurosci (2006) 7:46.[CrossRef][Medline]
Doty RL, Cometto-Muñiz JE. Trigeminal chemosensation. In: Handbook of olfaction and gustation—Doty RL, ed. (2003) 2nd ed. New York: Marcel Dekker. 981–1000.
Doty RL, Cometto-Muñiz JE, Jalowayski AA, Dalton P, Kendal-Reed M, Hodgson M. Assessment of upper respiratory tract and ocular irritative effects of volatile chemicals in humans. Crit Rev Toxicol (2004) 34:85–142.[CrossRef][Web of Science][Medline]
Finger TE, St Jeor VL, Kinnamon JC, Silver WL. Ultrastructure of substance P- and CGRP-immunoreactive nerve fibers in the nasal epithelium of rodents. J Comp Neurol (1990) 294:293–305.[CrossRef][Web of Science][Medline]
Flannery RJ, French DA, Kleene SJ. Clustering of cyclic-nucleotide-gated channels in olfactory cilia. Biophys J (2006) 91:179–188.[CrossRef][Web of Science][Medline]
Hoover KR, Coaxum R, Pustejovsky E, Stovall DM, Acree WE, Abraham MH. Thermochemical behavior of dissolved carboxylic acid solutes: part 4—mathematical correlation of 4-nitrobenzoic acid solubilities with the abraham solvation parameter model. Phys Chem Liq (2004) 42:339–347.[CrossRef]
Inoue T, Bryant BP. Multiple types of sensory neurons respond to irritating volatile organic compounds (VOCs): calcium fluorimetry of trigeminal ganglion neurons. Pain (2005) 117:193–203.[CrossRef][Web of Science][Medline]
Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature (2004) 427:260–265.[CrossRef][Medline]
Keele CA. The common chemical sense and its receptors. Arch Int Pharmacodyn Ther (1962) 139:547–557.[Web of Science][Medline]
Kobayashi K, Fukuoka T, Obata K, Yamanaka H, Dai Y, Tokunaga A, Noguchi K. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. J Comp Neurol (2005) 493:596–606.[CrossRef][Web of Science][Medline]
Liman ER. Use it or lose it: molecular evolution of sensory signaling in primates. Pflugers Arch (2006) 453:125–131.[CrossRef][Web of Science][Medline]
Macpherson LJ, Geierstanger BH, Viswanath V, Bandell M, Eid SR, Hwang S, Patapoutian A. The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol (2005) 15:929–934.[CrossRef][Web of Science][Medline]
Macpherson LJ, Hwang SW, Miyamoto T, Dubin AE, Patapoutian A, Story GM. More than cool: promiscuous relationships of menthol and other sensory compounds. Mol Cell Neurosci (2006) 32:335–343.[CrossRef][Web of Science][Medline]
Malnic B, Hirono J, Sato T, Buck LB. Combinatorial receptor codes for odors. Cell (1999) 96:713–723.[CrossRef][Web of Science][Medline]
Mizrahi A, Matsunami H, Katz LC. An imaging-based approach to identify ligands for olfactory receptors. Neuropharmacology (2004) 47:661–668.[CrossRef][Web of Science][Medline]
Montell C. The TRP superfamily of cation channels. Sci STKE (2005) 2005:re3.
Niimura Y, Nei M. Evolutionary dynamics of olfactory and other chemosensory receptor genes in vertebrates. J Hum Genet (2006) 51:505–517.[CrossRef][Web of Science][Medline]
PharmaAlgorithms. In: ADME Boxes. Version 3.0 (2006) Toronto (ON): PharmaAlgorithms.
Ramsey IS, Delling M, Clapham DE. An introduction to TRP channels. Annu Rev Physiol (2006) 68:619–647.[CrossRef][Web of Science][Medline]
Rawson NE, Yee KK. Transduction and coding. Adv Otorhinolaryngol (2006) 63:23–43.[Medline]
Schwarzenbacher K, Fleischer J, Breer H. Formation and maturation of olfactory cilia monitored by odorant receptor-specific antibodies. Histochem Cell Biol (2005) 123:419–428.[CrossRef][Web of Science][Medline]
Silver WL, Clapp TR, Stone LM, Kinnamon SC. TRPV1 receptors and nasal trigeminal chemesthesis. Chem Senses (2006) 31:807–812.
Sutherland SP, Cook SP, McCleskey EW. Chemical mediators of pain due to tissue damage and ischemia. Prog Brain Res (2000) 129:21–38.[Medline]
Tcatchoff L, Nespoulous C, Pernollet JC, Briand L. A single lysyl residue defines the binding specificity of a human odorant-binding protein for aldehydes. FEBS Lett (2006) 580:2102–2108.[CrossRef][Web of Science][Medline]
Thuerauf N, Kaegler M, Dietz R, Barocka A, Kobal G. Dose-dependent stereoselective activation of the trigeminal sensory system by nicotine in man. Psychopharmacology (Berl) (1999) 142:236–243.[CrossRef][Medline]
Thuerauf N, Markovic K, Braun G, Bleich S, Reulbach U, Kornhuber J, Lunkenheimer J. The influence of mecamylamine on trigeminal and olfactory chemoreception of nicotine. Neuropsychopharmacology (2006) 31:450–461.[CrossRef][Web of Science][Medline]
Tominaga M, Tominaga T. Structure and function of TRPV1. Pflugers Arch (2005) 451:143–150.[CrossRef][Web of Science][Medline]
Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, Campi B, Amadesi S, Gray J, Jerman JC, Brough SJ, et al. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci (2002) 5:546–551.[CrossRef][Web of Science][Medline]
Accepted 20 April 2007
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||