Chem. Senses 27: 593-598,
2002
© Oxford University Press 2002
Sensitization and Desensitization to Allyl Isothiocyanate (Mustard Oil) in the Nasal Cavity
Laboratoire de Neurosciences, Faculté des Sciences, Université de Franche-Comté, Place Leclerc, 25000 Besançon, France
Correspondence to be sent to: Gerard Brand, Laboratoire de Neurosciences, Faculté des Sciences, Université de Franche-Comté, Place Leclerc, 25000 Besançon, France. e-mail: gerard.brand{at}univ-fcomte.fr
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Abstract |
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The aim of this study was to investigate the response, acute effects and time-course of sensitization and desensitization to allyl isothiocyanate (mustard oil) nasal stimuli in healthy subjects. Sixty subjects participated in the experiment, which employed psychophysical (intensity ratings) and psychophysiological (skin conductance response) measurements. Nasal stimuli were delivered three times with different inter-stimulus intervals. The results showed that the psychophysical and psycho-physiological data were correlated and that the successive nasal stimuli after a short period of time (<2 min) produced increased intensity of irritation, whereas the stimuli delivered after >3 min produced a markedly decreased intensity of irritation. These findings are in agreement with those obtained with capsaicin, the most frequently used irritant molecule.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Trigeminal sensitivity has been investigated for a long time. Parker (Parker, 1912
) using the term
`common chemical sense', was the first to recognize that the sense of
irritation produced by chemical stimuli was distinct from olfaction and
gustation. Subsequently, many investigations have described several aspects
and characteristics of chemical irritation
(Green et al., 1990).
One question which remains without a definitive response concerns the
differential responses produce by repetitive stimulation. Indeed, the
intensity of irritation varies according to the inter-stimulus intervals
(ISIs) and the nature of chemical stimuli
(Cain, 1990). Repeated stimuli
with odors and tastes typically show a reduction in rated stimulus intensity
if the ISI is brief. In contrast, trigeminal stimuli can produce increases in
rated intensity during repeated stimulation with short ISI, a phenomenon known
as sensitization. Moreover, if the ISI is long the intensity markedly
decreases, a phenomenon known as desensitization. Sensitization and
desensitization by a chemical irritant have been principally investigated on
the cutaneous receptors and the tongue. The first psychophysical evidence of
such an effect in the oral cavity came from Stevens and Lawless
(Stevens and Lawless, 1987),
who observed that when an irritant (capsaicin or piperine) was presented twice
within a short interval, the second presentation produced a more intense
sensation than the first. Others (Green
and Gelhard, 1989) subsequently showed that when moderate
concentrations of NaCl were presented at 1 min intervals, the sensations
caused by salt increased regularly over a 15 min period. The authors noted the
similarity between these sequential effects and the phenomenon of
sensitization that occurs when polymodal nociceptors are subjected to intense
thermal stimulation or to a chemical irritant. However, sensitization cannot
be produced by irritants such as ethanol, which produce a nearly constant
sensation of irritation following successive stimuli, but the irritation
generated by an ethanol stimulus was greatly increased following a NaCl
stimulus (Green, 1990). The
cross-sensitization between NaCl and ethanol suggests that the two chemicals
stimulate many of the same sensory fibers. Contrasting the effect of chemical
sensitization is chemical desensitization. This phenomenon was reported in the
oral cavity with capsaicin when a subsequent stimulus was delivered after the
initial presentation (Green,
1989). The interval between conditioning and test stimulus had to
be >2.5 min but not longer than 5 min for desensitization to begin to
occur. Few studies have dealt with the question of
sensitization/desensitization by chemical irritants in the nasal cavity, but
it would appear that the publications over the last few years have been trying
to address this (Hummel,
2000).
In the nose, olfactory receptors (CN I) positioned in the upper recesses of
the nasal cavity coexist with free nerve endings of the ophthalmic and
maxillary divisions of the trigeminal nerve (CN V) distributed throughout the
nasal mucosa and olfactory epithelium
(Lang, 1989). Sensations
derived from the trigeminal nerve are somatosensory and include pain
sensations, burning, stinging, itching, tickling, cooling, warming and the
perception of atmospheric humidity
(Proctor and Andersen, 1982;
Kelly and Dodd, 1991). Two
major fiber systems, C-fibers (unmyelinated) and Adelta-fibers
(myelinated) participate in the afferent chemo-sensitive innervation of the
nasal respiratory epithelium (Anton and
Peppel, 1991; Sekizawa and
Tsubone, 1994). Both fibers are activated by the intracellular
accumulation of protons which modify the membrane conductance
(Steen et al., 1995).
However, C-fibers are preferentially involved in the mediation of burning
sensations and Adelta-fibers preferentially in stinging sensations
(Mackenzie et al.,
1975). Moreover, it is well known that responses mediated by
C-fibers and Adelta-fibers differ when exposed to repeated stimuli
(Price, 1972;
Price et al., 1977).
At short intervals, burning sensations increase due to a summation (central
nervous summation of the successive inputs related to C-fiber afferent
stimulation), whereas no such summation has been reported for stinging
sensations which decrease in relation to the desensitization of
Adelta-fibers.
In the nasal cavity, the most frequent molecule used in the field of
sensitization/desensitization is capsaicin
(Prescott, 1999), the pungent
ingredient of red peppers. In humans, psychophysical studies with capsaicin
have shown sensitization when a second stimulus was delivered shortly after
(<1 min) the first stimulus. In contrast, when the second stimulus was
delivered >3-4 min later, it produced desensitization
(Sicuteri et al.,
1989). Some pungent substances presenting the same activation as
capsaicin have been identified and one of them could be mustard oil. As with
capsaicin, mustard oil (allyl isothiocyanate) is widely used as a flavoring
agent in a variety of foods in numerous countries. Allyl isothiocyanate can be
prepared from the seeds of mustard plants, Brassica nigra or
Brassica juncea and synthetic allyl isothiocyanate has been produced
commercially since 1937. Allyl isothiocyanate applied on the skin leads to a
clear burning sensation (Magerl et
al., 1990) and has been found to activate all the cutaneous
receptors and predominantly excite C-fiber afferents in the upper skin layers
(Handwerker et al.,
1991). The toxicity of allyl isothiocyanate evaluated in animals
appears to be low (Jenner et al.,
1964) and carcinogenic data have indicated that there is no
evidence of incidence (Ioannou et
al., 1984).
The aim of the present work was to investigate the response, acute effects
and time-course of sensitization/desensitization to mustard oil (allyl
isothiocyanate) volatile nasal stimulation in healthy subjects during normal
breathing. From a methodological point of view, the study tested how intensity
ratings and skin conductance response (SCR) amplitudes could be modified by
repetitive stimuli of the intranasal trigeminal nerve when stimuli are
presented at different ISIs at the same concentration. The most widely
reported method of assessing sensitization/desensitization in humans has been
to use psychophysical tests (Green and
Lawless, 1991). The present work added SCR recording, because it
was considered to be a reactivity measure in terms of arousal and affect or
basic emotion. Skin conductance response (related to the autonomic nervous
system) has long been used to assess the level of arousal during specific
tasks or stimuli, especially sensory stimuli, including nasal stimuli (Brand
et al., 1999,
2000;
Brand and Millot, 2000). In
this field, Brauchli et al.
(Brauchli et al.,
1995) showed higher autonomic arousal in response to unpleasant
versus pleasant odorants and, more recently, it has been postulated
(Alaoui-Ismaïli et al.,
1997a) that autonomic analysis can distinguish among pleasant
odorants and those with a trigeminal component. Finally, the reliability of
both measures validates the subjective psychophysical estimation
(Alaoui-Ismaïli et al.,
1997b).
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Materials and methods |
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Subjects
A sample of 60 female volunteer students participated in this experiment. Their ages ranged from 19 to 27 years (mean age 23 years 5 months). All subjects were dextrals, non-smokers and reported normal smell and taste sensitivity; none of them had a history of nasal/sinus disease or extensive exposure to chemicals with potential olfactory or trigeminal toxicity. The study was conducted in accordance with the Declaration of Helsinki/Hong Kong.
Nasal stimuli
The nasal stimulus was allyl isothiocyanate (C4H5NS,
mol. wt 99.15) diluted in mineral oil. The concentration used was 25%, in a
suprathreshold higher than the standardized detection thresholds
(Devos et al., 1990).
The nasal stimulus in liquid form was presented in a bottle (7.5 cm high, 1 cm
in diameter at the opening) filled with 4 ml of liquid. The bottle was
presented three times to the subject during a limited period of 2 s (one
inspiration) at a distance of 1 cm from both nostrils using a holder to avoid
any olfactory or thermic interference from the experimenter's hand.
Three groups (A, B, C) of 20 subjects were constituted. For each group, a 30 s constant ISI (± 3 s) was used between the first and the second stimuli. ISIs between the second and the third stimuli were 1 min 30 s (± 3 s) for group A, 2 min 30 s (± 3 s) for group B and 3 min 30 s (± 3 s) for group C.
Procedure
The subjects were seated in a comfortable armchair in a quiet room (room temperature ranged from 20 to 22°C). Before the experiment, a control auditory stimulation (440 Hz, 60 dB, 1 s) was used for the dial readings and adjustment of the baseline in order to zero the GSR amplifier. Then, visual cues were excluded by a blindfold and auditory cues were excluded by a soundproof helmet. Additionally, the breathing cycle (mouth open) of the subjects was recorded with a Minigraph Lafayette instrument (Model 76107 equipped with pneumo bellows) and monitored to present the nasal stimulus at the outset of inspiration and to check that the inspiration amplitude did not change during the experiment. Ocular and oral irritations were excluded by the fact that the eyes and the mouth were closed. There was no evidence of a cutaneous irritation in so far as the procedure excluded contact between the liquid and the skin and no subject reported irritation.
The session began with a rest period of 5 min duration. The whole session
lasted 
20 min and was carried out between 10:00 a.m. and 12:00 noon.
After the experiment (so as not to disturb the SCR recordings), the subjects were asked to note the intensity of the last two stimuli on a scale ranging from 0 to 100 units (0, not perceived; 100, very high), in comparison with the first stimulus, graded 50, in order to have the same initial reference for all the subjects and the same rating either below or above this initial value.
SCR recordings
The SCR, expressed in microSiemens (µS), was recorded from the right hand with a MacLab system (GSR amplifier; ADInstruments) interfaced with a Macintosh computer. The GSR amplifier provided a low constant-voltage AC excitation (22 mV at 75 Hz). Skin preparation consisted of washing the hands in soapy water, followed by rinsing and thorough drying. The dry, bright-plated (no special electrolytes were needed) bipolar electrodes were attached with a Velcro attachment strap to the palmar surfaces of the middle phalanges of the first and second fingers of the right hand. When the electrodes were in position, the subject was told not to move and asked to relax to establish good baseline conductivity.
Data analysis
According to the classical recommendations
(Fowles et al.,
1981), SCR data were as follows: phasic stimulus-elicited SCR
amplitudes referring to the first response were 
0.02 µS, with a minimal
slope of 0.01 µS/s which occurred within an interval of 0.5-4 s after the
onset of the stimulus. For each of the observed SCR following the stimulation,
the compound response was scored from the inflection point to peak. If more
than one response occurred in the interval (0.5-4 s), only the first was
scored. The observations of a response occurring during a modified inspiration
were excluded.
Data for the three groups were statistically evaluated with a computer program (Statview II) using analysis of variance (ANOVA) with repeated measures. Post hoc analyses following significant ANOVA effects were conducted using Scheffe tests. The arithmetic mean and the standard deviation (SD) were noted.
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Results |
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An example of SCR amplitude recordings related to ISIs, for a subject of group A and a subject of group C, is given in Figure 1 and the results of SCRs and of intensity ratings are reported in Figure 2.
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For group A, the ANOVA yielded significant differences for the SCR amplitude [F(2,18) = 22.89, P < 0.0001] and for the intensity rating [F(2,18) = 61.27, P < 0.0001].
SCR amplitude
Scheffe post hoc tests showed that the second stimuli (mean = 2.888, SD = 1.11) produced significantly higher SCR amplitudes [F = 16.07, P < 0.01] than the first stimuli (mean = 1.946, SD = 0.94). In the same way, the third stimuli (mean = 2.856, SD = 1.04) produced significantly higher SCR amplitudes [F = 18.21, P < 0.001] than the first.
Intensity rating
Scheffe post hoc tests showed that the intensity rating during the second stimuli (mean = 78.4, SD = 13.7) was significantly higher than the first stimuli graded 50 [F = 76.38, P < 0.0001]. In the same way, the intensity rating during the third stimuli (mean = 73.5, SD = 11.8) was significantly higher than the first [F = 50.71, P < 0.0001].
No differences were statistically significant between the second and the third stimuli for either SCR or intensity rating measures. The psychophysical and psychophysiological data were significantly correlated during the second (r = 0.787) and the third (r = 0.724) stimuli.
For group B, the ANOVA yielded significant differences for SCR amplitude [F(2,18) = 19.87, P < 0.0001] and for the intensity rating [F(2,18) = 48.25, P < 0.0001].
SCR amplitude
Scheffe post hoc tests showed that the second stimuli (mean = 3.025, SD = 1.18) produced a significantly higher SCR amplitude [F = 13.556, P < 0.01] than the first stimuli (mean = 2.203, SD = 0.85) and than the third stimuli [mean = 2.226, SD = 0.82; F = 15.11, P < 0.01].
Intensity rating
Scheffe post hoc tests showed that the intensity rating during the second stimuli (mean = 76.3, SD = 14.8) was significantly higher than the first stimuli graded 50 [F = 54.56, P < 0.0001], as well as the third stimuli [mean = 52.3, SD = 19.2; F = 35.23 P < 0.0001].
No differences were statistically significant between the first and the third stimuli for either SCR or intensity rating measures. The psychophysical and psychophysiological data were significantly correlated during the second (r = 0.809) and the third (r = 0.709) stimuli.
For group C, few subjects produced scorable SCR data during the third stimuli: 14 of the 20 subjects presented no SCR responses and the maximum SCR amplitude was 0.58 µS (mean = 0.371, SD = 0.19). In the same way, 12 of the 20 subjects noted intensity ratings as 0 for the third stimuli (mean = 16.4, SD = 5.71). Consequently, the data were not appropriate for repeated measures analysis. For SCR amplitude, a t-test between the data of the first (mean = 1.946, SD = 0.94) and the second stimuli (mean = 2.844, SD = 1.32) showed significant differences (t = 5.95, P < 0.001). For the intensity ratings, a t-test between the data of the first stimuli graded 50 and the second stimuli (mean = 76.5, SD = 15.1) showed significant differences (t = 8.45, P < 0.0001). The psychophysical and psychophysiological data were significantly correlated during the second stimuli (r = 0.791).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Firstly, the results of the present study indicate that mustard oil (allyl isothiocyanate) nasal stimuli produced an increase and a decrease in both intensity ratings and SCR amplitudes in relation to the ISIs. Specifically, in the present work allyl isothiocyanate induced a response which increased when delivered repeatedly at 30 s or 1 min 30 s intervals (sensitization), but then decreased markedly following a 3 min 30 s rest period (self-desensitization). The time-course of self-sensitization and self-desensitization for allyl isothiocyanate presented similar properties to those previously established for capsaicin (Stevens and Lawless, 1987
; Green, 1989;
Green and Lawless, 1991),
piperine (Stevens and Lawless,
1987) and NaCl (Green and
Gelhard, 1989). A recent study
(Prescott and Swain-Campbell,
2000) showed a high degree of inter-subject variability in oral
capsaicin irritation. As well, inter-subject variability could be further
explored in nasal trigeminal sensitization. The findings of the present work
are in agreement with those obtained using other techniques, such as
event-related potentials (Hummel and
Kobal, 1999) and functional magnetic resonance imaging
(Yousem et al.,
1997), which showed that habituation occurred with repeated
testing of olfactory nerve-mediated odorants, while differential responses
occurred with repeated exposure to odors that also stimulated the trigeminal
nerve in relation to ISIs.
The findings of this study are relevant because, as with capsaicin
(Green, 1989) or nicotine
(Hummel et al., 1992;
Greiff et al., 1993),
allyl isothiocyanate evokes a burning sensation. This suggest that, from a
neurophysiological point of view, mustard oil, as with other irritants such as
capsaicin, could strongly activate C-fibers (preferentially involved in the
mediation of burning sensations) in so far as most Adelta-afferents
adapt during sustained painful stimulation
(Adriaensen et al.,
1983). A neurophysiological explanation of the afferent nerve
fiber response activation is known for capsaicin
(Holzer, 1991;
Wang et al., 1998),
but it has not yet been established for allyl isothiocyanate. Further research
dealing with this question is needed to understand the mechanisms of
sensitization/desensitization with allyl isothiocyanate and, more
particularly, cross-sensitization and cross-desensitization. For example, in
the human nasal cavity it has been demonstrated that desensitization by
capsaicin decreased irritation by citric acid (Gepetti et al., 1993).
In this field, different irritant stimuli could be used to delineate the role
of molecular receptors and different cellular mechanisms related to
sensitization and desensitization with allyl isothiocyanate in relation to the
ISI.
Secondly, the results of the present study showed that the psychophysical
and psychophysiological data were significantly correlated in each
experimental condition. This fact could be typical of trigeminal activation in
the nasal cavity. Indeed, in a first experiment Brand et al.
(Brand et al., 2000)
showed differences in the SCR amplitude in relation to the odorant, i.e.
higher amplitude in response to unpleasant versus pleasant odorant, whereas
the intensity was similar for both odorants. More recent work
(Brand et al., 2002)
showed differences in the SCR amplitude in relation to the trigeminal
component of the nasal stimulus, i.e. higher amplitude in response to nasal
stimulus with high trigeminal stimulation versus nasal stimulus with low
trigeminal stimulation, whereas (in the birhinal condition) the intensity was
similar for both stimuli. The correlation between intensity self-rating and
level of autonomic activation could be explored further in relation to the
specificities of the intranasal trigeminal system, which mediates a relatively
limited spectrum of sensations (compared to the large number of different
odors mediated by the olfactory system) and projects differently into the
cortical pathways. More particularly, the olfactory system projects directly
into the limbic system and it is well known that the perception (including
intensity perception) is strongly linked to the emotional treatment of
olfactory information (Alaoui-Ismaïli et al.,
1997a,
b). In the same way as
autonomic analysis can distinguish between pleasant/unpleasant odorants, it
can be postulated that autonomic analysis can distinguish among nasal stimuli
which preferentially stimulate the olfactory or the trigeminal system.
Thirdly, from a methodological point of view, these findings are relevant
because general studies in olfaction have frequently used odorants which
stimulate both the olfactory nerve and the trigeminal nerve in the nasal
cavity (Cain, 1976;
Doty et al., 1978;
Cain and Murphy, 1980;
Brand and Jacquot, 2001).
Usually, the recording procedures are based on averaging the reactions to
repeated stimuli. Moreover, even most volatile organic compounds can elicit
odor sensation at low concentrations and pungency at higher concentrations
that represent the recruitment of chemesthesis via the stimulation of the
trigeminal nerve. Thus, the ISI used in experimental sessions could be
adjusted in relation to the trigeminal component of the intrasal stimulus.
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Accepted May 3, 2002
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