Chemical Senses Vol. 30 No. suppl 1 © Oxford University
Press 2005; all rights reserved
Lingual Heat and Cold Sensitivity Following Exposure to Capsaicin or Menthol
The John B. Pierce Laboratory and Department of Surgery (Otolaryngology), Yale University School of Medicine, New Haven, CT 06519, USA
Correspondence to be sent to: Barry G. Green, e-mail: green{at}jbpierce.org
Key words: capsaicin, desensitization, menthol, psychophysics, temperature
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Introduction |
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Capsaicin and menthol are the most extensively studied of all chemesthetic agents. Capsaicin is best known as a nociceptive stimulus and menthol as an artificial cooling agent, but both have a combination of thermal and nociceptive properties. Capsaicin can affect perception of nonpainful warmth and heat as well as burning pain and menthol can induce burning and stinging as well as cold. However, few studies have investigated capsaicin’s effects on temperature perception (Green, 1986b
) and only recently have psychophysical reports
of irritation from menthol (Green,
1992;
Dessirier et al., 2001) been
substantiated by evidence that it stimulates nociceptors as well as low-threshold cold
fibers (Okazawa et al.,
2004;
Wasner et al., 2004).
The identification of separate transient receptor protein (TRP) gated channels
sensitive to capsaicin and menthol has further increased interest in these chemicals.
TRPV1 is sensitive to capsaicin, heat and protons (Caterina et al., 1999) and has been localized in
taste papillae as well as other oral tissue (Ishida et al., 2002;
Kido et al., 2003). TRPM8 is
sensitive to menthol (McKemy et al.,
2002;
Peier et al., 2002) and is
assumed to be the primary receptor for innocuous cold. However, its high threshold
(<30°C) and recent evidence that it is sometimes co-expressed with TRPV1
(Okazawa et al., 2004)
leaves open the possibility that TRPM8 is expressed on some nociceptors as well.
Psychophysical studies of the effects of menthol and capsaicin on temperature
perception have yielded a complicated array of interactions. In the first study of
menthol’s oral thermal effects (Green,
1985), brief (5 s) exposures to L-menthol in water enhanced
perceived warmth but failed to enhance perceived cold. However, pre-exposure to
L-menthol not only led to the expected enhancement of cooling but also to a
suppression of warmth. Two later studies replicated the suppressive effect of warmth on
the lip (Green, 1986a) and forearm
(Green, 1992). On the other hand,
capsaicin has been shown to enhance warmth during transient oral exposures (Green, 1986b) and to suppress warmth following
repeated applications to the skin that are sufficient to induce self-desensitization
(Simone and Ochoa, 1991). What was
unclear in all of these studies was whether the reduced heat perception from the two
chemicals resulted from effects on warm receptors, nociceptors, or both.
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Experimental design |
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TopIntroductionExperimental designResultsDiscussionAcknowledgementsReferences |
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The present study was intended to answer this question by measuring the effects of menthol and capsaicin pre-treatments on nociceptive (i.e. burning, stinging) sensations as well as warmth and cold. Also of interest was any possible effect of both chemicals on nociceptive sensations during cooling. To establish baseline intensity ratings, subjects (n = 20 for menthol, n = 41 for capsaicin) first rated the perceived thermal (warm, cold) and nociceptive (burning, stinging) intensity of separate blocks of cold (30–10°C in 5° steps) and warm (36–44°C in 2° steps) stimuli. The thermal stimuli were presented in pseudo-random order using a computer-controlled 0.64 cm2 Peltier thermoelectric module (
T = ±1.5°/s) specially constructed for oral testing.
Intensity ratings were made using the Labeled Magnitude Scale displayed on a computer
monitor. After a short break, subjects received 10 L-menthol (experiment 1) or
10 capsaicin (experiment 2) stimuli in one of two concentrations (3.2 and 10 µM
menthol; 300 and 900 µM capsaicin). The chemicals were applied to the tongue tip
via cotton-tipped swaps at the rate of one per minute.
Thermal perception was measured again beginning 15 min after the final capsaicin
stimulus and either 5 or 15 min after menthol application. Two different post-stimulation
delays were used for menthol because previous research (Green, 1986a) had indicated that its post-excitatory effects
might change within this timeframe.
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Results |
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TopIntroductionExperimental designResultsDiscussionAcknowledgementsReferences |
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Because separate repeated-measures analyses of variance (ANOVAs) performed on data from the menthol and capsaicin experiments indicated that there was no effect of concentration on the thermal effects of either chemical, the data from both concentrations are combined in Figures 1 and 2.
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Figure 1 shows that the principle effect of pre-exposure to menthol was a significant reduction in warmth intensity that diminished as temperature rose [condition x temperature interaction; F(10,190) = 6.61, P < 0.0005]. There was no effect on nociceptive sensations and a trend toward lower cold ratings at the lowest four temperatures was not significant.
The results for capsaicin were more complex (Figure 2). First, during heating capsaicin pre-treatment reduced heat intensity as well as burning and stinging. The reduction in heat intensity showed an opposite trend to the effect of menthol, with a larger effect at higher temperatures [F(5,200) = 2.5, P < 0.05]. Nociceptive sensations were also strongly suppressed as temperature increased [F(5,200) = 14.4, P < 0.0001]. Cold sensation was unaffected despite a significant decrease in burning and stinging at the coldest temperatures [F(4,160) = 7.3, P < 0.0001].
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Discussion |
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TopIntroductionExperimental designResultsDiscussionAcknowledgementsReferences |
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Capsaicin and menthol have very different post-excitatory effects on temperature perception and thermal nociception. Capsaicin’s more complex effects reflect its ability to desensitize CPNs (Buck and Burks, 1986
;
Holzer, 1991) and, apparently,
low-threshold warm fibers. Nociceptive sensations from both heating and cooling were
reduced over the temperature range served by CPNs (<25 and >40°C). However, the
weakness of the nociceptive sensation and the absence of a change in cold sensation
(Figure
2) suggests that CPNs do not
contribute substantially to perception of nonpainful cold and the lesser desensitization
of heat at higher temperatures than at moderate temperatures is consistent with recent
evidence that noxious heat sensitivity is unaffected in TRPV1 knockout mice (Woodbury et al., 2004). Evidence of
warm fiber desensitization comes from the significantly lower warmth ratings at 38°C,
a temperature at which burning and stinging was less than barely detectable and was
unaffected by capsaicin treatment.
Simone and Ochoa (1991) had
previously found equivocal evidence of warm fiber desensitization.
The absence of a desensitizing effect of menthol on cold is not surprising in view of
previous work and implies that menthol does not readily desensitize TRPM8 to cold.
However, earlier reports of self- and cross-desensitization of irritation by menthol
(Cliff and Green, 1994;
Green and McAuliffe, 2000;
Dessirier et al., 2001)
indicates that menthol must stimulate and desensitize an as yet undiscovered receptor
that is expressed on nociceptors (Okazawa et
al., 2004). In addition, prior evidence of transient enhancement of
warmth by menthol (Green, 1985)
together with the reduced ratings of warmth and heat >36°C raises the possibility
that menthol stimulates and then desensitizes TRPV3 and/or TRPV4, two receptor-gated
cation channels that are believed to act as warm receptors (Guler et al., 2002;
Smith et al., 2002;
Xu et al., 2002). Studies of
menthol’s effects on warm fibers and on the these two TRP channels in particular,
would therefore be useful.
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Acknowledgements |
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TopIntroductionExperimental designResultsDiscussionAcknowledgementsReferences |
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This research was supported in part by NIH grant DC05002. The author thanks Mr Pravin George for collecting the data reported here.
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References |
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TopIntroductionExperimental designResultsDiscussionAcknowledgementsReferences |
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