Barry G. Green

Capsaicin sensitization and desensitization on the tongue produced by brief exposures to a low concentration

The intensity of sensations of burning and stinging produced by repeated exposures to capsaicin (at a nominal concentration of 3 ppm) was measured on a localized area of the tongue as a function of both the number of exposures and the time between them. It was discovered in the initial experiment that stimulation at the rate of 1/min (for up to 25 min) resulted in a monotonic increase in the intensity of burning sensations in a manner consistent with the phenomenon of sensitization. However, the insertion of a 15-min delay in stimulation resulted in a reduction in the intensity of the sensations produced by further stimulation, i.e., desensitization occurred. Desensitization was statistically significant even after exposure to as few as 5 stimuli prior to the delay. A subsequent experiment established that the minimum delay necessary to produce desensitization was between 2.5 and 5 min. Hence, paradoxically, the sensory response to capsaicin on the tongue increased as stimulation continued, then decreased after stimulation had ceased.

Sensory irritation and coolness produced by menthol: evidence for selective desensitization of irritation.

The temporal characteristics of the oral perception of menthol solutions were explored in two experiments. In Experiment 1, 10 samples of either 0.03% or 0.30% menthol were presented at 1 min intervals and rated for the perceived intensity of cooling and irritation. Reports of sensation quality (burning, tingling, stinging and numbing) and pain were also collected. At the higher concentration, a significant decrease in perceived intensity was observed over time for irritation, but not for cooling. Experiment 2 was designed to explore further the nature of the decline in irritation observed in Experiment 1. Employing 1-min and 5-min inter-stimulus intervals between solutions, it was found that the decrease in menthol irritation more closely resembled desensitization than adaptation. Decreases in the frequency of reports of the burning and stinging qualities, but not the tingling, numbing or cooling qualities, suggested that menthol has a specific desensitizing effect on a population of mucosal nociceptive fibers.

The sensory effects of l-menthol on human skin.

Psychophysical measurements were made of the sensory effects of l-menthol applied topically to the forearm under controlled thermal conditions. In the first experiment, subjects judged the intensity and quality of sensations produced by warming or cooling the skin in the presence of menthol or the vehicle. During cooling, menthol intensified cutaneous sensations and increased reports of burning. During warming, menthol intensified sensations transiently at low temperatures and weakened them lastingly at higher temperatures; the frequency of reports of burning varied with intensity. A second experiment tested the hypothesis that menthol would lower the threshold for warmth and raise the threshold for heat pain. No change in either threshold was observed. The primary sensory effects of l-menthol on hairy skin are therefore to heighten the perception of cooling and to attenuate the perception of moderate warming. In contrast with other common chemical irritants, menthols pungent qualities appear to be enhanced by cooling and suppressed by warming; this suggests that its sensory irritancy may be attributable to the stimulation of a population of high-threshold cold fibers or cold-sensitive nociceptors.

Sensitization and desensitization to capsaicin and menthol in the oral cavity: Interactions and individual differences

It was reported in a recent study that, like capsaicin, menthol is capable of producing a desensitization to sensory irritation in the oral cavity. Whereas capsaicin is known to be able to cross-desensitize with other chemical irritants, no such information exists for menthol. To address this question, the first experiment was designed to reveal whether cross-desensitization would occur between menthol and capsaicin. After a pretest on the tongue tip in which subjects rated the intensity of irritation and cold produced by 3.5 ppm capsaicin or 0.3% l-menthol, five samples of the same stimuli were sipped and swished at 1-min intervals for 5 min. Fifteen minutes later subjects were tested on the tongue tip with either capsaicin or menthol. The results 1) confirmed self-desensitization for both chemicals, 2) demonstrated cross-desensitization of menthol by capsaicin, and 3) revealed cross-sensitization of capsaicin by menthol. This series of outcomes suggests that menthol produces much of its sensory irritation via capsaicin-sensitive pathways, but that it excites and/or desensitizes those pathways via different mechanisms than does capsaicin. Analysis of the individual data revealed large differences in sensitization, and desensitization that were significantly correlated across chemicals, which suggests the possibility that the perceptual response to repeated exposures to irritants may be idiosyncratic. Contrary to earlier findings, the first experiment also revealed apparent self- and cross-desensitization of the menthol sensation of coolness. The latter outcome was investigated in a second experiment in which the effect of capsaicin desensitization on the perception of physical as well as chemical (menthol) cooling was measured when the stimuli were presented as oral rinses. No desensitization was found for either form of stimulation, which implied the apparent desensitization of coolness in Experiment I may have been due to the difficulty of discriminating sensations of cold from sensations of chemical irritation. The overall findings are discussed in terms of the complex sensory and perceptual interactions that take place within the chemesthetic modality.

The sensory response to capsaicin during repeated topical exposures: differential effects on sensations of itching and pungency

&NA; Changes in sensory irritation were measured during repeated topical exposures to capsaicin over 2 days. The perceived intensities of itching and pungent sensations, predominantly burning and stinging/pricking, were assessed every 60 sec during 5 applications of capsaicin at inter‐stimulus intervals (ISI) of 90 min (Exp. 1) or 15 min (Exp. 2) and in follow‐up tests 24 h later. Psychophysical measurements were obtained with a hand‐held dynamometer in conjunction with the method of magnitude production. When the ISI was 90 min, itching and pungency were both significantly reduced (i.e., desensitization occurred) by the fifth exposure; however, the reduction occurred more rapidly and dramatically for itching. After 24 h, desensitization remained significant only for itching. When the ISI was 15 min, the sensations on day 1 first intensified in a manner consistent with sensitization, then declined in a manner consistent with desensitization; compared to pungency, itch exhibited less sensitization and more desensitization. On day 2, overall intensity was less for both categories of sensation, primarily because of a reduction in sensitization. Marked individual differences were observed in the overall sensitivity to capsaicin, the time course of sensation, the susceptibility to capsaicin‐induced itch, and the rate and duration of sensitization and desensitization. The results are discussed in terms of current hypotheses about the sensory mechanisms that underlie chemically induced itch and the use of capsaicin as a topical analgesic and antipruritic.

Menthol modulates oral sensations of warmth and cold

Aqueous solutions of menthol were found to affect oral thermal sensation in the following ways: When menthol solutions were sipped and held in the mouth for 5 sec, solutions above oral temperature felt significantly warmer than deionized water of the same temperature (warmth enhancement). Menthol solutions below oral temperature felt cooler than water of the same temperature, but only slightly so (cold enhancement); Pretreating the mouth with 0.02% menthol for 5 min strengthened cold enhancement but attenuated sensations of warmth (warmth attenuation); Pretreating for 10 min produced continued cold enhancement while judgments of warmth returned to normal levels; L-menthol cooled more effectively than d-menthol, but d-menthol attenuated warmth at least as much as l-menthol. Possible explanations for the intermodal differences are discussed, and suggestions are made for future research into menthols unexpectedly complex perceptual effects.

Menthol inhibits the perception of warmth

The effect of l-menthol on the ability to perceive gradual increases in skin temperature was measured in two experiments. Experiment 1 established that suprathreshold sensations of warmth generated on the vermilion border of the lip could be significantly attenuated by exposure to menthol in concentrations of 0.2 and 2.0% (in mineral oil). Experiment 2 demonstrated that exposure to the 2.0% menthol solution caused the threshold for warmth to rise significantly whereas the threshold for heat pain was unchanged. Although masking of sensations of warmth by menthol-induced sensations of cold is discussed as a possible explanation for the results, a direct effect of the menthol molecule on warm receptors (i.e., inhibition or desensitization) is considered a more likely explanation.

The effect of cooling on the perception of carbohydrate and intensive sweeteners

The effect of cooling on the perceived intensity of sweetness was measured for four different compounds: glucose, fructose, aspartame and saccharin. Perceived sweetness was rated in a sip and spit paradigm when the taste solution, the tongue, or both were either held at 36 degrees C or cooled to 20 degrees C. It was discovered that for glucose and fructose perceived sweetness was significantly reduced by cooling, and that cooling the tongue reduced sweetness more than did cooling the solution. The perceived sweetness of aspartame was also lessened by cooling, but in that case the temperature of the tongue and the temperature of the solution had similar effects on sweetness. In contrast to the other compounds, the sweetness of saccharin was not affected by temperature. These results (when combined with data previously reported for sucrose) raise the possibility that as a group, carbohydrate sweeteners are affected similarly by temperature, whereas thermal effects on intensive sweeteners may be less predictable. The data thereby provide indirect support for the hypothesis that the sweet taste is mediated by more than one type of gustatory receptor.

Temporal characteristics of capsaicin sensitization and desensitization on the tongue

Previous work has demonstrated that repeated applications of capsaicin can sensitize the tongue to subsequent exposures to capsaicin. However, if stimulation is interrupted for a period of minutes, the contrasting phenomenon of desensitization occurs. The purpose of the present study was to investigate the effect of interstimulus interval (ISI) on the development of both sensitization and desensitization to sequential capsaicin stimuli. It was determined in the first experiment that the rate of sensitization varied inversely with ISI for intervals briefer than 3.5 min; when ISI was lengthened to 5.5 min, sensitization was replaced by a trend toward desensitization. A second experiment established that increasing ISI from 9.5 min to 14.5 min tended to reduce rather than to enhance desensitization. It was therefore concluded that the sensitization process can be optimized by decreasing the time between successive stimuli (ISIs less than 3.5 min), whereas the trend toward desensitization appears to be optimal when stimuli are separated by at least 5.5 min but by less than 14.5 min.

Spatial and temporal factors in the perception of ethanol irritation on the tongue

The sensitivity of the tongue to the irritation produced by ethanol was measured in five experiments. It was discovered in the first two experiments that both latency to the onset of irritation and perceived intensity of irritation varied with the locus of lingual stimulation. The tonguetip and the side of the tongue were found to be more sensitive (that is, they tended to produce higher magnitude estimates and shorter response latencies) than sites toward the middle of the tongue, with the tonguetip being the most sensitive area tested. However, even on the tonguetip the latency to onset of irritation (approximately 2–6 sec) was much longer than typical values for taste sensation. The third experiment demonstrated that increasing the size of the ethanol stimulus resulted in shorter response latencies and more intense irritation. The latter result indicates that the sensory system responsible for ethanol irritation is capable of significant (but incomplete) spatial summation. The final two experiments showed that significant summation also occurs when stimulus area is increased by adding a second stimulus at another lingual locus. Possible explanations for the regional differences in sensitivity and for the relatively long onset latencies of chemical irritation are discussed.