Oral irritant properties of piperine and nicotine: psychophysical evidence for asymmetrical desensitization effects.

Using a bipolar rating scale, human subjects rated the intensity of irritation sensation evoked by repeated application of piperine (75 p.p.m.) or nicotine (0.12%) to one side of the dorsal surface of the tongue. The intensity of irritation elicited by repeated application of piperine significantly increased, while irritation elicited by repeated nicotine significantly decreased. We additionally tested if nicotine or piperine desensitized the tongue. After either piperine or nicotine was repeatedly applied to one side of the tongue, a 5 or 10 min rest period ensued, followed by re-application of piperine or nicotine to both sides of the tongue. Subjects were asked to choose which side of the tongue gave rise to a stronger irritation in a two-alternative forced choice (2-AFC) paradigm. In addition, they gave separate ratings of the intensity of irritation on the two sides of the tongue. When piperine was applied bilaterally after unilateral pretreatment with piperine and a 10 min rest period, subjects consistently chose the non-pretreated side to yield stronger irritation and assigned significantly higher ratings to that side, indicative of piperine self-desensitization. A similar self-desensitization effect was found when bilateral application of nicotine followed unilateral treatment with nicotine and a 5 min rest period. Unilateral treatment with piperine also reduced nicotine-evoked irritation on the pretreated side (cross-desensitization), but treatment with nicotine did not affect piperine-evoked irritation. This asymmetrical cross-desensitization pattern is similar to that observed between capsaicin and nicotine and constitutes an additional similarity between piperine and capsaicin.     

Individual differences in perception of bitterness from capsaicin, piperine and zingerone

It was recently shown that in some subjects capsaicin can evoke bitterness as well as burning and stinging, particularly in the circumvallate (CV) region of the tongue. Because perception of bitterness from capsaicin is characterized by large individual differences, the main goal of the present study was to learn whether people who taste capsaicin as bitter also report bitterness from structurally similar sensory irritants that are known to stimulate capsaicin-sensitive neurons. The irritancy and taste of capsaicin and two of its most commonly studied congeners, piperine and zingerone, were measured in individuals who had been screened for visibility of, and reliable access to, the CV papillae. Approximately half of these individuals reported tasting bitterness from all three irritants when the stimuli were swabbed directly onto the CV papillae. Concentrations that produced similar levels of burning sensation across subjects also produced similar (though lower) levels of bitter taste. These results are consistent with the hypothesis that capsaicin and its congeners stimulate bitterness via a common sensory receptor that is distributed differentially among individuals. Additionally, bitter tasters rated gustatory qualities (but not burning and stinging) slightly but significantly higher than did bitter non-tasters, which suggests that perception of capsaicin bitterness is associated with a higher overall taste responsiveness (but not chemesthetic responsiveness) in the CV region.     

Ibuprofen as a chemesthetic stimulus: evidence of a novel mechanism of throat irritation

This paper reports a study of the oral and pharyngeal chemesthetic effects of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen [2-(4-isobutylphenyl)propanoic acid], which pilot experiments had indicated produces an unusual sensory irritation of the throat. In experiment 1 subjects swallowed aqueous solutions of ibuprofen prepared with different buffering agents and gave ratings of irritation and taste in the mouth and throat. The results showed that ibuprofen irritates the throat much more than the mouth, and that its quality in the throat is characterized primarily as sting/prick, itch and tickle (often leading to cough). Based upon the results obtained with the different buffering agents, we hypothesized that the sting/prick/itch qualities of throat irritation were pH-dependent. Parametric manipulation of solution pH in experiment 2 confirmed this hypothesis. The same experiment revealed that, in contrast to other oral irritants (e.g. capsaicin and menthol), repeated stimulation caused neither sensitization nor desensitization of throat irritation. In the final experiment we found that ibuprofen's throat irritation could not be modulated by temperature, as it should be if stimulation occurred via capsaicin-sensitive receptors. We therefore conclude that ibuprofen has novel chemesthetic properties, which are not mediated by capsaicin-sensitive (vanilloid) receptors, and that a major component of the throat irritation it produces occurs via a pH-dependent receptor mechanism.     

REGIONAL VARIATION IN SWEET SUPPRESSION

Differences in the sweet‐blocking efficacy of 2‐(4‐methoxyphenoxy) propanoic acid (PMP) for different sweeteners (sucrose and aspartame) and for various exposure areas of the mouth were found. Twenty participants rated sweetener solutions with and without PMP for sweetness, sourness, saltiness, bitterness and umami for stimulation of anterior tongue, posterior tongue and whole‐mouth areas. For sweetness ratings, suppression was significant for all stimulation areas. In the presence of PMP, stimulation of the posterior tongue yielded significantly higher sweetness ratings than stimulation of the anterior tongue for aspartame but not for sucrose. Sourness and bitterness ratings were significantly higher for anterior tongue than posterior tongue stimulations for aspartame but not for sucrose. The increases in sourness ratings in the presence of PMP were likely because of the sour taste PMP has at the concentration used. Results imply a difference between the front and the back of the tongue in the mechanisms involved in the perception of sweetness.     

Temporal interactions between oral irritants: piperine, zingerone, and capsaicin

Sequential presentation of 2 irritants may produce cross-sensitization or cross-adaptation effects upon introduction of the second irritant. In Experiment 1, subjects were given either 34 min of stimulation with zingerone, capsaicin, or piperine or one of those irritants for 23 min followed by blanks for 23 min. In Experiment 2, subjects received one irritant for 23-min irritants, followed immediately by another for 23 min (piperine --> zingerone, piperine --> capsaicin, zingerone --> piperine, or zingerone --> capsaicin). Cross-sensitization was observed for the piperine --> zingerone, zingerone --> piperine, and piperine --> capsaicin groups; cross-adaptation was observed for the zingerone --> capsaicin group. Cross-adaptation and cross-sensitization were predicted by adding the independent time courses of the respective irritants, starting the second at the offset of the first. These responses were also predicted by a mathematical model of central processing of primary afferent responses.     

Anterior Tongue Stiomulation with Amiloride Suppresses NaCl Saltiness, but not Citric Acid Sourness in Humans

Suppression of the saltiness of NaCI solutions by amiloride,a sodium channel blocker, has previously been reported a numberof times in humans. This suppression was seen with techniquesthat involved stimulation of small areas of the tongue. It wasnot certain, however, whether amiloride would suppress saltinesswith stimulation of a much larger area of the tongue; one publishedstudy, in fact, found negative results with whole mouth stimulation.For this study, eight subjects dipped a large part of the anteriorportion of the tongue into a 10-ml sample of NaCI solution,or a NaCI and amiloride solution, and reported its magnitudeof saltiness intensity. The results show that amiloride suppressedthe saltiness of NaCI when a large area of the anterior tonguewas stimulated. Consistent with previous studies, there wasindividual variability across subjects in this suppressive effectof amiloride. This study also used this method to test the effectsof amiloride on the sourness of citric acid, which was not expectedto be affected. No suppression of sourness was seen with amiloride.Chem. Senses 21: 113–120, 1996.     

Mouth Movements Diminish Taste Adaptation, but Rate of Mouth Movement does not Affect Adaptation

The degree of adaptation to five concentrations of sucrose wasmeasured. Solutions were kept in the mouth for 25 s; a sweetnessjudgement was given every 5 s. There were four conditions ofmouth movements: no movement, slow, medium and fast mouth movements.It was found that when mouth movements are made there is lessadaptation than when there is no mouth movement; however, therate of movement does not appear to influence the degree ofadaptation. Furthermore concentration was found to have an effect.In the no-movement condition, the degree of adaptation seemsto rise with concentration, whereas in the movement conditionsthe opposite effect occurs, i.e. a decrease in the degree ofadaptation occurs with increasing sucrose concentration. Thesephenomena might be explained by the stimulated tongue area,or by taste constancy. Chem. Senses 21: 545–551, 1996.     

Effects of chorda tympani nerve anesthesia on taste responses in the NST

Human clinical and psychophysical observations suggest that the taste system is able to compensate for losses in peripheral nerve input, since patients do not commonly report decrements in whole mouth taste following chorda tympani nerve damage or anesthesia. Indeed, neurophysiological data from the rat nucleus of the solitary tract (NST) suggests that a release of inhibition (disinhibition) may occur centrally following chorda tympani nerve anesthesia. Our purpose was to study this possibility further. We recorded from 59 multi- and single- unit taste-responsive sites in the rat NST before, during and after recovery from chorda tympani nerve anesthesia. During anesthesia, average anterior tongue responses were eliminated but no compensatory increases in palatal or posterior tongue responses were observed. However, six individual sites displayed increased taste responsiveness during anesthesia. The average increase was 32.9%. Therefore, disinhibition of taste responses was observed, but infrequently and to a small degree in the NST At a subset of sites, chorda tympani-mediated responses decreased while greater superficial petrosal-mediated responses remained the same during anesthesia. Since this effect was accompanied by a decrease in spontaneous activity, we propose that taste compensation may result in part by a change in signal-to-noise ratio at a subset of sites.      

Kinetics of tongue projection in Ambystoma tigrinum: Quantitative kinematics,muscle function,and evolutionary hypotheses

The projectile tongue of caudate amphibians has been studied from many perspectives, yet a quantitative kinetic model of tongue function has not yet been presented for generalized (nonplethodontid) terrestrial salamanders. The purposes of this paper are to describe quantitatively the kinnematics of the feeding mechanism and to present a kinetic model for the function of the tongue in the ambystomatid salamander Ambystoma tigrinum. Six kinematic variables were quantified from high-speed films of adult A. tigrinum feeding on land and in the water. Tongue protrusion reaches its maximum during peak gape, while peak tongue height is reached earlier, 15 ms after the mouth starts to open. Tongue kinematics change considerably during feeding in the water, and the tongue is not protruded past the plane of the gape. Electrical stimulation of the major tongue muscles showed that tongue projection in A. tigrinum is the combined result of activity in four muscles: the geniohyoideus, Subarcualis rectus 1, intermandibularis posterior, and interhyoideus. Stimulation of the Subarcualis rectus 1 alone does not cause tongue projection. The kinetic model produced from the kinematic and stimulation data involves both a dorsal vector (the resultant of the Subarcualis rectus 1, intermandibularis posterior, and interhyoideus) and a ventral vector (the geniohyoideus muscle), which sum to produce a resultant anterior vector that directs tongue motion out of the mouth and toward the prey. This model generates numerous testable predictions about tongue function and provides a mechanistic basis for the hypothesis that tongue projection in salamanders evolved from primitive intraoral manipulative action of the hyobranchial apparatus.     

Capsaicin cross-desensitization on the tongue: psychophysical evidence that oral chemical irritation is mediated by more than one sensory pathway

Psychophysical measurements were made of the perceived intensityand quality of sensations of chemical irritation before andafter the tip of the tongue had been desensitized to capsaicin(10 ppm). The results of the first experiment showed that capsaicindesensitization tended to reduce the perceived intensity ofirritation produced by approximately equipotent concentrationsof capsaicin (3 ppm), ethanol (30%), cinnamic aldehyde (2.5%)and NaCl (5M) applied to the tongue on filter paper disks; however,the reduction in irritation was less for the latter three compoundsthan for capsaicin and failed to reach statistical significancefor ethanol. Ratings of sensation quality suggested that thefour irritants produced different quality ‘profiles’,and that ethanol and cinnamic aldehyde were characterized bysensations of numbness as well as by sensations of burning andstinging/pricking. Follow-up experiments in which subjects ratedthe perceived intensity of individual sensation qualities showedthat desensitization dramatically reduced the burning and stinging/prickingcomponents of irritation, but left the sensations of numbnessand chemogenic warmth unchanged. It is concluded that lingualchemesthetic sensations are multidimensional, and mediated byboth capsaicinsensitive and capsaicin-insensitive sensory pathways.     

Time course of self-desensitization of oral irritation by nicotine and capsaicin

Nicotine contacting mucous membranes elicits irritation that decreases with repeated exposures (self-desensitization). We investigated the time course of nicotine self-desensitization and compared it with that of capsaicin. Nicotine (300 mM, 10 microl) was applied to one-half of the dorsal tongue and vehicle to the other. Following a rest period ranging from 0.5 to 48 h, nicotine (5 microl) was reapplied to each side of the tongue and subjects indicated on which side they experienced stronger irritation and separately rated the intensity of the sensation on each side. After intervals of 0.5, 1, and 24 h, a significant majority of subjects chose the vehicle-treated side as having stronger irritation and assigned significantly higher intensity ratings to that side, indicating self-desensitization. The effect was not present after 48 h. By comparison, 10 parts per million (ppm) (33 microM) capsaicin induced significant self-desensitization at 1 but not 24 h, whereas a higher concentration of capsaicin (100 ppm, 330 microM) induced significant self-desensitization at intervals of 1, 24, and 48 h. These results indicate that initial exposure to nicotine or capsaicin can markedly attenuate irritant sensations elicited by subsequent exposure to these irritants hours to days later.     

Functional morphology of tongue projection in Taricha torosa (Urodela: Salamandridae)

The kinematics of tongue projection by terrestrial adult California newts, Taricha torosa (Rathke, 1833), are described based upon high-speed cinematography. Tongue projection results from coupled anterior movements of the ceratohyals and branchial arches. Four distinct periods are defined during a projection sequence: preparation, tongue projection, tongue recovery and mouth closing. Key anatomical correlates of projection are described, with special emphasis on the mobility of the hyoid arch. Adult Taricha (Gray, 1850) have lost the mandibulo-hyoid ligament and reduced additional connective tissues present in larvae. These changes decouple the hyoid arch from mouth opening and release the ceratohyals to participate in a tongue projection system distinct from those of ambystomatids and plethodontids. These phylogenetic differences pose questions about the evolution of tongue projection systems in terrestrial urodeles. Currently available data are consistent with the interpretation that terrestrial urodeles have independently evolved specialized tongue projection systems at least twice: the ceratohyal-stable mode of plethodontids and the ceratohyal-mobile system of newts. In all cases, an essential underlying (= plesiomorphic) feature is the presence of the depressor mandibulae muscle. We regard this pathway for mouth opening as a prerequisite which liberated the hyobranchium for alternative function. Comprehensive studies of the mandibulo-hyoid ligament and depressor mandibulae will be vital to modelling the evolution of specialized tongue projection systems of urodeles.     

'Thermal taste' predicts higher responsiveness to chemical taste and flavor

Individual differences in taste perception have been explained in part by variations in peripheral innervation associated with the genetic ability to taste the bitter substances PTC and PROP. In the present study we report evidence of another source of individual differences that is independent of taste stimulus, taste quality, or gustatory nerve. Individuals who perceived taste from thermal stimulation alone (thermal taste) gave significantly higher taste ratings to chemical stimuli--often by a factor of >2:1--than did individuals who perceived no taste from thermal stimulation. This was true for all taste stimuli tested (sucrose, saccharin, sodium chloride, citric acid, quinine sulfate, MSG and PROP), for all three gustatory areas of the mouth (anterior tongue, posterior tongue and soft palate) and for whole-mouth stimulation. Moreover, the same individuals reported stronger sensations from the olfactory stimulus vanillin, particularly when it was sensed retronasally. The generality of the thermal-taster advantage and its extension to an olfactory stimulus suggests that it arises from individual differences in CNS processes that are involved in perception of both taste and flavor.     

PSYCHOPHYSICAL PROPERTIES OF MECHANICAL ORAL IRRITATION

A number of commonly consumed fruits and vegetables (e.g., kiwifruit, pineapple and taro) cause oral irritation, and there is anecdotal evidence that this influences the acceptability of such products. In each of these foods, oral irritation is produced by free crystalline calcium oxalate (raphides). The psychophysics of the mechanical oral irritation caused by raphides was studied in two experiments using a model system based on kiwifruit. In the first experiment, the location of irritant sensations and perceived intensity of the irritation caused by suspensions of raphides were determined using a ten-member trained sensory panel. Stinging and numbing were found to increase significantly with increasing concentrations of raphides. Stinging occurred principally on the tongue as well as in the throat and numbing principally on the tongue. The number of oral areas irritated was shown to increase with raphide concentration and to decrease over a 60-min period. In the second experiment, sugars (fructose, sucrose, glucose and inositol), acids (citric, malic and quinic) and an enzyme (actinidin) were added to the model to examine interactions between these chemical stimuli and the mechanical action of the raphides. Addition of acids to the model was shown to enhance irritation in addition to increasing sourness and suppressing sweetness. The addition of actinidin had no significant effects on irritation or tastes. It is suggested that acidity may aggravate irritation at low raphide concentration, but beyond a critical level of mechanical irritation the presence of acids has little additional effect. These results provide the first detailed data of the psychophysics of mechanical oral irritation in food, and have important implications for producing foods with lower levels of irritation and increased acceptability.     

Menthol Attenuates Respiratory Irritation and Elevates Blood Cotinine in Cigarette Smoke Exposed Mice

Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol’s effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking initiation and nicotine addiction.     

Differential sensitivity of tongue areas and palate to electrical stimulation: a suprathreshold cross-modal matching study

A cross-modal matching procedure was used, in twelve subjects,to evaluate regional differences in suprathreshold sensitivityof the oral cavity to electrogustometric stimulation. Stimulationof five loci on each side of the oral cavity was performed:tongue tip (one cm from the midline), anterior tongue side (2.5cm from tip on lateral margin), posterior tongue side (regionof the foliate papillae), posterior medial tongue (one cm frommidline on circumvallate papillae), and soft palate (one cmfrom midline, one cm above superior pole of anterior palatinearch). The tip of the tongue was significantly more sensitivethan the other areas to electric stimulation, as evidenced bythe slope and absolute position of the psychophysical powerfunctions. Strong correlations were observed in the sensitivitymeasures across tongue loci and between tongue and palate sides.No effects of subject gender or mouth side were found.     

Topographic distribution of taste responsiveness in the hamster medulla

The purpose of the present investigation was to map the multiunitresponsiveness of the gustatory portion of the nucleus of thesolitary tract (NTS) in the hamster, elicited by chemical stimulationof oral taste receptors. Neural responsiveness to four stimuli(0.1 M sucrose, 0.03 M NaCl, 0.003 M HCl, 0.001 M QHCl) deliveredto either the anterior tongue or other parts of the oral cavitywas examined at 37 NTS recording sites. Gustatory responseswere shown-to depend collectively upon the stimulus, the receptivearea being stimulated, and the location of the recording sitewithin the NTS. By comparing the proportional magnitudes ofintegrated responses across recording sites, unique topographicpatterns of responsiveness were demonstrated for sucrose, NaCIand QHCl. Responses to HCl and NaCl generated similar patterns.Further, the response patterns for each stimulus differed followingstimulation of the anterior tongue or posterior oral cavity.Spatial differences in NTS responsiveness arise as a resultof differences in peripheral gustatory nerve sensitivities andprovide a possible substrate for the coding of taste quality.     

The mechanism of chemical delivery to the vomeronasal organs in squamate reptiles: a comparative morphological approach

Vomeronasal chemoreception, an important chemical sense in squamate reptiles (lizards and snakes), is mediated by paired vomeronasal organs (VNOs), which are only accessible via ducts opening through the palate anteriorly. We comparatively examined the morphology of the oral cavity in lizards with unforked tongues to elucidate the mechanism of stage I delivery (transport of chemical-laden fluid from the tongue tips to the VNO fenestrae) and to test the generality of the Gillingham and Clark (1981. Can J Zool 59:1651-1657) hypothesis (based on derived snakes), which suggests that the sublingual plicae act as the direct conveyors of chemicals to the VNOs. At rest, the foretongue lies within a chamber formed by the sublingual plicae ventrally and the palate dorsally, with little or no space around the anterior foretongue when the mouth is closed. There is a remarkable conformity between the shape of this chamber and the shape of the foretongue. We propose a hydraulic mechanism for stage I chemical transport in squamates: during mouth closure, the compliant tongue is compressed within this cavity and the floor of the mouth is elevated, expressing fluid from the sublingual glands within the plicae. Chemical-laden fluid covering the tongue tips is forced dorsally and posteriorly toward the VNO fenestrae. In effect, the tongue acts as a piston, pressurizing the fluid surrounding the foretongue so that chemical transport to the VNO ducts is effected almost instantaneously. Our findings falsify the Gillingham and Clark (1981. Can J Zool 59:1651-1657) hypothesis for lizards lacking forked, retractile tongues.     

In vitro biocompatibility of denture relining materials

Objective: The aim of the present study was to evaluate the in vitro biocompatibility of denture relining materials using cell culture tests and a test for irritation mechanisms. Background: Denture relining materials contain non‐reacted constituents that may leach out during use inducing local toxic or irritative effects. Materials and methods: One chemically cured, four visible light cured and five dual‐cured products were included. Cured test specimens were used for the filter diffusion test, and extracts of cured specimens were applied in the MTT and the irritation test using the hen's egg test‐chorioallantoic membrane (HET‐CAM) method. Results: Five of the tested materials were slightly or moderately cytotoxic in the filter diffusion test, and one product coated with a liner induced severe toxicity. Cell cultures incubated for 24 hour with the test samples were more damaged than those incubated for 2 hour. In the MTT test, extracts of nine of the 11 products induced cytotoxicity. No extracts showed irritation, whereas the coating and two bonding agents tested were strong irritants. Conclusion: Most of the tested materials contained water soluble, toxic substances that leach out of the products and that some time was needed to obtain cytotoxic amounts of the leachables. Many dental materials elicit cytotoxic response, but this does not necessarily reflect the long‐term risk for adverse effects as the oral mucosa is generally more resistant to toxic substances than a cell culture.