three distinct categories of time course of pain produced by oral capsaicin

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Three Distinct Categories of Time Course of Pain Produced byOral Capsaicin

Carey D. Balaban,* Donald H. McBurney,† and Mark A. Affeltranger†

Abstract: Humans vary in oral pain tolerance. Our earlier studies noted that the responses ofsubjects show 1 of 3 qualitative response patterns to a single oral capsaicin concentration, which wetermed a tonic pattern (level detection response), a phasic pattern (change detection response), andan integrator pattern (cumulative irritation) response. These patterns were modeled quantitatively asthe sum of 3 underlying processes. Two time-varying capsaicin stimulus profiles were designed fromthe quantitative model. In the ascending step paradigm, 30 ppm capsaicin was presented to 42subjects for 15 minutes, followed immediately and without explanation by 300 ppm capsaicin for 25minutes. In the descending step paradigm, 300 ppm capsaicin was presented to 36 other subjects for24 minutes, followed by 10 ppm for 22 minutes. Subjective burn was rated at 1 minute and then at3-minute intervals throughout the presentation. Fuzzy cluster analysis identified 3 distinct responsephenotypes in each paradigm, corresponding to level detection, change detection, and cumulativeirritation response patterns identified previously. Discriminant functions permitted classification ofthese phenotypes from the response patterns. Thus, these paradigms provide the first quantitativephenotypic description of distinct oral pain responses to a common irritant, capsaicin.Perspective: This study examined the time-dependent behavior of pain produced by oral applicationof capsaicin. Three distinct temporal response phenotypes were identified objectively: level detection,change detection, and cumulative irritation detection. These time-dependent analyses provide a newdimension to understanding individual differences in pain sensation in clinical settings.

© 2005 by the American Pain Society
Key words: Capsaicin, pain intensity, oral, phenotypes, mathematical modeling.
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t is well recognized that marked individual differencesin pain sensation and pain tolerance reflect influencesof biologic, social, and cultural determinants.15 It is

nclear whether these differences reflect random varia-ions about a mean behavior or distinct response pheno-ypes for painful stimulation. In previous studies13,14 weoted 3 systematic patterns of human psychophysical re-ponses to a constant oral capsaicin stimulus, which weermed a tonic pattern (level detection response), a pha-ic pattern (change detection response), or a rising pat-ern (cumulative irritation response). We were able toescribe these patterns by a mechanistic model13 thatepresents individual responses to capsaicin as a sum of 3arallel processes (Fig 1). Each process corresponds to 1f the 3 temporal patterns just described. The stimulus-esponse relationship for each process appears to followdistinct power function.14

eceived October 13, 2004; Revised December 22, 2004; Accepted Janu-ry 5, 2005.rom the *Departments of Otolaryngology, Neurobiology and Commu-ication Sciences, Eye and Ear Institute, School of Medicine, and theDepartment of Psychology, University of Pittsburgh, Pittsburgh, Penn-ylvania.upported by the Eye & Ear Institute Foundation and by internal fundsrom the Department of Psychology, University of Pittsburgh.ddress reprint requests to Carey D. Balaban, MD, Department of Oto-

aryngology, University of Pittsburgh, 107 Eye & Ear Institute, 203 Lo-hrop Street, Pittsburgh, PA 15213. E-mail: [email protected]/$30.002005 by the American Pain Society

toi:10.1016/j.jpain.2005.01.346

The Journal of Pain, Vol 6, No 5

This model is also able to predict temporal interactionsermed sensitization, desensitization, and cross adap-ation.1,2 The model is also useful for designingime-varying stimuli to test whether our previous obser-ations reflect different phenotypic categories of sub-ects’ oral pain responses.

The model assumes that the response to 2 simulta-eous stimuli is the sum of the responses to the individ-al stimuli. On the basis of individual differences in re-ponses to single capsaicin doses,13,14 we predicted thatuccessive exposure to 2 concentrations of capsaicinould also distinguish 3 response phenotypes. The dura-

ions and capsaicin concentrations for stimuli were basedn these modeled responses.Here we use fuzzy cluster analysis and discriminant

nalysis to identify 3 distinct psychophysical responsehenotypes in 2 new stimulus paradigms: a double step

ncrease in stimulus intensity and a step decrease from aigh to a low intensity. These results yield a new methodf classifying human pain responses by temporal pat-ern, rather than threshold or magnitude of response.

ethods

ubjectsSeventy-eight undergraduate students participated in

he experiment for course credit. Forty-two subjects par-
icipated in the ascending concentration step experi-
315(May), 2005: pp 315-322

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316 Categories of Oral Capsaicin Pain Time Course

ent; 36 subjects participated in the descending concen-ration step experiment. The research protocol waseviewed and approved by the University of Pittsburghnstitutional Review Board, and informed consent wasbtained from each subject.

apsaicin StimuliCapsaicin (Sigma, St Louis, Mo; 98%) was dissolved in

5% ethyl alcohol to 6000 ppm. This stock solution wasiluted in water to the final concentration. All solutionsere stored at �10°C. Twenty-five microliters of the so-

ution was pipetted onto 1.27-cm diameter filter paperisks (Schleicher & Schuell, Keene, NH) and allowed tory. The filter papers were wetted with 50 �L of water

ust before being placed on the tongue. Subjects ratedhe burning sensation elicited by a capsaicin stimulus in aingle session. For the step-up experiment, 30 ppm cap-aicin was applied to the tongue for 15 minutes, fol-owed immediately and without explanation by 300 ppmapsaicin for 25 minutes. For the step-down experiment,00 ppm capsaicin was applied to the tongue for 24 min-tes, followed by 10 ppm for 22 minutes.

rotocolStandard, nonmodulus, magnitude estimation instruc-

ions were read to the subjects, and any questions werenswered. Because it assesses a temporal profile, freeagnitude estimation is appropriate to display proper-

ies such as an evolving integrator response. Subjectsere given practice judging the distance between thexperimenter’s hands. They wrote their responses to theapsaicin on index cards, which they turned over afterach trial. Filter papers were laid out in a matrix arrayefore the experiment to prevent the subject from sur-

igure 1. The transfer function for the model for psychophyesponses are modeled as a sum of 3 parallel processes: a tonicrocess with gain c. The Laplace representations of each transfe

ising that all stimuli were the same. There was an ex- f

ess of both filter papers and index cards to prevent theubject from anticipating the end of the session.The stimuli were placed on the end of the outstretched

ongue by means of forceps and left for 1 minute. Theubjects gently held the filter paper in place with aongue depressor. They were asked to keep the tonguextended between the closed lips for the duration of theession, but they were permitted to retract the tonguend close the mouth briefly as needed when the filterapers were changed every minute.At the end of the first 1-minute interval of stimulation

nd every third minute thereafter, subjects were askedo rate the burning sensation they felt at that moment. Aomputer beeped to signal the replacement of the filteraper and the rating of the stimuli.

ata TransformationData were transformed by multiplying each responsey a constant so that each subject’s mean response be-ame 100. This was done so that each subject wouldake an equal contribution to the average data. Note

hat this transformation obscures differences betweenubjects in overall response to capsaicin. Fuzzy C-meansluster analysis was performed in MATLAB (MathWorks,atick, Mass) by using the “fcm.m” algorithm in theFuzzy toolkit.” Fuzzy C-means cluster analysis is aethod for partitioning a data set into a specified num-

er of clusters, on the basis of an iterative minimizationf the within groups sum of square error for the selectedartition.4 In contrast to classic cluster analysis, whichorces each observation into a single cluster, fuzzy clusternalysis generates a membership function matrix (valuesanging from 0 to 1) that specifies the grade of member-hip of each observation in each cluster and an objective

responses to capsaicin is shown in block diagram form. Thess with gain a, a phasic process with gain b, and an integratorction are shown in the boxes associated with each process.

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unction specifying the location of the center of each

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317ORIGINAL REPORT/Balaban et al

luster. Because the sum of the membership matrix en-ries for each observation is 1, the membership matrixntries are analogous to the likelihood of membershipn each cluster. The theory and applications of these

ethods are described in detail in the statistics litera-ure. Discriminant analysis was performed with SYSTAT0.2 (www.systat.com) software.

odel Implementation and ParameterstimationThe model has 3 free parameters: tonic gain, phasicain, and integrator process gain. The 3 time constantsnd relative response magnitudes to the 2 concentra-ions of capsaicin were fixed on the basis of previoustudies.2,13,14 The input to the model is first transformedo reflect the exponential relationship between stimulusoncentration and normalized burn sensation for eachrocess.14 For the ascending step stimuli (30 to 300 ppm),he tonic input was simulated as a constant step of 48.7,ollowed by a step to 91.3. The phasic input (which satu-ates at 100 ppm) was simulated as an initial step of 43.6,ollowed by a step to 98.8, whereas the input to thentegrator was set as a step to 15.8, followed by a step to3.6. For the descending step stimuli (300 to 10 ppm), theonic input was simulated as a constant step of 91.3,ollowed by a step down to 36.1. The phasic input (whichaturates at 100 ppm) was simulated as an initial step of8.8, followed by a step to 19.8, whereas the input to the

igure 2. Median subject responses during exposure to ascendiinutes) and descending (lower panel, 300 ppm for 24 minutes f

he filled circles represent the median group response at eachesponses of each group. The gains in the inset are a least squa
integrator gain) from the model, shown schematically in Fig 1 and d
ntegrator was set as a step to 63.6, followed by subtrac-ion of a response to a step of size 55.5 (the differenceetween the 63.6 magnitude for a 300-ppm stimulus andhe 8.1 magnitude for a 10-ppm stimulus). The transferunctions of the individual processes (including the timeonstants) are identical to the model in our previous pub-ications.2,13,14 As in our previous studies, the model wasimulated in MATLAB for least squares estimation of theain of each process by using “leastsq.m” algorithm.

esultsThe group median response to the ascending step

howed 2 distinct limbs (Fig 2). During application of thenitial 30-ppm stimulus, the response rose with a roughlyxponential time course to approximately 60 arbitrarynits. Application of the 300-ppm stimulus produced aecond, roughly exponential rise to approximately 150rbitrary units at the conclusion of the trial. The medianesponse to the descending step stimulus profile (Fig 2)ose to a plateau at 150 arbitrary units during applicationf the initial 300-ppm stimulus, followed by a roughlyxponential fall to 0 during application of the 10-ppmtimulus.The behavior of the integrator response has not been

ested for a large decrease in capsaicin concentration.ne possibility is that the response continues to inte-rate, but at a rate dictated by the reduced stimulus. Aecond possibility, however, is that the integrator re-

pper panel, 30 ppm for 15 minutes followed by 300 ppm for 25ed by 10 ppm for 22 minutes) step concentrations of capsaicin.point. The solid line displays the fit of a single model to the

stimate of the parameters a (tonic gain), b (phasic gain), and c

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ponse could “discharge” on the precipitous reduction ofrritant concentration. The model was first fitted to theata from the descending step experiment to chooseetween 2 versions of the integrator process. The firstersion assumed that the integrator component wouldontinue to increase when the stimulus was decreasedecause of continued integration of the lower intensity.he second version assumed that the integrator wouldischarge at the drop in concentration with the sameate with which it had charged. The active integratorischarge was implemented by adding an integrator re-ponse to a negative step of the same magnitude as theoncentration drop. The discharging version yielded aetter fit, particularly of the second (lower) concentra-ion portion of the data. Next, the model was fit simul-aneously to the median data from both experiments,ielding a single set of parameters that maximized the fito the 2 sets of data. The group median responses for the

experiments were fitted well by a weighted sum ofonic (gain � 0.55), phasic (gain � 1.70), and integratorgain � 0.66) components (Fig 2).Consistent with our previous observations, objective

tatistical methods identified 3 different temporal re-ponse profiles that characterize groups of subjects.uzzy C-means cluster analysis4 was performed on squareoot transformed responses of individual subjects todentify heterogeneous underlying response patterns.

igure 3. Level detection response cluster. The upper panel sholuster 1 (13 subjects) from the group of subjects given ascendedian burn sensation from the corresponding cluster of subjec

oncentrations. The curves on each panel show the fit of a mode
stimates of the 3 gains in the model are listed in the figure.
hese analyses were done separately for the 2 experi-ents. Subjects were characterized as belonging to a

ingle cluster (group response pattern) if their member-hip set value was greater than 0.45 for that cluster andess than 0.4 for any other cluster. Subjects with approx-mately equal membership values for 2 clusters were notsed for characterizing the properties of any cluster.Three distinct response patterns were identified for

he ascending capsaicin steps. Thirteen of the 42 subjectsell into Cluster 1, which might be described as a tonicesponse profile (Fig 3). The responses of these subjectshowed a simple exponential rise to an initial plateau inhe range of 50 to 100 arbitrary units during applicationf the initial 30-ppm stimulus, followed by a similar riseo a plateau of 120 to 200 arbitrary units. By contrast, the2 subjects in Cluster 2 showed a more phasic responseattern (Fig 4) that rose within 5 minutes to a medianlateau of approximately 60 arbitrary units, followed byjump to a slowly increasing response pattern after ap-lication of the second capsaicin concentration. Finally,he 9 subjects in Cluster 3 showed a “rising pattern”bserved in our previous studies.13,14 These responseshowed a simple exponential rise to the first stimulus,ollowed by a rising response during application of theigher stimulus concentration (Fig 5). The remaining 8ubjects showed patterns that were almost equally likely

e median burn sensation that characterizes the pattern termedcapsaicin stimulus concentrations. The lower panel shows the� 13) from the group exposed to descending capsaicin stimulush a single set of parameters to the responses. The least squares

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o be (1) in cluster 1 or cluster 2 (5 subjects) or (2) inluster 1 or cluster 3 (3 subjects).The responses to the descending capsaicin steps also

howed 3 distinct patterns. The median response for the3 subjects in Cluster 1 (Fig 3) was virtually identical tohe median response for all subjects (Fig 2). The responseose rapidly to a plateau during application of 300 ppmapsaicin. When the stimulus concentration dropped to0 ppm, the response declined within about 12 minuteso a plateau between 0 and 50 arbitrary units. The 7ubjects in Cluster 2 (Fig 4) showed a response that roseapidly to a peak, followed by a flat to declining responseuring the 300-ppm stimulation. When the stimulus con-entration dropped to 10 ppm, the response declinedrecipitously, reaching 0 by the end of the session in allubjects. The 8 subjects in Cluster 3 (Fig 5) showed a slowise during the 25-minute exposure to 300 ppm capsaicin,ollowed by a slow decline during exposure to 10 ppmapsaicin. Among the 8 individuals with intermediate re-ponse patterns to descending steps, 7 showed a patternntermediate between clusters 1 and 2, and 1 subjecthowed a pattern intermediate between clusters 2 and 3.To test the hypothesis that the clusters from both ex-eriments constitute the same 3 subject types with dis-inct response characteristics, a least squares regressiont was performed to obtain a single set of parameters for

igure 4. Change detection response cluster. The upper paneermed Cluster 2 (n � 12 subjects) from the group of subjects ghows the median burn sensation from the corresponding clustetimulus concentrations. The curves on each panel show the fit oquares estimates of the 3 gains in the model are listed in the fi

model fit to the response to both the ascending con- 1

entration subjects and descending concentration sub-ects. Responses of Cluster 1 subjects from both experi-

ents (Fig 3) were described by a single model with aonic gain of 0.68, a phasic gain of 1.65, and an integra-or gain of 0.61, which behaves as a level detector. Re-ponses of Cluster 2 subjects from both experiments (Fig) were described by a single model with a phasic gain of.72 and an integrator gain of 0.28, which behaves in aanner that is highly sensitive to changes in concentra-

ion. Responses of Cluster 3 subjects from both experi-ents (Fig 5) were attributed to a sum of a small tonic

ain (0.15), a moderate phasic gain (0.65), and a largentegrator gain (1.90), which reflects high sensitivity toumulative irritation. Thus, these findings support ourarlier suggestion that there are 3 phenotypic patternsor subjective burning sensations elicited by oral irrita-ion by capsaicin. It is noteworthy that this classificationpproach ignores individual differences in perceived in-ensity. This contrasts sharply with all previous studies,ecause they are based on sensitivity and intensity, nothe time course.Within each 2-step stimulus paradigm, the subject’s re-

ponse phenotype could be identified by a discriminantnalysis of the responses across time points. This ap-roach yielded 2 canonical variables for classifying sub-

ect responses from each experimental paradigm (Tables

ws the median burn sensation that characterizes the patternascending capsaicin stimulus concentrations. The lower panel

ubjects (n � 7) from the group exposed to descending capsaicinodel with a single set of parameters to the responses. The least.

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cation of the subjects that were classified by the C-eans fuzzy cluster analysis (Fig 6). Among subjects who

ould not be classified unambiguously by the C-meansnalysis, 4 of 8 ascending step responses were classifieds a response phenotype by the discriminant function,hereas only 1 of 8 was classified for the descending

igure 5. Cumulative irritation response cluster. The upper panermed Cluster 3 (n � 9 subjects) from the group of subjects givenhe median burn sensation from the corresponding cluster oftimulus concentrations. The curves on each panel show the fit oquares estimates of the 3 gains in the model are listed in the fi

able 1. Discriminant Function for Ascendingapsaicin Steps Paradigm

TERM

FACTOR 1COEFFICIENT

FACTOR 2COEFFICIENT

onstant 31.477 15.248min 0.514 0.198min 0.240 0.005min �0.098 �0.6870 min 0.200 1.0023 min �0.476 �0.8026 min �0.153 0.4029 min �0.131 �0.7182 min 0.421 �0.0995 min �0.770 �0.0768 min �0.096 0.1821 min �1.323 �0.1944 min �0.253 0.1817 min 0.152 �0.972

g0 min �0.547 0.248

esponses; these discriminant classifications were consis-ent with the membership set values from fuzzy C-meansnalysis.

iscussionOur findings show that time-dependent behavior addsnew dimension to classification of oral sensitivity to

hemical stimuli. All previous classification schemata forndividual difference in response to chemical stimuliwhether tastants or irritants) have been based on in-tantaneous measures of magnitude or threshold. Be-ause pain responses, like all biologic processes, takelace over time, instantaneous measures of magnitudeace the problem of choice of the appropriate moment.ur approach, by contrast, permits an objective classifi-

ation based on the temporal response profile of eachubject to a single experimental exposure, independentf the absolute magnitude or choice of a single moment.The labeled magnitude scale is a visual analog scale

nchored by verbal descriptors and having ratio-levelroperties.9 Bartoshuk3 has modified the upper limit toead, “strongest imaginable sensation of any kind,” toermit a more valid comparison between subjects. Weelieve this generalized labeled magnitude scale is stillubject to ceiling effects, especially in studies that do notresent examples of extremely strong stimuli at the be-

ows the median burn sensation that characterizes the patternnding capsaicin stimulus concentrations. The lower panel showsects (n � 8) from the group exposed to descending capsaicinodel with a single set of parameters to the responses. The least.

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row considerably over time, especially for integratorsnd for higher concentrations,14 we believe that freeagnitude estimation is preferable in studies of the time

ourse of capsaicin irritation. Of course, the normaliza-ion of data used in the present study thereby ignoresndividual differences in magnitude of pain.

In our previous studies, the time course of the subjec-ive burning sensation to oral capsaicin was modeledxplicitly as a linear sum of 3 underlying processes: aonic mechanism, a phasic mechanism, and an integratoromponent. This study provided one refinement of theodel structure for a previously unexplored experimen-

al condition, a precipitous decrease in capsaicin concen-ration. Under these conditions, the integrator processppears to discharge. When the discharging of the inte-rating component is incorporated, the results of thistudy support the adequacy of this linear modeling ap-roach because the 3 phenotypic responses could beodeled effectively as distinct linear sums of the 3 com-onent processes. It is also noteworthy that the modelsed in this study was highly constrained and had only 3ree parameters. Specifically, the time constants of theserocesses and the psychophysical scaling factors of eachrocess for capsaicin concentration were fixed by esti-ates from our earlier studies. Because our initial study

ound that the tonic component and the integrator com-onent show long-term adaptation to capsaicin expo-ure, the response phenotypes likely represent an inter-ction between genetics and history of exposure. Ourrevious data14 indicate that response phenotypes aretable for separate applications of different concentra-ions of capsaicin, separated by at least a 1-week interval.Fast et al8 and Prutkin et al16 have extensively docu-ented the importance of 6-N-propylthiouracil (PROP)

nd/or phenylthiocarbamide (PTC) sensitivity as a predic-or of individual differences in taste and oral irritant sen-

igure 6. Discriminant factor scores (Table 1) provide a distintandard deviation) confidence ellipse, centered around the mee used to classify subjects as level detectors (Cluster 1), change

itivity. The inability to taste PROP or PTC was originally4

elieved to be a simple mendelian recessive trait,5,19

ith homozygous PROP tasters displaying highest sensi-ivity.11,17 Genetic linkage studies7,10,12,17,18 have pre-ented evidence for loci on chromosomes 7q, 16p, andp. Positional cloning studies by Drayna et al6,7 and Kimt al12 have identified 3 distinct polymorphisms withinhe PTC gene on chromosome 7q, which affect aminocids 49, 262, and 296 of the TAS2R receptor protein.hey also demonstrated that distinct haplotypes are as-ociated with different sensitivities to PTC and PROP, sohat expression of the PAV haplotype is associated withigh PROP sensitivity. Because one of our previous stud-

es13 indicated that PROP taster status is associated with

able 2. Discriminant Function for Descendingapsaicin Steps Paradigm

TERM

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onstant �38.521 �0.064min 0.236 0.561min 0.725 �0.419min 0.630 �0.4340 min �0.288 0.6833 min �0.260 �0.2416 min �0.355 0.7629 min 0.056 �0.1732 min 1.702 �1.0515 min �0.711 0.8018 min 0.867 �0.3151 min 0.737 0.1764 min �0.426 0.2147 min 0.683 �0.2330 min 0.833 �0.5443 min 0.025 0.200

ssification of 3 subject response populations. A P � .6827 (1indicated for each cluster. These discriminant functions mightctors (Cluster 2), or cumulative irritation detectors (Cluster 3).

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rising capsaicin response phenotype, a temporal classi-cation of oral irritant responses might be a powerfulpproach for identifying genetic linkages of individual
ifferences in oral sensation. l
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cknowledgmentsWe wish to thank Kristin McGinnis, Alexander Puskar,

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eferences

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. Balaban CD, McBurney DH, Stoulis M: Time course ofurn to repeated applications of capsaicin. Physiol Behav6:109-112, 1999

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. Blakesley AF, Fox AL: Our different taste worlds. J Hered-ty 23:97-110, 1932

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. Drayna D, Kim U, Wooding S, Jorde L, Floriano W, God-ard WA: Genetics of PTC taste sensitivity in humans. Pre-ented at the 2004 Meeting of the Association for Chemo-eception Sciences, Sarasota, Fla.

. Fast K, Duffy VB, Bartoshuk LM: New psychophysical in-ights in evaluating genetic variation in taste, in Rouby C,chaal B, Dubois D, Gervais R, Holley A (eds): Olfaction,aste, and Cognition. New York, NY, Cambridge Universityress, 2002, pp 391-407

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1. Kalmus H: Improvements in the classification of theaster genotypes. Ann Hum Genet 22:222-230, 1958

2. Kim U, Jorgenson E, Coon H, Leppert M, Risch N, Drayna: Positional cloning of the human quantitative trait locusnderlying taste sensitivity to Phenylthiocarbamide. Science99:1221-1225, 2003

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5. Melzack R: The Puzzle of Pain. New York, NY, Basicooks, 1973

6. Prutkin J, Duffy VB, Etter L, Fast K, Gardner E, LucchinaA, Snyder DJ, Tie K, Weiffenbach J, Bartoshuk LM: Geneticariation and inferences about perceived taste intensity inice and men. Physiol Behav 69:161-173, 2000

7. Reed DR, Bartoshuk LM, Duffy VB, Marino S, Price A:ropylthiouracil tasting: Determination of underlyinghreshold distributions using maximum likelihood. Chemenses 20:529-533, 1995

8. Reed DR, Nanthakumar E, North M, Bell C, BartoshukM, Price RA: Localization of a gene for bitter taste percep-ion to hyman chromosome 5p15. Am J Hum Genet 64:1478-480, 1999

9. Snyder LH: Studies in human inheritance. IX. The in-eritance of taste deficiency in man. Ohio J Sci 32:436-
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three distinct categories of time course of pain produced by oral capsaicin

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