The roles of TRPV1, TRPA1 and TRPM8 channels in chemical and thermal sensitivity of the mouse oral mucosa.

Spices in food and beverages and compounds in tobacco smoke interact with sensory irritant receptors of the transient receptor potential (TRP) cation channel family. TRPV1 (vanilloid type 1), TRPA1 (ankyrin 1) and TRPM8 (melastatin 8) not only elicit action potential signaling through trigeminal nerves, eventually evoking pungent or cooling sensations, but by their calcium conductance they also stimulate the release of calcitonin gene-related peptide (CGRP). This is measured as an index of neuronal activation to elucidate the chemo- and thermosensory transduction in the isolated mouse buccal mucosa of wild types and pertinent knockouts. We found that the lipophilic capsaicin, mustard oil and menthol effectively get access to the nerve endings below the multilayered squamous epithelium, while cigarette smoke and its gaseous phase were weakly effective releasing CGRP. The hydrophilic nicotine was ineffective unless applied unprotonated in alkaline (pH9) solution, activating TRPA1 and TRPV1. Also, mustard oil activated both these irritant receptors in millimolar but only TRPA1 in micromolar concentrations; in combination (1 mm) with heat (45 °C), it showed supraadditive, that is heat sensitizing, effects in TRPV1 and TRPA1 knockouts, suggesting action on an unknown heat-activated channel and mustard oil receptor. Menthol caused little CGRP release by itself, but in subliminal concentration (2 mm), it enabled a robust cold response that was absent in TRPM8-/- but retained in TRPA1-/- and strongly reduced by TRPM8 inhibitors. In conclusion, all three relevant irritant receptors are functionally expressed in the oral mucosa and play their specific roles in inducing neurogenic inflammation and sensitization to heat and cold.

Cigarette smoke has sensory effects through nicotinic and TRPA1 but not TRPV1 receptors on the isolated mouse trachea and larynx.

Cigarette smoke (CS) exposes chemosensory nerves in the airways to a multitude of chemicals, some acting through the irritant receptors TRPV1 and TRPA1 but potentially also through nicotinic acetylcholine receptors (nAChR). Our aim was to characterize the differences in sensory neuronal effects of CS, gas phase, and particulate matter as well as of typical constituents, such as nicotine and reactive carbonyls. Isolated mouse trachea and larynx were employed to measure release of calcitonin gene-related peptide (CGRP) as an index of sensory neuron activation evoked by CS, by filtered CS gas phase essentially free of nicotine, and by dilute total particulate matter (TPM) containing defined nicotine concentrations. With CS stimulation of the superfused trachea, TRPV1 null mutants showed about the same large responses as wild-type mice, whereas both TRPA1(-/-) and double knockouts exhibited 80% reduction; the retained 20% response was abolished by mecamylamine (10 µM), indicating a distinct contribution of nAChRs. These phenotypes were accentuated by using TPM to stimulate the immersed trachea; 50% of response was retained in TRPA1(-/-) and abolished by mecamylamine. In contrast, the gas phase acted like a sheer TRPA1 agonist, consistent with its composition, among other compounds, of volatile reactive carbonyls like formaldehyde and acrolein. In the trachea, the gas phase and CS were equally effective in releasing CGRP, whereas the larynx showed much larger CS than gas phase responses. Thus nicotinic receptors contribute to the sensory effects of cigarette smoke on the trachea, which are dominated by TRPA1. How this translates to human perception affords future research.

Cigarettes with different nicotine levels affect sensory perception and levels of biomarkers of exposure in adult smokers.

INTRODUCTION: Few clinical studies involving cigarettes have provided a comprehensive picture of smoke exposure, test article characterization, and insights into sensory properties combined. The purpose of these pilot studies was to determine whether cigarettes with different levels of nicotine but similar tar levels would affect sensory experience or smoking behavior so as to significantly alter levels of selected biomarkers of exposure (BOE). METHODS: In 2 confined, double-blind studies, 120 adult smokers switched from Marlboro Gold cigarettes at baseline to either 1 of 2 lower nicotine cigarettes or 1 of 2 higher nicotine cigarettes and then to the other cigarette after 5 days. Urinary excretion of exposure biomarkers (nicotine equivalents [NE], total and free 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol [NNAL], 1-hydroxypyrene, and 3-hydroxypropyl mercapturic acid) as well as carboxyhemoglobin and plasma cotinine were measured at baseline, Day 5, and Day 10. Daily cigarette consumption was monitored and sensory characteristics were rated for each cigarette. RESULTS: With higher nicotine yield, urine NE, urine total NNAL, and plasma cotinine increased while nonnicotine BOE decreased without changes in cigarette consumption. In contrast, with lower nicotine yield, urine NE, urine total NNAL, and plasma cotinine dropped while nonnicotine BOE and cigarettes per day increased. Higher nicotine cigarettes were rated harsher and stronger than at baseline while lower nicotine cigarettes were less strong. All 4 test cigarettes were highly disliked. CONCLUSIONS: These studies demonstrate that abrupt increases or decreases in nicotine and the resulting sensory changes impact BOE through changes in intensity or frequency of smoking.

Chemo-somatosensory evoked potentials: a sensitive tool to assess conditioned pain modulation?

UNLABELLED: Abstract Background: Chemo-somatosensory evoked potentials (CSSEPs) elicited by chemical stimulation (CO2 gas) of the nasal mucosa have been shown to be sensitive enough to pick up even weak analgesic effects. With the present study we wanted to investigate whether CSSEPs are also a sensitive tool to capture endogenous pain inhibitory mechanisms elicited by conditioned pain modulation (CPM; where a first conditioning stimulus reduces the sensitivity for a second test stimulus) with a conditioning stimulus of rather low noxious load. METHODS: Seventeen healthy participants were tested for CPM effects (conditioning stimulus: tonic heat pain with intensities around the pain threshold induced via a thermode; test stimulus: chemonasal stimulation (73% and 78% CO2)) on CSSEPs and on self-report ratings. RESULTS: We found significant CPM effects in the CSSEPS, with reduced amplitudes and prolonged latencies at several electroencephalogram (EEG) recording positions when using the lower CO2 concentration (73% CO2). In contrast to the visible inhibitory effects on the CSSEPs, subjective ratings of the test stimulus did not reflect CPM action. DISCUSSION: The experimental pain model using CO2 stimuli to elicit CSSEPs proved to be sensitive enough to capture weak CPM effects elicited by a conditioning stimulus of rather low noxious load. The usage of such mild noxious conditioning stimuli-in contrast to stimuli of higher noxious load (e.g., cold pressor test)-has the advantage that the activation of other types of pain inhibitory mechanisms in parallel (like attentional distraction, stress-induced analgesia) can be avoided.

Bimodal concentration-response of nicotine involves the nicotinic acetylcholine receptor, transient receptor potential vanilloid type 1, and transient receptor potential ankyrin 1 channels in mouse trachea and sensory neurons.

High concentrations of nicotine, as in the saliva of oral tobacco consumers or in smoking cessation aids, have been shown to sensitize/activate recombinant transient receptor potential vanilloid type 1 (rTRPV1) and mouse TRPA1 (mTRPA1) channels. By measuring stimulated calcitonin gene-related peptide (CGRP) release from the isolated mouse trachea, we established a bimodal concentration-response relationship with a threshold below 10 µM (-)-nicotine, a maximum at 100 µM, an apparent nadir between 0.5 and 10 mM, and a renewed increase at 20 mM. The first peak was unchanged in TRPV1/A1 double-null mutants as compared with wild-types and was abolished by specific nicotinic acetylcholine receptor (nAChR) inhibitors and by camphor, discovered to act as nicotinic antagonist. The nicotine response at 20 mM was strongly pHe-dependent, - five times greater at pH 9.0 than 7.4, indicating that intracellular permeation of the (uncharged) alkaloid was required to reach the TRPV1/A1 binding sites. The response was strongly reduced in both null mutants, and more so in double-null mutants. Upon measuring calcium transients in nodose/jugular and dorsal root ganglion neurons in response to 100 µM nicotine, 48% of the vagal (but only 14% of the somatic) sensory neurons were activated, the latter very weakly. However, nicotine 20 mM at pH 9.0 repeatedly activated almost every single cultured neuron, partly by releasing intracellular calcium and independent of TRPV1/A1 and nAChRs. In conclusion, in mouse tracheal sensory nerves nAChRs are 200-fold more sensitive to nicotine than TRPV1/A1; they are widely coexpressed with the capsaicin receptor among vagal sensory neurons and twice as abundant as TRPA1. Nicotine is the major stimulant in tobacco, and its sensory impact through nAChRs should not be disregarded.

Tonic stimulation of the pharyngeal mucosa causes pain and a reversible increase of inflammatory mediators.

OBJECTIVE AND DESIGN: To develop a model of the inflammatory component of non-infectious sore throat using tonic stimulation and quantification of inflammatory mediators in pharyngeal lavage fluid. MATERIAL OR SUBJECTS: Forty-five healthy volunteers. TREATMENT: Cold dry air. METHOD: Tonic stimulation of the pharynx was achieved using a constant stream of cold dry air to the back of the throat. Following optimization of stimulation conditions (phase 1), pharyngeal pain, irritation, and swallowing discomfort were assessed using visual analog scales, and the concentration of inflammatory markers were measured in pharyngeal lavage fluid (phase 2). RESULTS: Optimum conditions for tonic pharyngeal stimulation were cold dry air at 12 °C, relative humidity 20 %, at a flow rate of 12 L/min for 15 min. Analysis of pharyngeal lavage fluid collected 5 min after stimulation showed significant increases in prostaglandin E2 (P = 0.018), thromboxane B2 (P < 0.001), and substance P (P < 0.001), but no increase in peptidoleukotriene. When the stimulus was removed, the level of inflammatory markers in pharyngeal lavage fluid returned to baseline by 30 min post-stimulation. These objective measures mirrored subjective pain ratings. CONCLUSIONS: Tonic stimulation of the pharyngeal mucosa with cold dry air causes pain and an increase of inflammatory mediators which are reversible.

The multi-faceted food odorant 4-methylphenol selectively activates evolutionary conserved receptor OR9Q2.

4-Methylphenol is a food-related odor-active volatile with a high recognition factor, due to its horse stable-like, fecal odor quality. Its ambivalent hedonic impact as key aroma compound, malodor, and semiochemical has spurred the search for its cognate, chemosensory odorant receptors across species. A human odorant receptor for the highly characteristic 4-methylphenol has been elusive. Here, we identified and characterized human receptor OR9Q2 to be tuned to purified 4-methylphenol, but not to its contaminant isomer 3-methylphenol. This highly selective function of OR9Q2 complements an exclusive phenol detection gap in the ancient, most broadly tuned human odorant receptor OR2W1. Moreover, a 4-methylphenol function is evolutionary conserved in phylogenetically related OR9Q2 orthologs from chimpanzee, mouse, and cow. Notably, the cow receptor outperformed human OR9Q2 10-fold in signal strength, consonant with previous reports of 4-methylphenol as a bovine pheromone. Our results suggest OR9Q2 as best sensor for the key food odorant, malodor, and semiochemical 4-methylphenol.

Evaluation of the effect of ammonia on nicotine pharmacokinetics using rapid arterial sampling.

INTRODUCTION: The nicotine bolus theory states that the dependence-producing potential of cigarettes relates to a rapid increase in nicotine at brain receptor sites. It has been suggested that ammonia, a compound typically found in tobacco products, further increases the amount of nicotine absorbed and its absorption rate. The aim of this study was to determine whether different ammonia yields in cigarettes affected the rate or amount of nicotine absorption from the lungs to arterial circulation. METHODS: 34 adult smokers received 3 separate puffs from each of 2 test cigarettes with different ammonia yields (ammonia in smoke: 10.1 µg per cigarette vs. 18.9 µg per cigarette), followed by rapid radial arterial blood sampling (maximum one sample per second) with 30 min between puffs. Arterial blood samples were assayed for nicotine by liquid chromatography tandem mass spectrometry. Pharmacokinetic modeling was performed and the two test cigarettes were assessed for bioequivalence. RESULTS: No significant differences were found in area under the curve, C(max), or T((max)) and the 2 test cigarettes were found to be bioequivalent based on 2 one-sided tests at a significance level of 5%. In addition, the zero-order rate constant (k(0)) obtained from the initial slope of the curves and the model-dependent first-order rate constant (k(a)) were not significantly different. CONCLUSIONS: This study provides strong evidence that the different ammonia yields of the test cigarettes had no impact on nicotine pharmacokinetics; thus, the ammonia did not increase the rate or amount of nicotine absorption from a puff of cigarette smoke.

Rapid automated blood sampling system for pharmacokinetics studies of cigarette smoking.

INTRODUCTION: We developed an automated sampling system to allow multiple, discrete blood samples from a human participant to be collected rapidly and immediately following cigarette smoke exposure. We reported the details of the sampling system along with the results of a pilot study for evaluation of the system. METHODS: Components of the system include silastic tubing, solenoid pinch valves, a peristaltic pump, and a fraction collector. This system incorporates a smoking machine that allows precise delivery of cigarette smoke through a mouthpiece and intricate timing to correlate blood samples with smoke inhalation. All components are controlled via integration from a user interface and are fully customizable. We performed several tests to evaluate the equipment, including tubing dead volume, leakage tests, and sample reproducibility. We also performed a pilot study with 6 adult smokers, who received 6 controlled puffs of a research test cigarette. Each inhalation was followed by radial arterial blood collection (1 sample per second tapered to 1 sample every 4 s) for 1 min. Samples were evaluated for nicotine via liquid chromatography-tandem mass spectrometric methods. RESULTS: Sampling times and volumes were sufficient for nicotine analysis. No adverse effects were seen in the pilot study, and a 30-min washout period was deemed appropriate between puffs. A significant rise in plasma nicotine levels above baseline after inhalation of smoke was consistently detected in all participants. DISCUSSION: The unique advantage of this system is to allow rapid blood sampling after a puff of cigarette smoke, with the benefits of reproducibility, reduction in labor intensity, and high temporal resolution.

Activation of olfactory and trigeminal cortical areas following stimulation of the nasal mucosa with low concentrations of S(-)-nicotine vapor--an fMRI study on chemosensory perception.

Applied to the nasal mucosa in low concentrations, nicotine vapor evokes odorous sensations (mediated by the olfactory system) whereas at higher concentrations nicotine vapor additionally produces burning and stinging sensations in the nose (mediated by the trigeminal system). The objective of this study was to determine whether intranasal stimulation with suprathreshold concentrations of S(-)-nicotine vapor causes brain activation in olfactory cortical areas or if trigeminal cortical areas are also activated. Individual olfactory detection thresholds for S(-)-nicotine were determined in 19 healthy occasional smokers using a computer-controlled air-dilution olfactometer. Functional magnetic resonance images were acquired using a 1.5T MR scanner with applications of nicotine in concentrations at or just above the individual's olfactory detection threshold. Subjects reliably perceived the stimuli as being odorous. Accordingly, activation of brain areas known to be involved in processing of olfactory stimuli was identified. Although most of the subjects never or only rarely observed a burning or painful sensation in the nose, brain areas associated with the processing of painful stimuli were activated in all subjects. This indicates that the olfactory and trigeminal systems are activated during perception of nicotine and it is not possible to completely separate olfactory from trigeminal effects by lowering the concentration of the applied nicotine. In conclusion, even at low concentrations that do not consistently lead to painful sensations, intranasally applied nicotine activates both the olfactory and the trigeminal system.

Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen.

The aim of this study was to determine the analgesic effect of acetaminophen compared to a combination of both caffeine and acetaminophen or caffeine alone using tonic and phasic pain stimulation. Twenty-four subjects were treated orally with 1000 mg acetaminophen, 130 mg caffeine, and a combination of both in a 4-way crossover, double-blind, placebo-controlled study. Pharmacokinetics and analgesic effects were assessed by means of an experimental pain model based on pain-related cortical potentials after phasic stimulation of the nasal mucosa with CO(2) and based on pain ratings after tonic stimulation with dry air. Analgesic effects of acetaminophen and acetaminophen plus caffeine but not caffeine alone caused a significant reduction of pain-related cortical potentials beginning 30 minutes after medication. The combination demonstrated an enhanced effect throughout the observation time up to 3 hours. Caffeine accelerated acetaminophen absorption, indicated by enhanced early AUCs. Significant analgesic effects of the combination on tonic pain ratings were found throughout the observation time as compared to acetaminophen and placebo. In this study, caffeine enhanced and prolonged the analgesic activity of acetaminophen.

Impact of continuous low level heatwrap therapy in acute low back pain patients: subjective and objective measurements.

OBJECTIVES: Muscular pain is usually associated with increased muscle tension resulting in a vicious tension-pain-cycle, leading to increased alertness and stress. However, this has not been broadly evaluated using objective methods, for example, looking at neurophysiologic changes. The focus of this study was, therefore, to combine objective [spontaneous electroencephalogram (EEG) as a surrogate of alertness and stress] with subjective parameters (self-assessed pain affected variables) to investigate the effect of continuous low-level heat therapy in low back pain (LBP)-patients. METHODS: This investigation was a randomized, active controlled, parallel-designed study. Thirty patients were randomly assigned to one of 2 groups: the control group, in which patients were provided with oral analgesics (nonsteroidal anti-inflammatory drug) and instructed to use it if needed, and the treatment group, in which patients in addition to oral analgesics as rescue medication were provided with a heatwrap therapy. The objective parameters were assessed by measuring the power of frequency bands in the spontaneous EEG. The subjective parameters (sleep pattern, well-being, pain intensity, etc.) were assessed by a Pain, Sleep, and Stress Questionnaire. RESULTS: In the EEG-recordings, the heatwrap therapy group showed decreased power in Beta-1 and Beta-2 frequency bands compared with the control group, indicating a reduction in arousal. Also, in comparison to the control group, the heatwrap therapy group reported significantly reduced LBP, everyday situations being less stressful, a better night's sleep, and a decreased number of daytime naps. DISCUSSION: In addition to classic psychophysical assessment of pain-related parameters and sleep quality, performance in daily life, we were able to obtain objective measures (EEG) that suggest an acute therapeutic relaxation on the basis of the central nervous system effects accompanying the reported significant pain relief. We believe that this was due to a reduced nociceptive information load in LBP-patients after the use of the heatwrap therapy.

Electro-olfactograms are present when odorous stimuli have not been perceived.

After chemical stimulation of the human olfactory epithelium it is possible to record a negative response (electro-olfactogram, EOG) which is interpreted as the summated generator potential of olfactory neurons. The aim of the present investigation was to test whether the EOG is present when olfactory stimuli have not been perceived. Stimulation was performed with vanillin and eugenol at supraliminal and subliminal levels. Twelve healthy volunteers participated in the experiments. Stimuli were applied at an interstimulus interval of approximately 60s. Although recordings were successful in 4 of the 12 subjects, for both stimulants EOG could be obtained even when the stimuli had not been perceived by the subjects. EOG recordings in response to supra- and subliminal stimuli exhibited no major differences, except for the onset of the EOG in response to subliminal eugenol-stimuli which were prolonged compared to supraliminal stimulation. All in all, the present data provide a physiological basis for the subliminal influence of odorous stimuli on human behavior.

Pain-related electrical potentials of the human nasal mucosa elicited by chemical stimulation.

For the first time a non-invasive method was employed to record pain-related electrical potentials from the human respiratory nasal mucosa. Gaseous stimulants at painful concentrations were presented by the newly developed stimulating device. The amplitudes of the potentials were found correlated (a) with concentrations of the stimulants, and (b) with subjective estimations of pain intensity. The local anesthetic tetracaine hydrochloride, and also a systemically administered analgesic drug pentazocine given prior to painful stimulation decreased the amplitude of the negative potentials. The peripheral response was interpreted as a summated receptor potential from chemical nociceptors. It is thought to be analogous to the electro-olfactogram. This non-invasive technique of stimulation and recording offers an objective and quantitative measure related to pain sensations and their inhibition by analgesic drugs.

Bilateral hyperalgesia to chemical stimulation of the nasal mucosa following unilateral inflammation.

The aim of the present study was to investigate the bilateral sensory changes to chemical noxious stimuli in the trigeminally innervated areas following unilateral nasal inflammation. Twenty healthy volunteers took part in five experiments. Intranasal inflammation was induced by means of a constant flow of cold air (145 ml/s); temperature and humidity of the airstream were varied across experiments. For the non-inflamed (NOI) condition, air temperature was 36 degrees C and its humidity 80%. In the other experiments the airstream's humidity was either 25% or 80% with a constant temperature of 20 degrees C; the airstream was applied to the left or right nostril. In order to produce noxious chemical stimuli, gaseous CO2 was applied to the left nostril (36 stimuli of 200 ms; 65% v/v CO2; interstimulus interval 30 s). Subjects rated the pain intensity of the stimuli by means of a visual analogue scale (VAS). As an indicator for hyperalgesia, the subjective pain ratings to CO2 stimuli increased not only while they were applied at the inflamed site, but also during their application contralaterally to the inflamed side. These results demonstrate the occurrence of bilateral hyperalgesia to noxious chemical stimuli in the nasal mucosa following unilateral inflammation which indicates the involvement of central changes.

Sensitivity of the negative mucosal potential to the trigeminal target stimulus CO(2).

CO(2) is frequently used in an experimental pain model and in imaging studies investigating the central processing of trigeminal nociceptive information because of its specific trigeminal stimulation properties. The aim of the current study was (1) to investigate the sensitivity of the NMP to small increments of CO(2) stimulus concentrations (3% CO(2), v/v) and (2) to characterize the sensory input of CO(2) by determining NMP, detection and pain thresholds and by registering subjective verbal descriptions. Ten subjects participated in the first experimental sessions investigating NMP responses to stimuli of 62, 65, 68% CO(2) (v/v) (stimulus duration: 1000 ms). Our statistical analysis revealed a dose-dependent increase of the NMP amplitudes and areas under the curves (AUCs) demonstrating the high dynamic resolution of the NMP. Ten subjects participated in the second experimental sessions determining thresholds for NMP, detection and pain (stimulus duration: 1000 ms). MANOVA analysis revealed significantly different thresholds for detection, NMP and subjective pain judgements (mean and S.D. as percentage CO(2) (v/v): detection: 20.6+/-9.6, NMP: 42.6+/-12.5, pain: 50.4+/-12.0). We could demonstrate the existence of a prepain range below subjective pain thresholds with activation of trigeminal nociceptive sensors resulting in the generation of NMPs. The detection threshold of 20.6% CO(2) (v/v) was surprisingly low, i.e. 22% CO(2) (v/v) below the NMP threshold. The involvement of newly discovered alpha-gustducin positive trigeminal chemosensory cells in CO(2) detection is hypothesized.

Anesthesia affects olfaction and chemosensory event-related potentials.

OBJECTIVE: Olfactory and trigeminal systems interact and contribute to the perception of odorants. This study was aimed at investigating the effect of local anesthesia on olfaction. METHODS: One percent of tetracaine on a cotton swab was applied intranasally at three different locations in 20 volunteers and 4% of lidocaine was applied to the olfactory cleft in a head-down position. Before and after anesthesia, self-assessment, psychometric testing and olfactory event-related potentials [OERPs, using H(2)S and phenyl ethyl alcohol (PEA)], and chemosomatosensory event-related potentials (CSSERPs, using CO(2)) were examined. RESULTS: Anesthesia at all four locations significantly lowered the perceived self-assessment of olfaction, while using the cotton swab only anesthesia in the middle meatus elevated threshold (P = 0.020), lowered discrimination (P = 0.015), and prolonged OERP (PEA, P = 0.008; H(2)S, P = 0.016), as well as CSSERPs latencies (CO(2), P = 0.020). However, complete temporary anosmia was only achieved after applying 4% lidocaine into the olfactory cleft. CONCLUSIONS: Intranasal anesthesia applied with a swab reduced self-assessment of olfaction but was unable to produce anosmia. Psychometric test results were concordant with changes in chemosensory event-related potentials. SIGNIFICANCE: Temporary anosmia is technically difficult to achieve but could be demonstrated for the first time using local anesthesia. Even though anesthesia influences self-assessment, measurable olfactory function can remain unchanged.

Test-retest reliability of chemosensory evoked potentials.

This study investigated the test-retest reliability of chemosensory event-related potentials in humans. Olfactory event-related potentials and chemosomatosensory event-related potentials were evaluated in 20 healthy, normosmic subjects. Phenyl ethyl alcohol (PEA, 40% v/v) and H(2)S (4 ppm) served as olfactory stimuli whereas CO(2) (60% v/v) was the chemosomatosensory stimulus. Fifteen stimuli of each compound were applied to each nostril. Identical stimulation sequences were used during three test sessions. Sessions 1 and 2 were separated by a mean of 6.8 days; sessions 2 and 3 by 12.5 days. Electroencephalographic recordings were made from Fz, Cz, Pz, C3, and C4. Amplitudes and latencies of P1, N1, P2, N2, and P3 were measured. Pearson's correlation coefficient was calculated to test the test-retest reliability, and the general linear model examined the differences. Most correlations ranged between 0.4 < r < 0.75. Latencies correlated significantly better (P = 0.008) between sessions than amplitudes, even though with CO(2) stimulus amplitudes correlated significantly better than with PEA (P = 0.006) or H(2)S (P = 0.003). No differences arose between measurements from different nostrils for any stimulus. Chemosensory event-related potentials show good test-retest reliability. Carbon dioxide amplitudes exhibit better signal-to-noise ratios than PEA or H(2)S amplitudes. Chemosensory event-related potentials are a clinically valuable objective and are reproducible.

Pain in the trigeminal system: irritation of the nasal mucosa using short- and long-lasting stimuli.

The paper describes methods which allow intranasal irritation using short- and long-lasting painful stimuli in humans. Short-lasting pain is induced by gaseous CO(2), while long-lasting pain is induced by a stream of dry air. Both models have been explored regarding their major determinants, e.g. stimulus duration, stimulus intensity, or repeated stimulation. Short-lasting, non-inflammatory pain stimuli seem to provide specific indicators of A(delta)-fiber function, while responses to long-lasting, inflammatory pain appear to be indicative of C-fiber function. Responses to both types of painful stimuli are modulated by analgesic drugs. As these well-investigated models allow the detailed and precise analysis of modulatory effects on intranasal nociception, they appear to be suited for the investigation of subtle changes of intranasal irritation, e.g. induced by environmental agents.

The Candy Smell Test in clinical routine.

BACKGROUND: The "Candy Smell Test" (CST) has been introduced as a new testing method for the evaluation of the human sense of smell. In contrast to other established orthonasal smell tests, the CST addresses the retronasal application of odors, typical for food aroma effects during mastication and swallowing. The aim of this study was to evaluate the CST in a clinical setting in patients with olfactory dysfunction and normal controls against the Sniffin' Sticks test. Furthermore, cutoff points for normal and pathological results in the CST should be determined. METHODS: The olfactory performance of 96 patients presenting with olfactory disorders and 71 healthy controls was evaluated with the CST-comprised of 23 different aromatized smell candies and the extended Sniffin' Sticks test (threshold, discrimination, and identification). The control group was gender matched but included also younger persons. RESULTS: The tested subjects could easily understand the procedures and were motivated to participate. The CST correlated well with the Sniffin' Sticks for all tested subjects and for patients (n = 96) and controls (n = 71). The proposed cutoff value to differentiate normosmia from hyposmia in the CST was a score of <16 (i.e., 16 correctly identified odors) of 23. A score below 13 in the CST was the cutoff value for anosmia. CONCLUSION: The CST is an easy-to-handle reliable tool to investigate retronasal olfaction suited for clinical determination of normosmia, hyposmia, and ansomia. In addition, it can be used for investigation where self-application is necessary such as in large survey studies.