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J Dent Res 82(4): 303-307, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Differences Between Tooth Stimulation and Capsaicin-induced Neurogenic Vasodilatation in Human Gingiva

P. Kemppainen1,*, N.-L. Avellan1, H.O. Handwerker2, and C. Forster2

1 Institute of Dentistry, PO Box 41, 00014 University of Helsinki, Finland, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital (HUCH); and
2 Department of Physiology and Experimental Pathophysiology, University of Erlangen/Nürnberg, Germany;

*corresponding author, pentti.kemppainen{at}helsinki.fi


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animal experiments have shown that the application of capsaicin to oral mucosa leads to a neurogenic inflammation associated with blood flow elevations in gingivomucosal tissues. In this investigation, we measured the tooth stimulation and capsaicin-evoked blood flow responses in maxillary gingiva in humans to study whether axon-reflex-mediated vasodilatation crosses the midline of the maxilla. The vasoactive reactions were mapped by laser Doppler imaging. Unilateral stimulation of alveolar mucosa and attached gingiva by capsaicin evoked a distinct neurogenic vasodilatation in ipsilateral gingiva, which rapidly attenuated at the midline. Capsaicin stimulation of alveolar mucosa provoked clear inflammatory reactions. In contrast to capsaicin stimuli, tooth stimulation produced symmetrical vasodilatations bilaterally in the gingiva. The ipsilateral responses were significantly smaller during tooth stimulation than during capsaicin stimuli. Analysis of these data suggests that capsaicin-induced inflammatory reactions in gingivomucosal tissues do not cross the midline in the anterior maxilla. The enhanced reaction found during stimulation of alveolar mucosa indicates that alveolar mucosa is more sensitive to chemical irritants than attached gingiva.

KEY WORDS: neurogenic inflammation • blood flow • gingiva • capsaicin • laser Doppler imaging


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is well-documented that the activation of cutaneous nociceptive afferents induces local vasodilatation (Bruce, 1913; Magerl et al., 1987; Wårdell et al., 1993), which is caused by the release of inflammatory mediators from the peripheral nerve terminals and, thus, is called axon-reflex-mediated neurogenic inflammation (Holzer, 1988). Axon-reflex vasodilatation usually spreads symmetrically around the nociceptive stimulus and corresponds to the size of the receptive fields of stimulated nociceptive afferents (Wårdell et al., 1993), but in skin areas near the midline, asymmetric flare responses that do not cross the midline have been found (Mentis and Lynn, 1992). In clinical dentistry, it is recognized that toxins, enzymes, and metabolites of various bacteria of the dental plaque are responsible for the initiation of inflammation in the periodontium (Listgarten, 1987). More recent animal studies (Fazekas et al., 1990; Kondo et al., 1995) have shown that similar inflammatory reactions in gingivomucosal tissues can be induced experimentally by capsaicin activation of the nociceptive fibers of these tissues. However, there have been no systematic studies on the existence and characteristics of neurogenic inflammatory reactions in human gingival tissues.

In this investigation, we studied the characteristics of capsaicin-induced axon-reflex-mediated vasodilatation in the human gingiva. Earlier animal studies have suggested that peripheral axons of the trigeminal nerves may cross the midline and innervate maxillary incisors bilaterally (Anderson et al., 1977). Here, we designed a series of experiments to determine whether capsaicin-evoked vasodilatation in gingiva crosses the midline of the maxilla. If this axon-reflex vasodilatation crossed the midline, the experiments might show functional evidence for transmedian innervation in maxillary gingiva. Our previous studies (Kemppainen et al., 2001a,b) have indicated that high-intensity tooth stimulation evokes vasodilatation in the lips, which is not based on the axon-reflex mechanism. Therefore, the present study was also conducted to clarify whether there are differences between tooth stimulation and capsaicin-evoked vasoactive responses in gingiva.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Seven trained volunteers, ranging in age from 21 to 41 years, were tested in three separate experiments in this study. The subjects were healthy graduate students or researchers, and informed consent was obtained from each subject before the experiments, according to the ethical guidelines of the Helsinki Declaration of 1975. Each of the three experimental sessions was completed on six subjects. Five of them participated on all three experiments. Of the remaining two subjects, one participated on only the tooth stimulation experiment, and the other took part in the two capsaicin experiments. The Ethics Committee of the medical faculty of the University of Erlangen-Nürnberg approved the study protocol. All subjects had excellent oral health and were free of any clinical signs of infection in their oral tissues.

Stimulation Techniques
Capsaicin (Sigma Chemical Co., St. Louis, MO, USA) was dissolved in olive oil to achieve a 3% solution of capsaicin. For stimulation, filter paper (4 x 1.5 mm) moistened with 10 µL of this solution was positioned unilaterally to either the attached gingiva or the alveolar mucosa between the permanent upper right first (tooth 11)/second incisor (tooth 12), or permanent upper left first (tooth 21)/second incisor (tooth 22). In three of the six subjects who completed the capsaicin experiments, alveolar mucosa was stimulated first, followed by stimulation of the attached gingiva on the other side of the maxilla.

The dental stimulation was generated with a constant-current tooth stimulator as has been described (Kemppainen et al., 1985). During the experimental sessions, electrical stimulation of the permanent upper right incisor was performed at an intensity of three times the individual threshold.

Blood Flow Measurements
Simulation-induced blood flow changes in buccal attached gingiva and oral mucosa were mapped by means of a laser Doppler perfusion imager (LDI) as described previously (Wårdell et al., 1993; Kemppainen et al., 2001a). Scanning times of 60 sec (capsaicin experiments) and 90 sec (tooth stimulation experiments) were used during which the bilateral images from the oral mucosa and attached gingiva of the anterior maxilla could be documented (Fig. 1Go).



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  		Figure 1. Photo and corresponding image of the gingivomucosal blood flow measured by laser Doppler imaging during unilateral stimulation of gingiva by capsaicin.

 
Sympathetically maintained vasoconstriction of peripheral skin vessels, which is modulated by pain reflexes (Kemppainen et al., 2001a,b), was monitored by blood flow measurements on the skin of the right index finger, by laser Doppler flowmetry (LDF; Periflux Pf2B, Perimed AB, Stockholm, Sweden).

Course of the Experiments
Each subject sat comfortably in a dental chair. The investigation consisted of three separate experimental sessions in which painful stimulation of the alveolar mucosa and gingiva (capsaicin stimulation) and central incisor (electrical stimulation) was completed on six human volunteers. For each subject, the tooth stimulation experiment was done first, followed by two separate capsaicin experiments. Five of the subjects completed all three experimental sessions. The interval between the experiments was one week.

In each capsaicin experiment, a sequence of 15 LDI scans (each lasting 60 sec) was taken, the first 3 of which served as the pre-capsaicin baseline, followed by scans 4 to 15 with capsaicin. During the tooth stimulation experiment, a total of 10 LDI scans (duration, 90 sec) was taken, the first 2 of which served as the pre-stimulation baseline, followed by the third scan with tooth stimulation, and scans 4 to 10 after tooth stimulation.

During each experiment, subjective pain levels were assessed via an electronic visual analogue scale, VAS (0 = no pain, 100 = the worst imaginable pain intensity). During the experiments, mean arterial blood pressure (MAP) and heart rate (HR) responses were monitored continuously from the left middle finger by a non-invasive cuff method (Finapress, Ohmeda, Zürich, Switzerland). With the help of an external trigger, the initiation of LDF, MAP, and HR recording was synchronized with the beginning of the first LDI scan.

Data Analysis
All data (except rating) were normalized to baseline. The mean of the 3 baseline values was taken as 100%, and all succeeding values were expressed as a percent change of the individual baseline (Kemppainen et al, 2001a). For statistical analysis, the continuous data record was similarly reduced to average response values of three-minute time windows: 1 prior (= baseline) and 4 after the stimulation began. For the analysis of LDI data, the positions of the areas of interest were corrected if movements of the subject could be detected between different images.

To compare the responses in gingival blood flow, we performed an analysis of variance (ANOVA), repeated-measure design, with the factors stimulus type (capsaicin in oral mucosa, capsaicin in attached gingiva, and tooth stimulation) and time period. For this, the data from the five subjects who participated in all experiments were used. Post hoc planned comparisons were performed on significant factors. Changes to baseline were tested by means of a Wilcoxon matched-pair test of the data from all subjects. A probability value (P) of less than 0.05 was considered to represent a significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The average pain magnitude estimates were significantly higher during tooth stimulation than during capsaicin stimulation of the alveolar mucosa and attached gingiva. The respective maximum VAS scores were 78 ± 4, 32 ± 3, and 17 ± 4.

Fig. 2Go shows the average extensions of vasodilatation in gingivomucosal tissues induced by the unilateral application of capsaicin in alveolar mucosa. In every subject, this capsaicin-induced vasodilatation rapidly attenuated in the midline. Similar asymmetric vasodilatation was found when capsaicin was applied to the attached gingiva.



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  		Figure 2. Extension of gingival blood flow responses. Average (N = 6) extension of vasodilatation along a horizontal line over the gingivomucosal tissues. Vasodilatation was induced by unilateral application of capsaicin in alveolar mucosa. The stimulation site is marked by a gray rectangle and was between teeth 11/12 or 21/22. The vasodilatation clearly stopped at the midline between teeth 11 and 21. Analysis was performed on the mean vasodilatation in the period 6 to 9 min after the start of stimulation. Only data from the experiments with capsaicin in alveolar mucosa are shown.

 
In ipsilateral gingiva, the vasodilatation responses (Fig. 3AGo) were affected by the stimulation paradigm: The highest responses were caused by capsaicin on alveolar mucosa, the second highest by capsaicin on attached gingiva, and the lowest effects by tooth stimulation. Planned comparison revealed that these differences were significant during the entire capsaicin stimulation period. The maximum increases in vasodilatation were 201 ± 17.8%, 150 ± 4.6%, and 118 ± 1.4%, respectively.



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  		Figure 3. Gingival blood flow and its relation to pain intensity. (A) Average changes (mean ± SEM, N = 6) of ipsilateral gingival blood flow during the different stimulation conditions. Shown are the changes from baseline after the start of stimulation. The open stars mark significant differences as compared with baseline (Wilcoxon matched-pairs), while the asterisks denote significant differences between stimulation conditions (ANOVA planned comparison). Data are normed to baseline (baseline = 100%). (B) Average changes (mean ± SEM, N = 6) of contralateral gingival blood flow during the different stimulation conditions. (C) Correlation between the VAS score of the pain rating and changes in contralateral gingival blood flow during capsaicin stimulation to the gingiva and alveolar mucosa. The line shows the correlation, which is r = 0.432.

 
On contralateral gingiva, the vasodilatation responses also depended on the stimulation paradigm: The highest vasodilatation was caused by painful tooth stimulation (Fig. 3BGo). The maximal blood flow elevations in contralateral gingiva were 112 ± 3.1%, 111 ± 2.6%, and 103 ± 3.6% during tooth stimulation, capsaicin on alveolar mucosa, and capsaicin on attached gingiva, respectively. In comparison with capsaicin stimuli, planned comparison showed that tooth stimulation induced a significantly higher flow response during the stimulation period and 3 min after stimulation. The contralateral responses during capsaicin stimulation were positively correlated (r = 0.432) with VAS scores (Fig. 3CGo).

High-intensity tooth stimulation induced a transient elevation in MAP and HR concomitant with a significant blood flow reduction in the finger. Neither of the capsaicin stimuli provoked any significant changes in MAP or HR responses (Fig. 4Go). In comparison with capsaicin stimuli, the more painful tooth stimulation tended to induce a more marked blood flow reduction in the finger.



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  		Figure 4. Cardiovascular changes. The left side shows the maximum increase of mean arterial blood pressure (MAP) after the start of stimulation. The middle Fig. shows the maximum change in heart rate and the right side the minimum blood flow in the finger. The latter is an indication of vasoconstriction. The values shown are changes from baseline. The asterisks mark significant differences between stimulation conditions (Wilcoxon matched-pair test). Shown are medians ± 95% confidence intervals (N = 6 for each bar).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, capsaicin stimuli of the gingivomucosal tissues evoked a pronounced vasodilatation in ipsilateral gingiva that rapidly attenuated at the midline of the anterior maxilla. In contrast to this, painful stimulation of the upper central incisor produced comparable blood flow elevations bilaterally in the maxillary gingiva. The contralateral vasodilatations were increased as a function of increasing stimulus-evoked pain estimates. These results indicate that axon-reflex-mediated vasodilatation in the gingiva does not cross the midline of the maxilla, and, importantly, that pain may contribute to trigeminal blood flow regulation in humans.

In our investigation, we applied the LDI technique for the first time to record blood flow in human gingiva. Although an indirect measure, LDI has been shown previously to be a successful method for the documentation of orofacial blood flow changes (Kemppainen et al., 2001a, b). In contrast to LDF, as used, for example, in the determination of blood flow in healthy (Baab et al., 1986) and diseased human gingiva (Baab et al., 1990), LDI has the advantage of giving information on the spatial distribution of vasoactive changes from separate tissues simultaneously. The current finding—that tooth stimulation evokes bilateral vasodilatation while capsaicin stimulation of the gingiva mainly produces unilateral vasodilatation—emphasizes the usefulness of LDI in clarifying spatial features of neurogenic vasoactive changes in the intra-oral tissues.

In the present study, capsaicin stimulation of the oral mucosa or attached gingiva induced a pronounced vasodilatation in the vicinity of the stimulus site. Earlier animal studies have shown that gingival tissues also contain capsaicin-sensitive nociceptive C-fibers (Györfi et al., 1992), the activation of which can lead to local axon-reflex-mediated neurogenic vasodilatation (Györfi et al., 1996; Flores et al., 2001) in these tissues. Thus, the present capsaicin-evoked vasodilatation in the unilateral gingiva is most likely based on an axon-reflex mechanism. Interestingly, this pronounced ipsilateral reflex rapidly attenuated at the midline. Since axon-reflex vasodilatation is known to spread symmetrically around the nociceptive stimulus and corresponds to the size of the receptive fields of stimulated nociceptive afferents (Wårdell et al., 1993), the present results do not favor the hypothesis of functional transmedian innervation of gingival tissues in anterior maxilla, or that peripheral axons are crossing the midline of anterior maxilla in significant numbers. A similar asymmetric blood flow response in relation to the midline has been found in the skin of the posterior part of the neck (Mentis and Lynn, 1992). Our results are also in agreement with those from several anatomical (Fuller et al., 1979; Byers and Matthews, 1981) and electrophysiological (Saag and Reid, 1981; Foster and Robinson, 1994) studies in animals showing that cross-innervation of maxillary and mandibular nerves exists rarely if at all. In comparison with the attached gingiva, stimulation of alveolar mucosa by capsaicin provoked larger neurogenic inflammatory reactions. Magnusson and Koskinen (2000) showed that capsaicin-evoked physiological responses clearly correlated to the percutaneous penetration of topically applied capsaicin. Thus, the present differences in inflammatory reactions could be due to weaker perfusion of capsaicin through keratinized gingiva than non-keratinized alveolar mucosa. Furthermore, these findings suggest that, in comparison with alveolar mucosa, keratinized gingiva serves a superior protective function for inflammatory effects induced, for example, by irritating chemicals and possibly bacterial toxins.

In contrast to mainly ipsilateral responses during the present capsaicin experiments, unilateral stimulation of the upper incisor caused comparable vasodilatations on both sides of the anterior maxillary gingiva. This is in line with our previous findings showing that high-intensity tooth stimulation provokes bilateral blood flow elevations in the upper and lower lips (Kemppainen et al., 2001a). The current tooth-pain-evoked bilateral vasodilatation in the gingiva, from an anatomical point of view, is difficult to explain by an axon-reflex mechanism.

In the present study, the transient changes in HR and BP were not correlated to the blood flow changes during any of the different pain stimuli. Thus, the observed blood flow increases in mucogingival tissues were not a secondary consequence of the rise in BP and HR, but most likely were due to some active pain-induced mechanism.

In our investigation, the contralateral vasodilatations during different stimuli were increased as a function of increasing stimulus-evoked pain responses. There is good evidence that several orofacial organs (Lundberg et al., 1982; Kaji et al., 1988) are innervated by parasympathetic fibers releasing vasodilator transmitters such as acetylcholine and vasoactive intestinal peptide (VIP), a vasodilator substance with a long half-life (Goadsby and Macdonald, 1985). Moreover, noxious stimulation of the oral structures has been shown to induce active somato-parasympathetic vasodilatation at numerous intra-oral sites in cats (Izumi and Karita, 1992; Shoji, 1996). Thus, the present bilateral vasodilatation during tooth stimulation and the contralateral responses during capsaicin experiments could well be based on a pain-evoked centrally mediated parasympathetic vasodilator mechanism.

The present investigation shows that capsaicin produces an axon-reflex-mediated neurogenic inflammatory reaction in human gingivomucosal tissues, which does not cross the midline of the anterior maxilla. The enhancement of this reaction during mucosal stimulation suggests that alveolar mucosa has a higher susceptibility than attached gingiva to inflammatory effects induced by chemical irritants in the oral cavity. The more extended vasoactive changes in contralateral gingivomucosal tissues during different stimuli are most likely based on a pain-evoked, possibly parasympathetic, vasoactive reflex mechanism.


   ACKNOWLEDGMENTS
 
This study was financially supported by the Academy of Finland, the Deutsche Forschungsgemeinschaft, SFB 353, and the Finnish Dental Society.

Received July 8, 2002; Last revision November 22, 2002; Accepted January 14, 2003


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 ABSTRACT
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 MATERIALS & METHODS
 RESULTS
 DISCUSSION
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