osmotic excitants of pain in human dentine

Arch. oral Bid. Vo1.7, pp.513-523, 1962. Pergamon Press Ltd. Printed in Ct. Britain.

OSMOTIC EXCITANTS OF PAIN IN HUMAN DENTINE

D. J. ANDERSON and G. A. RONNING*

Physiological Laboratory, Guy’s Hospital Medical School,

London S.E. 1

Abstract-Various substances in solutions exerting osmotic pressures from approximately 25 to 2800 atmospheres have been applied to human dentine with the object of establishing a relationship between osmotic pressure and pain-producing power. The existence of such a relationship is compatible with the results obtained with CaCl,, but is not clearly shown with other substances. Altering the contents of the dentinal tubules by applying AgNOp and eugenol did not abolish the sensitivity to CaCI,. Likewise, the application to the dentine of self-polymerizing resins which others have shown to cause odontoblast aspiration, left the dentine sensitive to stimulation with CaCI,.

INTRODUCTION

ANDERSON, CURWEN and HOWARD (1958) and ANDERSON and NAYLOR (1961, 1962)

have shown that a range of substances which when applied in solution to the exposed

base of a blister caused pain (ARMSTRONG et al., 1953) did not have this effect when

applied to human dentine. 2 M sucrose and a concentrated sugar syrup (sucrose

32.5 g, invert sugar 47.9 g per 100 g of solution) did evoke pain and it therefore

seemed possible that the osmotic characteristics of solutions might have some bearing

on their effectiveness in producing pain from dentine. This paper reports experiments in which a variety of solutions with calculated osmotic pressures between 25 and

2760 atmospheres have been applied to human dentine, with the object of testing

their ability to produce pain.

METHODS

The general procedure was the same as in the first investigation of this series (ANDERSON et al., 1958). The subjects were young adults and the teeth used were

slightly carious lower premolar teeth in which a cavity was cut from the occlusal

surface just into the dentine, or, in a few subjects, more deeply when the spread of

caries required it. The cavity was prepared with a slow-running tungsten carbide bur

under a stream of cold water. After preparation, the dentine was dried with cotton wool and the solutions were then applied on cotton wool at a temperature of about

37°C and left in position for 30 set, after which the cavity was washed out with warm water and dried with cotton wool before the next test. Each sequence took about

3 min and this time included that taken for the subject to give a brief description of any sensation experienced. Every solution was applied twice in random order and

neither the operator who applied them, nor the subject, was aware of the identity or order of application of the solutions. Furthermore, the subject was not told how

* Present address: University of Oregon Dental School, Sam Jackson Park, Portland 1, Oregon, U.S.A.

513

514 D. J. ANDERSON AND G. A. RONNLNG

many tests were to be made. As in previous experiments, the dentine was tested immediately after cavity preparation and 1 week later, the cavity having been filled

with gutta percha during the intervening period. MASSLER (1956) has shown that the

pulp under a cavity filled with gutta percha is hyperaemic and in our previous experi-

ments we found that teeth treated thus were more sensitive than when tested

immediately after cutting. This report covers three experiments involving eighteen

subjects, in which the effects of solutions with different osmotic pressures were tested.

Experiment 1

Eight subjects were used in this experiment in which nine substances in solutions

exerting calculated osmotic pressures in the range 25-2760 atmospheres at 37°C were applied to dentine immediately after cavity preparation and 1 week later. The

TABLE 1

Approx osmotic pressure Ethanol Urea Glycerol Dextrose NH&l NaCl CaCl, Syrup

(atmospheres)

25 0 0 0 0 - - - 50-80 0.125 0 0 0.125 0.25 - 0.25 - 100 0 0.75 0.25 0 0 0.125 - - 200-250 - - - - 0.25 0.50 0.375 - 830 - - - - - - 1.00 - 900 - - - - - 0.285 2760 - - - - - - 0.75 -

The figures in each column represent number of painful responses/number of stimulations with 1 M, 2 M and 4 M solutions shown from above downwards. The figure at the foot of the CaCl, column was obtained with a saturated solution at 37°C. The cohunn on the left shows the approximate osmotic pressures of the solutions, and the arrangement of the results makes it possible to compare data obtained with solutions of different molarity but similar osmotic pressure. Results were obtained immediately after cavity preparation. The osmotic pressure of the syrup was calculated from determinations of its vapour-pressure lowering effect.

TABLE 2

Approx osmotic pressure Ethanol Urea Glycerol Dextrose NH&l NaCl CaCl, SYruP

(atmospheres)

25 0.50 0.25 1 .oo 0.50 - - - 50-80 0.25 0.375 0.375 0.375 0.25 0.5 0.25 - 100 0.25 0 0.25 0.50 0.5 0,875 - - 200-250 - - 0.5 1.00 0.625 - 830 - - - - - l*OO - 900 - - - - - - - 0.875 2760 - - - - - 1.00 -

The figures in each column represent number of painful responses/number of stimulations with 1 M, 2 M and 4 M solutions shown from above downwards. The figure at the foot of the CaCl, column was obtained with a saturated solution at 37°C. The column on the left shows the approximate osmotic pressures of the solutions, and the arrangement of the results makes it possible to compare data obtained with solutions of different molarity but similar osmotic pressure. Results were obtained 1 week after exposing dentine.

OSMOTIC EXCITANTS OF PAIN IN HUMAN DENTINE 515

solutions used and the results obtained are set out in Tables 1 and 2. In this series

there was a gap in the osmotic pressure range between approximately 900 atmospheres syrup and approximately 2760 atmospheres Sat. CaCl,, which was covered in the second experiment.

Experiment 2 In this experiment on five subjects, sugar syrup and sevencon centrations of CaCl,

were used, covering the range 200-2760 atmospheres. In addition to the usual

procedure of testing on two occasions, a third test was made 24 hr after the second,

TABLE 3. APPROXIMATE OSMOTTC PRESSURES IN ATMOSPHERES

Calcium chloride SYruP

200 600 1000 1400 1800 2200 2169 900

First session 0 0 4 4 4 2 8 3

Second session 4 6 7 6 8 9

:8

5

Third session 1 5 3 2 6 8 3

Total 5 11 14 12 18 19 28 11

The number of painful responses to ten stimulations (twice on five subjects) with solutions of

calcium chloride and sugar syrup exerting calculated osmotic pressures in the range 200-2760

atmospheres. Session 1 was immediately after exposing the dentine, Session 2 was 1 week later, the cavity having been filled with gutta percha. Session 3 was 24 hr after Session 2. A self polymeriz-

ing resin filling occupied the cavity during the period of 24 hr between Sessions 2 and 3.

having filled the cavity during the intervening period with a self-polymerizing resin.

KRAMER and MCLEAN (1952) and KRAMER (1955, 1956) have shown that pulp tissue

under cavities filled with this type of material is usually hyperaemic and also showed

that odontoblast cell nuclei can sometimes be seen aspirated into the tubules com- municating with the cavity. NAYLOR (unpublished) has shown aspiration of the

odontoblasts in all of six subjects in whom unlined cavities were filled with self-

polymerizing resin for 24 hr before extraction of the teeth. Because of the possible

role of the odontoblast cell and its process in transmitting disturbances to the pulp,

TABLE 4

a b S.E.6 Responses to minimum concentration

Pooled data 4.40 0,762 10.110 5.90 (A 1.4) Session 1 -0.34 0.244 &0.081 o-14 C&0.7) Session 2 4.11 0.212 40.033 4.53 (kO.1) Session 3 -0.43 0,380 I-to.081 0.33 (1-0.7)

Data for regression equation y=a+bx for the lines in Figs. 14 from Experiment 2. y = number of responses. x=osmotic pressure of CaCl$ solution in atmospheres with a minimum of 200 atmospheres.

The calculated mean number of responses to this concentration of CaCl, is shown in the last column with the standard error of the mean in brackets. b corresponds to the slopes of the lines shown in Figs. 14.

516 D. J. ANDERSON AND G. A. RONNINO

30 -

28 -

26 -

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220 . :: & .la -

I El6 -

$4 -

z” 012 -

8 210 -

0 I, I I, I, I I I, I,,

0 2 4 6, 8 10 12 14 16 18 20 22 24 26 28

OSMOTIC PRESSURE OF CaC12 SOLUTIONS IN ATMOSPHERES x 100

FIG. 1. Pooled data from Experiment 2.

Ir,lllllllll,

0 i 4 6 8 10 12 14 16 18 20 22 24 26 28 OSMOTIC PRESSURE OF CaClq SOLUTIONS

IN ATMOSPHERES x 100

FIG. 2. Data from Session 1, Experiment 2.


g 2-

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20 I I I I I1 I I1 I 41 J ,

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 OSMOTIC PRESSURE OF CaCl2 SOLUTIONS

IN ATMOSPHERES x 100


5; 10

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

OSMOTIC PRESSURE OF CaC12 SOLUTIONS IN ATMOSPHERES x 100


filling a cavity with self-polymerizing resin might be expected to influence sensitivity by distorting the transmitter mechanism. Table 3 shows the results and, for those obtained with CaCI,, regression lines have been fitted by the method of least squares as shown in Figs. 1-4, and their equations are given in Table 4. The last column of

518 D. J. ANDERSON AND G. A. RONNINC

this table gives the calculated mean number of responses at the lowest concentration of CaCl, with the standard errors of these means in brackets.

Experiment 3 Experiments on dye diffusion through dentine in freshly extracted teeth (ANDERSON

and RONNING, 1962) showed that mechanical cutting of the dentine can reduce its permeability to dyes such as Evans blue (T 1824), whereas dentine exposed by

fracturing a cusp allows free penetration of the dye through its tubules. Experiments

in vivo confirmed that cut dentine did not allow dye diffusion, although the effect

was not seen consistently. It therefore seemed possible that the variations in sensi-

tivity might be associated with variations in dentine permeability. To investigate the

possible relationship between dentine permeability and sensitivity it was necessary

either to test the sensitivity of dentine exposed by fracturing, or to find some simple

procedure which would consistently block dye diffusion and to test the sensitivity

before and after subjecting the dentine to such treatment. The first alternative was

not practicable since the teeth used in the experiments were not to be extracted and in any case it is not a procedure to which volunteers can be subjected. Precipitation

of the protein of the dentine tubules and the deposition of a precipitate of silver by treating the cavity with silver nitrate and eugenol seemed a possible solution to the

problem. Experiments on extracted teeth (ANDERSON and RONNING, 1962) showed

that Howe’s ammoniacal silver nitrate penetrates dentinal tubules rapidly and presumably alters the tubule contents, since it is a protein precipitant and it also

consistently prevented subsequent dye diffusion through the treated tubules. Tn five subjects two small separate occlusal cavities were cut into the dentine in

the anterior and posterior portions of the occlusal fissure of a lower first or second premolar. Both cavities were tested twice with four solutions which were 2 Molal,

6.3 Molal and saturated CaCl,, and sugar syrup. The arrangement of the eight tests

for each cavity was random, although the cavities were tested alternately. After testing, they were filled with gutta percha for a week. Immediately before the next

TABLE 5

Responses in first session Responses in second session

A B A(AgN0, treated) B(untreated)

Subject 1 5 (m) 2 (d) 2 2 2 3 (d) 3 (m) 5 6 3 2 (d) 2 (m) 4 4 4 3 (d) 1 (m> 2 3 5 2 (m) 1 (d) 5 5

Total 15 9 18 20

The number of painful responses to four solutions (2 M, 6.3 M and saturated CaCl, and sugar syrup) applied to dentine in five lower premolar teeth, immediately after cavity preparation and 1 week later. Every solution was applied twice. The results from the more sensitive cavity in every tooth in the first session are grouped in column A and these cavities were chosen for treatment with AgNOS and eugenol just before testing in the second session. The cavities with results in column B provided tbe untreated controls in the second session. The letters (m) and (d) indicate the positions (mesial and distal) of the cavities in the teeth.


test, the cavity which had previously shown the higher number of painful responses (or in the case of equal numbers, the more unpleasant sensations) was chosen for treatment with ammoniacal silver nitrate for 2 min and eugenol for 3 min; the procedure which had been employed in extracted teeth. After this, the cavity was washed and dried with cotton wool and then both were tested as before. The results are shown in Table 5.

Experiment 4 One factor not taken into consideration in the experiments reported so far was the

pH of the solutions employed in testing sensitivity. With the exception of NH&I used in Experiment I, the pH was not expected to deviate markedly from neutrality

TABLE 6. STARTING pH AND QUANTITY OF 0.5 N NaOH REQUIRED TO BRING 20 ml OF THE SOLUTION T9 pH 7.00 (Titrations in ml)

Molar concentrations 1M 2M 4M Saturated at 37°C

Solutions pH Titration pH Titration pH Titration pH Titration

Ethanol 5.34 0.007 6.23 0.002 6.28 0.002 - Urea 5.48 O+IO6 6.52 0.002 6.80 O+)Ol Glycerol 5.31 0.007 5.59 0.005 6.08 0.002 _. Dextrose 6.50 OWl 6.42 0.003 6.15 0.014 - NH&l 5.10 0.189 5.08 0.346 4,92 0.736 - -. NaCl 5.50 0.003 5.50 0.004 5.70 0.004 CaCl, 4.69 0.009 4.60 0.004 3.30 0.013 5.50 0402

and in any case the significance of pH measurements made on highly concentrated solutions is open to question. In spite of this however, determinations were made using a glass electrode and the amount of 0.5 N NaOH required to bring 20 ml of the test solution to pH 7 was also measured. The results are shown in Table 6.

TABLE 7

First Second Third Fourth quarter quarter quarter quarter

First session Second session

(1 week later) Third session

(24 hr after second)

14 3 2 19 13 8

16 10 7 4

Data from Experiment 2: The number of responses to sixteen stimulations in five subjects (eighty stimulations in all) on three occasions using seven concentrations of CaCl, and sugar syrup. Solutions applied in random order. The results have been grouped in four quarters of twent) stimulations.

520 D. J. ANDERSON AND G. A. RONNING

Sut7jective results RESULTS

The numerical scores recorded in this investigation cover a range of sensations from just awareness of discomfort to a severity of pain which made the subject ask for the solution to be washed out before the usual 30 set period of stimulation had elapsed. No precise classification of the comments made by the subjects has been attempted owing to their diversity, but it can be recorded that sugar syrup and saturated CaCl, solutions caused ‘pain which, whether immediate or delayed in onset, often increased in severity and was occasionally described as throbbing. Sometimes it was necessary to wash the dentine more than once to abolish the pain.

The relationship between osmotic pressure and pain production

The results of Experiment 1 merely suggest that solutions with high osmotic pressures are more likely to cause pain than solutions with low osmotic pressures. A more clear-cut trend is shown in Experiment 2 by the results obtained with CaCl,. The results obtained with sugar syrup appear to fit into the picture better in Experi- ment 2 than in Experiment 1, for in Experiment 2 the syrup scored eleven painful responses out of thirty applications. This score corresponds fairly well with that achieved by CaCl, solutions exerting osmotic pressures near the syrup value of about 900 atmospheres.

The results of statistical treatment of the data obtained with CaCl, in Experiment 2 (shown in Table 4) indicate that there is no difference between Sessions 1 and 3, but the difference between the calculated mean numbers of responses to the minimum concentration of CaCl, in Sessions 1 and 2 is 4.4 (S.E. f0.75); this would be expected to arise by chance less than 1 in 1000 times. The slopes of the lines for data from Sessions 1 and 2 are not different however, and the difference between the slopes from Sessions 1 and 2 on the one hand and Session 3 on the other hand is significant only at the 1 in 10 level. These statistical data allow the conclusion that covering the dentine with gutta percha and testing after 1 week (Session 2) increases the sensitivity of the dentine as compared with the freshly cut preparation (Session 1). The difference in sensitivity appears to be maintained throughout the range of concentrations used, since the slopes of the two lines do not differ. In addition, these data suggest that the sensitivity of dentine, raised after exposure to gutta percha for a week, is lowered as a result of contact for 24 hr with self-polymerizing resin, to a level similar to that found in the freshly cut state.

Changes in sensitivity

In many cases, not only the severity of the pain, but the number of responses decreased during the course of a testing session. This is well shown in Table 5 in which the results (eighty stimulations) from all the five subjects of Experiment 2 have been divided into four groups of twenty, the first group consisting of the results obtained in the first quarter of every session and so on to that last group comprising all the results from the fourth quarter of every session. In spite of the differences in sensitivity which may be present on the three occasions, there is obviously a decrease in semitivity throughout the experimental sessions.


The effkct of AgNO, and eugenol The results of Experiment 3 in Table 5 confirm previous observations (ANDERSON

et al., 1958) that exposure of dentine to gutta percha for a week results in an increase

in the number of responses to stimulation over the control values. This increase takes

place in spite of treatment with AgNO, and eugenol before the second test, but in

the AgNO,-treated cavities the increase is only from fifteen to eighteen responses, whereas with the initially less sensitive control group it is from nine to twenty.

The acidity of the stimulating solutions In Table 6 it can be seen that the pH values of some of the stimulating solutions

are surprisingly low. However, the titrations with 0.5 N NaOH using 20 ml of the test solutions show that the quantities of hydrogen ions introduced into the tooth cavity with these solutions must have been negligible.

DISCUSSION

These experiments were designed to test the possible relationship between osmotic

pressure of solutions and their pain-producing power in dentine. If osmotic pressure

is in some way linked with pain production in dentine, then whatever may be the nature of the link it is reasonable to expect substances of different chemical compo-

sition but the same osmotic pressure to be equally effective in pain production.

This has not been demonstrated in a convincing manner by the results of Experi-

ment 1, although in Experiment 2 there seems to be a recognizable trend in pain-

producing power associated with differences in osmotic pressure. In this experiment the wide range of osmotic pressures exerted by CaCl, made it possible to test the possible relationship between osmotic pressure and pain-producing power more

thoroughly than with the majority of solutions in Experiment 1 which, even in high

concentrations, were capable of exerting only comparatively low osmotic pressures.

However, the results of Experiment 2 do not rule out the possibility that CaCl, has a

specific pain-producing effect which would presumably be greater with higher concentrations but the fact that the results with sugar syrup in Experiment 2 reach the

figure expected on the basis of its calculated osmotic pressure supports the osmotic pressure-pain production relationship.

The object in Experiment 2 of testing sensitivity after exposure of the dentine

to self-polymerizing resin was to determine the effect on sensitivity of disorganization

of the odontoblast layer. However, we have no histological evidence to show that this disorganization occurred in our experiments, since the teeth we tested were not extracted. We therefore cannot conclude that the decrease in sensitivity following this

treatment was associated with odontoblast aspiration and it will be necessary as material becomes available to repeat these experiments on teeth to be extracted, so

that histological and physiological findings can be correlated. The apparent decrease in sensitivity during the course of an experimental session

as shown in Table 6 was also seen in previous experiments (ANDERSON et al., 1958). ARMSTRONG et al. (1953), with the blister-base preparation, reported that after successful stimulations with acetylcholine, the area remained refractory to further

522 D. J. ANDERSON AND G. A. RONNING

stimulation for as long as 10 min. In our experiments only about 3 min elapsed between successive stimulations, but whether the fall in sensitivity was due to

refractoriness of nervous elements in the dentine or pulp, or had some other cause, it is

not possible to say. However, an explanation arises from the results of BRANNSTRWS

experiments (1960), which showed that a sensation of pain could be evoked by playing

a jet of dry air on to dentine and further, that odontoblast cells with processes in

dentinal tubules thus treated, were aspirated into the tubules. If, as BR~~NNSTR~~M suggests, pain and odontoblast aspiration both occurred as a result of drying the

dentine, then the aspiration must have been irreversible or only slowly reversible, since it persisted long enough to be demonstrable histologically after removal of the tooth.

BR;~NNSTR~~M found that although the initial response to a jet of air was a sensation of

pain, this decreased, and with prolonged exposure to the air jet, the pain often

disappeared. Subsequently, the dentine was insensitive to scraping with a probe.

Thus it would appear that the sensation of pain and aspiration of odontoblasts are

closely associated and that once the odontoblasts are aspirated the receptor mechanism

for pain is impaired. This sequence may also have occurred in our experiments, but

it has so far not been possible to find histological evidence for this in a preliminary

series of experiments in which solutions with a high osmotic pressure were placed in freshly cut cavities in dentine before extraction of the teeth and during subsequent

fixation. In a large series of teeth filled with self-polymerizing resin, KRAMER (1955)

reported that there was pain in only nine teeth out of a total of forty-one in which

odontoblasts were aspirated, compared with twenty-one out of 111 in which there

was no aspiration. KRAMER therefore concludes that there is no association between

pain and odontoblast aspiration.

It is surprising that pain can be evoked from dentine after treatment with ammoniacal silver nitrate and eugenol, since this treatment must modify the protein

in the dentinal tubules immediately subjacent to the cavity and has been shown to alter the dye-diffusion characteristics of the tubules. However, although it has been

possible to evoke a sensation of pain from dentine treated with silver nitrate and

eugenol, this treatment was given to dentine after filling the cavity with gutta percha which has been frequently shown to increase sensitivity. Thus the cavities of the control group B (Table 4) gave nine responses to a total of forty stimulations in the

first session, and after filling with gutta percha gave twenty in the second session,

whereas those of group A gave fifteen in the first session and eighteen after AgNO, treatment in the second. Comparable data obtained with the same group of solutions

in Experiment 2 were fourteen reponses out of forty stimulations in the first session and twenty-five in the second. It therefore appears that although silver nitrate treatment after filling with gutta percha does not abolish sensation it causes the number

of responses to fall below the expected value. More data are required before this can

be accepted as a firm conclusion. From the results obtained in these and previous experiments, support is provided

for the conclusion that the receptor mechanism for pain in dentine does not behave as though it were composed of nervous elements in the dentinal tubules. This con-

OSMOnC EXClTANTS OF PAIN IN HUMAN DENTINE 523

elusion is partly based on a comparison of the results obtained on dentine with those

obtained by ARMSTRONG ef al. (1953) on the blister-base preparation and the evidence

may be summarized as follows : (1) Pain was never evoked by acetylcholine and other substances in concentrations

which are effective on the blister-base preparation, and only rarely when acetylcholine and KC1 were used in much higher concentrations (ANDERSON et al., 1958; ANDERSON

and NAYLOR, 1961, 1962).

(2) Warm water does not cause pain in dentine but is effective in the blister base.

(3) Gross osmotic disturbances were required to cause pain in dentine. Yet

hypotonic NaCl (0.35 %) and hypertonic NaCl (5.0 %) are painful when applied to the blister base.

(4) It is highly probable that concentrated solutions of CaCI, precipitate the protein i.1 the dentinal tubules, yet a saturated solution of CaCl, was more successful in pain production than any other material tested.

(5) Treatment of dentine with silver nitrate and eugenol may have reduced, but

did not abolish, sensation from dentine, although it blocks dye diffusion and must

precipitate the protein contents of the dentinal tubules.

These results are only compatible with a receptor mechanism of a more rugged

nature than the fine nerve fibrils frequently postulated.

Acknowledgements-The authors are very grateful to the large number of subjects who have taken part in this investigation. This investigation was supported by U.S.P.H.S. Research Grant D-1037 from the National Institute of Dental Research, National Tnstitutes of Health, Bethesda, Maryland, U.S.A.

REFERENCES

ANDERSON, D. J., CURWEN, M. P. and HOWARD, L. V. 1958. The sensitivity of human dentme. J. dent. Res. 37, 669-671.

ANDERSON, D. J. and NAYLOR, M. N. 1961. Sensation in human dentine. J. dent. RES. 40, 1275 (Abstract).

ANDERSON, D. J. and NAYLOR, M. N. 1962. Chemical excitants of pain in human dentine and dental pulp. Arch. oral Biol. 7, 413-415.

ANDERSON, D. J. and RONNING, G. A. 1962. Dye diffusion in human dentine. Arch. oral Biol. 7, 505-512.

ARMSTRONG, D., DRY, R. H. L., KEELE, C. A. and MARKHAM, J. W. 1953. Observations on chemica excitants of cutaneous pain in man. J. Physiol. U&326-351.

BRKNNSTRGM, M. 1960. Dentinal and pulpal response-II. Acta odont. stand., 18 17-28.

KRAMER, I. R. H. and MCLEAN, J. W. 1952. The response of the human pulp to self-polymerising acrylic restorations. Brit. dent. J. 92, 255-261,281-287, 311-315.

KRAMER, I. R. H. 1955. The relationship between dentine sensitivity and movements in the contents of the dentinal tubules. Brit. dent. J. 98, 391-392.

KRAMER, I. R. H. 1956. The reaction of the pulp to self-polymerising acrylic resins containing methacrylic acid. Brit. dent. J. 101, 378-387.

MASSLER. M. 1956. Effects of filling materials on the pulp. N. Y. J. Dent. 26, 183-198.

osmotic excitants of pain in human dentine

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