Eiubd Dent Traumiitol 1994; 10: 201-209liinted in Denmark . All rights reserved

Copyright (C Munksf-aard 1994

Endodontics &Dental Traiunatology

ISSM 0109-2502

Inflammation and dental pain in man

Invited authors

Ahlquist A'lL, Franzen OG, Inflammation and dental pain inman, Endod Dent Traumatol 1994; 10: 201-209, © Munksgaard,1994,

Abstract - In the present article special interest has been focusedon indicators of latent and manifest pulpal inflammation studiedby psychophysical and electrophysiological techniques, Intradcn-lal A-delta nerve activity was recorded from two electrodesplaced in the dentin on the labial tooth surface. The phychophys-ical measures were obtained by means of direct scaling methodsin combination with sensory verbal descriptors. For stimulationcooling (ethyl chloride) and heating (hot guttapercha) of the toothsurface were employed. In addition, potentially algogenic sub-stances, bradykinin and histamine, were administered on partlyexposed pulps. Hot guttapercha induced a more complex neuralresponse pattern than ethyl chloride. In all the recordings theresponses evoked by heat showed a characteristic pattern consist-ing of three phases: an initial phase of short duration (i) followedby a depression in activity relative to the baseline (ii) and a slowspontaneously emerging activity in the absence of a physicalstimulus (iii). The latter neutral event (iii) passed unnoticed byall the subjects. In the light of earlier experiments on felinepulp it was hypothesized that this third phase of the neuralresponse was an indication of hyperexcitability in dental pulpsand thus inflammation. Those subjects who experienced pulsat-ing, dull, lingering pain (clinically diagnosed as pulpitis)showed a poor correlation between magnitude estimates of theirmixed pain percepts and the total flux of ,A-delta nerve activity,Bradykinin and histamine evoked dull pain in the majority ofcases probably caused by excitation of pulpal C fibers. In oneexperiment A-delta neural discharge of short duration could alsobe triggered by histamine. However, the pain sensation scaledby means of fmger span significantly outlasted the neural re-sponse which may indicate a simultaneous activation of the A-delta and C units. The dual response to histamine was interpretedas a sign of pulpal inflammation which may be a prerequisite forhistamine to become an algogenic substance.

M. L Ahlquist', 0, G.Departments of ^Endodontics, School of Denfisfry,Karolinska Institufe, Huddinge, ^Human Anafomy,Uppsala University, Sweden

Key words: denfal pain: inflammation:

elecfrophysioiogy and psycfiopfiysics.

Micfiaei Afiiquist, Department of Endodontics,

Scfiooi of Dentistry, Karoiinska Institute, Box 4064,

t41 04 Huddinge, Sweden,

Accepted October 26,1993

'Ihe nature of inflammation in the pulp may not beVf'ry different from that in other parts of the body,Local inflammation causes endogenous inflamma-tory agents such as bradykinin, histamine, sero-tonin, prostaglandins and some other vasoactive

substances to be formed or released from cells andtissue (review 1), This sequence of events resultsin a rise in intravascular pressure and flow in thecapillaries which precipitates increased capillarypermeability. This change in permeability of the

201

Ahlquist & Franzen

capillary walls may lead to extravasation of fluidinto the surrounding tissue, thereby creating edemawhich in its turn will produce elevation in pulptissue pressure (2), Simultaneous recordings ofpressure from inflamed and non-inflamed areas ofthe same pulp indicated that a rise in pressure doesnot necessarily spread to other parts of the pulp butremains a highly localized phenomenon (3, 4), Inthe case of severe, persistent inflammation, however,the increased tissue pressure may successively spreadin apical direction resulting in compression of theblood vessels and eventually in a total pulp necrosis

It is a common observation that patients withtooth-ache have pulpal inflammation but that path-ological conditions of the pulp may not always causepain (6-9),

The present report describes pulpal mechanismsof pain and latent or manifest inflammation usingbehavioral, biochemical and/or neurophysiologicalmethods,

Materiai and methoils

The experiments were carried out on human teethwhich in the majority of cases were to be extractedfor periodontal reasons (10-15), In the chnicalexamination that preceded the main experimentthese teeth showed no hypersensitivity to thermalstimuli or tenderness upon percussion nor did thesubjects experience any spontaneous pain. The pro-ject was approved by the medical ethics committeeat Huddinge hospital.

a thin layer of amalgam. In this cavity stainless steolcannulae were placed in contact with the amalgamand stabilized by composite filling material. Therecording unit was connected to standard electro-physiological equipment (Fig, 1), The electrical ac-tivity recorded from dentin (Fig, 2) represents inall probability the total number of nerve impulseselicited in pulpal A-delta flbers located in the pulpbetween the recording electrodes (16, 10, 14, 15),

Steps taken before chemical stitnulation

Before the preparation of the tooth it was anesthet-ized with mepivacain (Carbocain Dental 30 mg/ml,Astra) for at least 20 min, during which time acavity for stimulation was prepared at the level ofthe most incisal part of the pulp. The floor of thecavity was partly removed, thereby exposing thepulp without causing any visible bleeding. Whenthe anesthesia had worn off, the sensitivity of thepulp was tested by applying NH,C1 (0,77 M), Thechemical test compound was put in the cavity insuch a way that under a stereo-microscope inspec-tion no bubbles were seen at the bottom of thecavity. Each stimulation was terminated by washingthe cavity with physiological saline solution. Thepulp was prevented from drying by letting this solu-tion remain in the cavity between stimulations,which did not cause any pain at all.

When intradental nerve activity (INA) was to berecorded during chemical stimulation, it was necess-ary to prepare the stimulation cavity incisally to therecording electrodes.

Intradental nerve recording

Two cavities were prepared on the labial surface ofeach tooth, one at the level of the pulpal horn andthe other as far apically as possible on the exposedroot. The pulpal wall of the cavity was covered with

Fig. J. A schematic drawing of the experimental arrangementfor electrophysiological and psychophysical recordings.

Tlme(sec)

Integrated INA

PAS(finger span)

Cold stimulation ^^ _ _Fig. 2. The result of three cold stirnuh applied in succession (0thM, 8th s and 2,5th s) on the tooth surface. The multi-unit activityevoked by the second and third stimulus was superimposed on analready ongoing neural activity. The subject seemed to respondaccurately to these changes in neural input (From Franzt'n,Ahlquist 1989),

Intlammation S dental pain

Thermal and chemical stimulation

Thermal stimuli (cold and heat) were delivered byapplying either evaporating ethyl chloride or aheated guttapercha stick onto the tooth surface (15),

Chemical stimtilation was achieved by the appli-cation of histamine (histamine dihydrochloride Sig-ma, 10 mg/ml), bradykinin (bradykinin-2-acetateSigma, 10 |Jg/ml) in the stimulation cavity.

During the course of the experiment the vitaUty(ifthe pulp was tested by means of sodium chloride(0,77 M, 1,54 M) and ammonium chloride (0,77M, 1,54 M) and the quahty of the sensations evokedhv these substances was determined. This consti-tttted part of the experimental protocol for continu-ous assessment that the pulp under investigationremained in good condition.

In electrophysiological experiments on animals(cats) hypertonic sodium chloride solution placedin dentinal cavities induced nerve activity (17—20),This solution excited in all likelihood the intradentalner\'es directly by increasing the sodium ion concen-tration of ihe fluid in the extracellular space :'18,19:,

,Ammonia solutions gave rise to pain when ap-plied to the mucous membrane or when injectedinto the skin (21, 22), However, the detailed mech-anism of excitation is not fully understood. It hasheen suggested that pain evoked by ammonia wasprobably the result of an increased concentration ofNH, ions around the nerve endings in the tissue(22, 20, 23), a stimulation process similar to whathas been proposed for hypertonic NaCl,

In the tooth pulp a number of substances as e,g,hislamine, prostaglandin, substance P influence andmodulate dental sensitivity, vasodilatation, vascularpermeability, and inflammatory reactions (24), His-tamine is a chemical compound derived from theamino-acid histidine, Histamine is stored in gran-ules of mast cells (25), Degranulation of mast cellsleads to a release of histamine (26),

At the same time as sensory impulses evoked byhistamine propagate centrally, action potentials passantidromically into the terminal arborizations of thenerve fibers (the axon-reOex) and release in its turnsubstance P, a polypeptide, which may also be re-sponsible for the axon reflex and for the associatedhvperalgesia (27),

During conditions of local inflammation in thetissue, bradykinin, another polypeptide, belonginglo an important group of algogenic substances isformed (28, 29), It is assumed to be indirectly associ-ated with the release of histamine and also withsensitization of nociceptive fibers in the pulp andthe skin (30-32), Bradykinin and histamine simul-taneously superfused on stripped skin caused theproduction of prostaglandins (33) which points to

a complex interaetion between mediators in the de-velopment of inflammation and hyperaigesia.

Ratings ot pain quality and intensity

The quality of pain was assessed by the subject'schoice of one or more qualitative expressionscharacterizing various aspects of pain sensationsevoked by the cold and heat stimulus or the twochemical agents. The intensity of pain was rated bythe subject, who selected a sensory verbal descriptorthat best described the peak sensation following eachstimulation. The \ erbal descriptors covered the fullrange of pain intensity from no pain to the maximalpain previously experienced or imagined by thesubject.

During the course of the recording of evoked in-tradental nerve activity (INA) the magnitude of thepain sensation was determined at the same time bymeans of an intermodal scaling procedure calledfinger span (proprioceptive analog scale, PAS; 34),In this procedure the subject was required to adjustthe distance between the thumb and index fingerattached to two metal arms that were connected toa linear potentiometer. The subjects were trainedto set the distance between the two fingers in pro-portion to the perceived magnitude of numbers be-tween 0 and 100 read to the subject in randomorder before the main experiment. In all subjectsfinger span was approximately proportional to thesubjective impression of these numbers (Fig, 4a),

Results and discussion

Phenomenology of pain

In a significant number of trials the subjects feltsharp/shooting pain when their tooth was exposedto inorganic ions, which was expected since hyper-tonic solutions of these ions have been reported toevoke A-delta activity in the feUne pulp (20), Onthe other hand the poiypeptides, histamine and bra-dykinin, induced preferably sensations of dull throb-bing pain (11),

Cold stimulation produced a sensation of distinct,sharp pain in an overwhelming majority of the stim-ulations (15),

However, in a few subjects this stimulus produceddull, throbbing pain which remained for a ratherlong period of time after stimulation, Histamineevoked mainly sensations of dull pain but gave alsorise to sharp, shooting pain in 3 of 17 stimulationsin the 5 subjects participating in the experiments.

Signs of pulpal pathology

The pulp of periodontally afflicted teeth is alwaysthreatened by bacterial invasion through deep gin-

203

Ahlquist S Franzen

gival pockets, which may lead to an inflammatorycondition. When the cementum of the root is re-moved, the pulp itself produces a layer of reparativedentin along the pulpal wall of the affected dentin(35), In many teeth with this kind of afHiction thepulp undergoes local degeneration and atrophy(36), which may ultimately result in an inabihty toproduce reparative dentin. Therefore, teeth with apathological periodontal condition may in somecases have open contact between the pulp and theouter environment through fluid in the tubules ofthe exposed dentin (37), When bacterial plaque isformed on the dentin surface, bacteria may pen-etrate into the tubules (38), This may cause thedeath of odontoblasts and as a consequence bac-terial toxins may penetrate the dentin and thusproduce an acute inflammatory reaction (39, 40),

However, the tissue damage caused by such infec-tions may be insufficient to cause pain. Moreover,the amount of inflammatory mediators such as hista-mine and bradykinin, both potent vascular per-meability factors, may have to reach a certain levelof concentration before these vasoactive substancescan excite the nerve fibers and the inflammationbecomes manifest as either an abnormal dischargepattern in the neural records or as a toothache feltby the subjects.

In a few subjects cold stimulation produced dull,throbbing pain which remained for a time periodof a few minutes after stimulation (14), This circum-stance can be regarded as one indication of a pulpin a hyperalgesic state of inflammation (41, 42),Percepts having a quality of mainly dull pain areconventionallv considered as correlates of C flber

Integrated ^INAr'500ms

Pain (PAS)

Coldstimulation 20 sec

Fig. 3. The labelling a, b, and c represent neural and psychophys-ical records after three successive stimulations with ethyl chloride,Intradental A-delta nerve activity (INA) and pain (PAS) fbrone subject, B,L,, who perceived dull, pounding pain followingcold stimulations. Despite a pain quality indicating C fiber activ-ity, the electrophysiological records of INA appear normal withrespect to waveform, slope and duration.

activity (43, 37) and are evidently inappropriate A-delta correlates.

In this context it is worthwhile to consider recentfindings that high sustained neural activity inducedby noxious sensory stimulation may also have conse-quences for the topographic organisation of CNS asexpressed in the level of c-fos protein. This markermay explain long-term potentiation of neuronal ac-tivity in the spinal cord and higher nervous centers(44),

Another instance of manifest pulpal inflammationcan be found in subject BL, who experienced dull,pulsating and throbbing pain that lingered for arather long period after the end of stimulation. Hisrecords of INA (Fig, 3) appeared normal in termsof waveform and shape, but in this case the neuralresponses were poor predictors of the magnitude ofthe perceptual responses. The correlation coefficientbetween the integrals of INA and PAS for two seriesof experiments on this subject was 0,22 and 0,24,This poor correlation may be best understood byassuming that the subject rated a mixed percept ofsharp stimulus-evoked, shortlasting pain and sus-tained dull, throbbing pain, since both the A-deltaand the C nociceptive were probably activated inthis early state of inflammation, (Fig, 4a, b).

The quality of the sensation elicited by cold stim-ulation as well as the low correlation between de-

I 6"

Fig. 4. Finger span matchings to numbers {numerical scale) readby the experimenter. Finger span was approximately pro-portional to the subjective impression of these numbers. Fig- 4bRecordings from the same subject (B. L.) as in Fig. 3 plotted asthe integral of intradental nerve activity (INA) against the inte-gral of PAS in log-log coordinates (From Franzen, Ahlquist1989). BL I and BL II represent data collected in the samesubject BL in two separate experimental sessions.

2114

Inflammation & dental pain

pendent and independent variables n:iay be indi-cations of pulpal pathology.

Slow burning C fiber-related pain is preferentiallyreduced or suppressed by therapeutic dosages ofmorphine (45). Endorphins belonging to a class ofneuropeptides (46, 47) and morphine seem to oper-ate on common specific opoid receptors located inthe central nervous system. In a group of 14 patientsFranzen et al. (48) found that the preoperative en-dorphin levels differed almost sixfold between theindividual patients. If that would be the case for thesubjects of the study by Franzen & Ahlquist (14),some of the variability in the pain estimates couldbe explained by the modulatory action exerted bythe endogenous opoid system on a pathway trans-mitting dull, throbbing pain.

During the early phase of inflammation of a se-quence of events may result in a rise in intravascularpressure and flow in the capillaries which precipi-tates increased capillary permeability. This con-dition leads to extravasation of fluid into the sur-rounding tissue thereby creating edema which in itsiurn results in elevated pulp tissue pressure (49, 2).However, the elevated pressure in an inflamed pulpmay be a highly localized phenomenon (3, 50, 4)and it may be an important factor for the develop-ment of throbbing pain, a sensation characteristicof pulpitis (51, 41, 42). Nerve impulses recordedfrom animal afferent intradental nerves were foundto fire in synchrony with the heart beat (52-55)indicating a link between changes in blood pressureand excitation of pulpal nerves in a state of hyperex-citability.

The effect of heat stimulation on the INA andpulpal pain is of special clinical interest since manyprocedures used by the chnician in his daily workmay generate heat.

Histological investigations have revealed thateven a moderate increase in temperature at the pulp-dentinal junction was sufficient to cause a morpho-logically detectable pulpal injury (56, 57).

When heat stimulation was applied to the tooththe following response pattern was elicited from thevery first stimulation (Fig. 5). There was an initialburst of 3-5 s duration (phase I), followed by adepression relative to the baseline lasting for 20-30s (phase II), that gradually turned into phase III,during which phase there was a slow increase infiring rate relative to the prestimulus noise level.The spontaneously emerging activity (phase III) inthe absence of a physical stimulus passed unnoticedby all subjects.

Phase III deserves special attention inasmuch asthe subject never experienced any sensation of pain.T here may be several explanations for this fact.Either the slow course of events produced a centralhabituation (58, 59), or else the rate of increase in

Temperature

Pain

Fig. 5. Intradental nerve activity (INA) and pain response (PAS)to hot guttapercha applied to the tooth surface (Ahlquist et al.1986),

discharge may be too slow to trigger those percep-tual pathways involved in the processing of pain.Ihe latter reasoning is in concordance with theobservations of Kenshalo et al. (60) who demon-strated markedly increased detection thresholds forwarmth at very low rates of stimulus change. Byanalogy, a low firing frequency in cutaneous A-delta (61) and C fibers may not lead to a sensation(62, 63).

In inflammatory reactions, prostaglandins are re-leased in all tissues (64). The formation of prosta-glandins in the presence of critical enzymes is ac-complished by the cascade of arachidonic acid me-tabolism, ln the early stages of inflammationcyclooxigenase generates the cyclic endoperoxidaseintermediates (65) and these unstable substancescan be converted to thromboxanes (66) or prosta-cyclin (67) as well as to the stable prostaglandins.

A non-steroidal drug such as aspirin and an as-pirin-like drug such as indomethacin are able toinhibit the prostaglandin biosynthesis (68) by block-ing the synthesis of cyclooxygenase (69). Vane pro-posed this process as one of the mechanisms of anti-inflammatory action.

Studies of immediate relevance in this connectionare those carried out on fehne teeth by Ahlberg(70) who exposed the cat tooth to intense heat.It was only after repeated heat provocations thatAhlberg could evoke an intradental nerve activitythat consisted of three phases similar to what wehave shown in Fig. 5. Assuming that phase III ofthe intradental nerve activity was due to an acuteinflammation of the feline pulp, Ahlberg (71) couldmarkedly reduce the magnitude of this phase III bysystemic administration of a prostaglandin synthesisinhibitor such as indomethacin. We conclude, there-fore, that phase III in the human neural recordsmay be interpreted as an indication of sensitizationof the A-delta nerve endings as well as an electro-physiological sign of an incipient inflammation (12).This is also consistent with the fact that prosta-

205

Ahlquist & Franzsn

glandins are usually present in the laier stages ofinflammation.

On the basis of these findings it appears inadvis-able to use dental procedures that may produceheat, since they may inflict damage on the pulporgan, especially in teeth with advanced peri-odontal disorders.

Under inflammatory conditions algogenic sub-stances such as bradykinin and histamine are pres-ent in the tissue (72), Many studies on the skin haveshown that these two substances are able to evokepain (22, 26, 73, 74) and to excite cutaneous affer-ents (31, 72, 75), However, some controversy existsregarding the interpretation of results from studiesof chemical stimulation of human and cat dentalpulp.

In psychophysical studies in man it was foundthat bradykinin caused no pain sensation when ap-plied on exposed dentin (76), This finding is spuri-ously consistent with results from animal experi-ments in which bradykinin either applied in deepdentinal cavities (77) or on exposed pulp (78) didnot evoke any recordable nerve activity, Histaminehas been shown to cause pain when applied to ex-posed human pulp (79) but failed to evoke painwhen applied on human dentin (80), Apphcationof histamine on the exposed pulp, on the other hand,could elicit nerve activity only in C fibers (81) butapplied on cat dentin it could also evoke intradentalA-delta nerve activity under conditions of sensitiza-tion (18),

The present investigation in humans may offeran opportunity to disentangle the diverging resultsobtained with these substances by the use ofphenomenological and psychophysical assessmentsof sensory pain in combination with neurophysiol-ogical recordings of pulpal A-delta nerve activity.

The sensation of dull pain elicited by exogenouslyadministered bradykinin and the absence of record-able activity in the human pulps are fully in agree-ment with findings from a recent electrophysiolog-ical study of single units of the inferior alveolarnerve in the cat, where only C fibers could be drivenby bradykinin (32),

Bradykinin is unquestionably a physiological me-diator of pain, and its receptors are selectively local-ized, among several other sites, to the thin unmyeli-nated C fibers (82), It is of particular interest tonote that myelinated A-delta nociceptive fibres re-sponding only to damaging mechanical stimulationof the integument showed no response to the appli-cation of bradykinin (83), This suggests that thesefibres may have responsive characteristics similar tothose studied by us in the dental pulp (13),

Histamine produced a sensation of pain that sig-nificantly outlasted a short burst of INA (Fig, 6),which may be another instance of neural activity

INA

INA T SOOmspmIntingmr span

histamino

tapplication

\

—/„__

wash

— — — ^

20 s*c w»sb

Fig. 6. Intradental nerve activity (INA) recorded from humantooth pttip and psyehophysical rating of pain intensity afterhistamine {10 mg/ml) administration in a very deep dentinalcavity i Ahlquist et al. 1985),

associated wilh an inflammatory process. The shortA-delta burst of nerve activity and the subject's painresponse of very long duration indicated that bothA-delta and C fibers may be activated. Consideringthe sensitizing and potentiating effects of prosta-glandins on the response to histamine administra-tion (84), the animal studies by Olgart (18) andthose by Narhi (81) may suggest that they recordedfrom pulpal fibers sensitized to different degreesbecause tissue damage causing the production ofprostaglandins may be a prerequisite for makinghistamine an algogenic substance capable of excit-ing the A-delta as well as the C fiber population,since Tuckett et al, (85) demonstrated that hista-mine introduced into the skin using iontophoreses,a non-traumatic procedure, induced itch withoutproducing pain. The electrophysiological and psy-chophysical responses to histamine administrationin the present human study may accordingly be twoindicators of inflammation in that histamine elicitedA-delta activity and also evoked C fiber relatedpain,

Prostaglandins are, as we know, potent agents inthe development of inflammatory diseases and theymay cause degranulation of mast cells which in theirturn release histamine. This substance functionsthen as a chemotactic factor to which eosinophilsrespond. One of the four proteins contained in theeosinstaining granules is the eosinophilic cationicprotein (ECP) that has a great neurotoxic potential(86) and that it is capable of damaging sensorynerve endings resulting in discharge of neuropep-tides such as substance P and calcitonin gene relatedpeptide (CGRP) (87), Franzen et al, (88) haveanalyzed and measured the amount of ECP in bloodsamples from 20 patients with ankylosing spondylitis(Bechterew's disease). The patients were requiredto scale their subjective intensity of pain using visualanalog scale (VAS) and sensory verbal descriptors.The correlation between the magnitude of pain andECP concentration turned out to be very close tozero. Even though this is another instance wherewe have a biological marker of inflammation thatmay not be directly related to pain intensity expen-

cnced by the patient, it would be a matter of greatclinical interest to investigate the interaction be-tween histamine and ECP in pulpitis and to explorehow this inflammatory process is exacerbated byincreased sympathetic efferent drive. Levine et al.(89) have recently provided evidence for the contri-bution of the peripheral limb of the sympatheticdivision of the autonomic nervous system to inflam-matory reactions in patients with the syndrome ofvegetative dystrophy.

Acknowledgement — This study was supported by theSwedish Medical Research Council (24X-816), theSwedish Dental Association, Praktikertjanst AB, theSchool of Dentistry, Karohnska Institute, Stock-holm and the Sweden-America foundation.

References

1, HiGGS GA, MoNCADA S. Interactions of arachidonatr prod-ucts with other pain mediators. In: Bonica JJ, Lindblom U,Iggo A, eds. Advances in pain research and therapy. NewYork: Raven Press, 1983; J; 617-626.

2, KIM S, Microcirculation of the dental pulp in health anddisease. J Endodon 1985; U: 465-471.

3, VAN HASSEL H J , Physiology of the human denta! pulp. OralSurg, Oral Med Oral Pathol 1971; 32: 126-134,

4, ToNDER KJH, KviNNSLAND I. Micropuncture measurementsof interstitial fluid pressure in normal and inflamed dentalpulp in cats. J Endodon 1983; 9; 105-109.

5, HEYERAAS KJ. Pulpal, microvascular, and tissue pressure. JDent Res 1985; 64: 585-589.

6, TYLDESLEY W R , MUMFORD JM, Dental pain and the histo-logical conditions of the pulp. Dent Pradit 1970; 20: 333-336.

7, SELTZER S. Classification of pulpal pathosis. Oral Surg OralMed Oral Pathol 1972; 34: 269-287.

8, DowDEN W, LANGELAND K . A correlation of pulpal histo-pathology with clinical symptoms. J Dent Res 1979; 48: 183.

9, DRUMMER P M H , HICKS R , HUWS D. Clinical signs and symp-

toms in pulp disease. In! Fndodontic J 1980; 13: 27.10. AHLQUIST ML, EDWALI. LE, FRANZEN OG, HAEGERSTAM

GAT. Perception of pulpal pain as a function of intradentatnerve activity. Pain 1984; 19: 353-366.

11. AHLQUIST ML, FRANZEN OG, EDWALL LE, FORS U G , HAEG-

ERSTAM GAT. Quality of pain sensations following local ap-plication of algogenic agents on the exposed human toothpulp: a psychophysical and electrophysiotogical study. In:Fields HL, Dubner R, Gervero F, eds. Advances in painresearch and therapy. New York: Raven Press, 1985; 9:351-359.

12. AHLQUIST ML, FRANZEN OG. EDWALL LE, FORS UG, HAEG-

ERSTAM GAT. The relation between intradental nerve activ-ity and pulpal pain after heat stimulation. Acta Physio! Scand1986; 127: 1-7.

I"'. AHLQUIST ML, FRANZEN OG. Psychophysica! and neuro-

physiological indicators of latent and manifest pulpal inflam-mation. In: Sharma KN, Nayar U, Bhattacharya N, eds.Pain mechanisms and management, current trends in painresearch and therapy. laipur: Indian Society for Pain Re-search and Therapy 1988; / / / : 98-110.

l4, FRANZEN OG, AHLQUIST ML. The intensive aspect of infor-mation processing in the intradenta! A-delta system in man:a psychophysiological analysis of sharp dental pain. BehavBrain Res 1989; 33: 1-13.

^^- AHLQUIST ML, FRANZ^N OG. Encoding of the subjective

Inflafflmation & dental pain

intensity of sharp dental pain. Endod Dent Traumatol 1994;10: 153-166.

16. HAEGERSTAM G . The origin of impulses recorded from den-tinal cavities in the tooth of the cat. Acta Physiol Scand 1976;97: 121-128.

17. HoRiucHi H, MATTHEWS B. In vitro observations on fluidflow through human dentine caused hy pain-producing stim-uh. Arch Oral Biol 1973; 18: 275-294.

18. OLGART L. Pharmacological analysis of intradental sensorynerve excitability. An experimental study in the cat. PhDThesis. Karolinska Institute, Stockholm: 1974.

19. ORCHARDSON R . An electrophysiological investigation of thesensitivity of intradental nerves in the cat to changes in theionic composition of extracellular fluid. Arch Oral Biol 1978;23: 391-395.

20. PANOPOULOS P, Intradental sensory nerve responses to somefactors affecting dentin and pulp, PhD Thesis, KarolinskaInstitute, Stockholm: 1983.

21. LiNDAHL O. Experimental skin pain induced by injectionsof water-soluble substances in humans. Acta Fhysiol Scand1961; i ; . Suppl. 179.

22. KEELE GA, ARMSTRONG D. Subsiances producing pain anditch. London: Edvard Arnold, 1964; 3-24.

23. PANOPOULOS P, MEJARE B, EDWALL L. Eflects of ammonia

and organic acids on the intradental sensory nerve activity.Acta Odontol Scand 1983; 41: 209-215.

24. BYERS MR. Dental sensory receptors. In: Sniythies JR, Brad-ley RJ, eds. International review of neurobiology. New York:Academic Press, 1984; 25: 39-94.

25. RiLEY JF, WEST G B . The presence of histamine in tissuemast cells, J Fhysioi 1953; 120: 528-537.

26. KEELE GA, ARMSTRONG D. Mediators of pain. In: Lim RKS,

ed. Pharmacology of pain. Oxford: Pergamon Press, 1968;3-24.

27. FOREMAN J G . The role of histamine in inflammation. In:Higgs GA. Williains TJ, eds. Inflammatory mediators. VCH,Weinheim: Verlag Ghemie 1985; 7-18.

28. RocHA E, SiLVA M, BERALDO WT, ROSENFIELD G. Bradykin-in, a hypotensive and smooth muscle stimulating factor re-leased from plasma globulin by snake venoms and by trypsin.Am J Physiol 1949; J56: 261-273.

29. RocHA E, SiLVA M, ANTONIO A. Release of bradykinin andthe mechanisms of production of a "Thermic edema (45 °G)"in the rat's paw. Med Exp 1960; 3: 371-382.

30. FjALLBRANT N, IGGO A. The effect of histamine, 5-hydroxytryptamine and acetylcholine on cutaneous afferent fibres.J Physiol 1961; 156: 578-590.

31. BECK PW, HANDWERKER PO. Bradykinin and serotonin ef-

fects on various types of cutaneous nerve fibres. PJluegersArch 1974; //,- 209-222.

32. NXRHI M , JYVASJARVI E, HUOPANIEMI T. HIRVONEN T. Func-

tional differences in intradental A- and C-nerve units in thecat. Pain 1984; suppl. 2 242.

33. GAMP R D R , CUNINGHAM F M , WOOLLARD et al. The inflam-

matory properties of eicosanoids in human skin. In: HiggsGA, Williams TJ, eds. Inflammatory mediators, DeerfieldBeach:VCH Publishers, 1985; 47-55.

34. FRANZEN O, BERKLEY M . Apparent contrast as a functionof modulation depth and spatial frequency: a comparisonbetween perceptual and electrophysiological measures. Vi-.nonRes 1975; 15: 655-660.

35. HATTLER AB, LISTGARTEN MA. Pulpal response to root plan-ing in a rat model. J Endodon 1984; 10: 471-476.

36. SELTZER S, BENDER IB. The dental pulp. Philadelphia: Lip-pincott, 1984; 306-309.

37. TROWBRIDGE H O . Intradental sensory units: physiologicaland clinical aspects. J Endodon 1985; !1{1\): 489-498.

38. OLGART L, BRANNSTROM M , JOHNSON G. Invasion of bacteria

into dentinal tubules. Acta Odontol Scand 1974; 32: 6H70.

Ahlquist & Franzen

39. BERGENHOLTZ G , LINDHE A. Eflect of soluble plaque factorson inflammatory reaction in the dental pulp. Scand J DentRes 1975; 83: 153-158.

40. BERGENHOLTZ G. Effect of bacterial products on inflamma-tory reactions in the dental pulp, Scand J Dent Res 1977; 85:122-129.

41. MASSLER M , PAWLACKJ. 1961. The affected and infected

pulp. Oral Surg, Oral Med, Oral Pathol 1977; 43: 929-947.42. GoHEN S. Diagnostic procedures. In: Cohen S, Burns RC,

eds. Pathways of the pulp. St. Louis: Mosby, 1984; 31.43. MUMFORD JM, BOWSHER D. Pain and prothopathic sensibili-

ty. A review with particular reference to teeth. Pain 1976;2: 223-243.

44. HUNT SP, PINI A, EVAN G. Induction of c-fos-tike protein in

spinal cord neurons following sensory stimulation. Nature1987; 525; 632-634.

45. FRANZEN O , COOPER B. VIERCK C, AHLQUIST M . Sensory

magnitude functions of heat pain before and after intramus-cular injection of morphine. Acta Physiol Scand 1985; 124.Suppl 542: 254.

46. TERENIUS L . Endorphins and pain. Front Harm Re<. 1981; 8:162-177.

47. TERENIUS L. Neuropeptide interaction with pain. In: Fran-zen O, W'estman J, eds. Information processing in the soma-tosensory system, Wennergren International symposiumseries, London: Macmillan 1991; 57: 453-459.

48. FRANZEN O , TAMSEN A, TERENIUS L. The reciprocal action

of endorphins and systemic morphine on the magnitude ofpostsurgical pain (submitted).

49. ANDREWS SS, VAN HASSEL HJ, BROWN AC. Correlation be-

tween intrapulpal pressure and sensory response in pulpalpathosis. J Dent Res 1971; 51: Abstr. 700.

50. BROWN AC, NELSON D, VAN HASSEL HJ. Time course of

intrapulpal pressure gradients following pulp exposure, JDent Res 1971; 51: Abstr, 698.

51. MUMFORD JM. Toothache and orofacial pain. Edinburgh:Churchill-Livingstone, 1976.

52. FuNAKOSHi M, ZoTTERMAN Y. A Study in the excitationof dental pulp nerve fibres. In: Anderson DJ, ed. Sensorymechanisms in dentine. Oxford: Pergamon Press, 1963;60-70.

53. WINTER H F , BISHOP JG, DORMAN HL. Use of afferent nerve

fiber activity as an assay of pain responses from teeth. TexasDental J 1966; 84: 4-9,

54. SCOTT D, JR . The arousal and suppression of pain in thetooth. Int Dent J 1972; 22: 20-32.

55. NARHI M . Activation of dental pulp nerves of the cat andthe dog with hydrostatic pressure. Proc Finn Dent Soc 1978;74: 1-63.

56. ZAGH L, COHEN G . Pulp response to externally applied heat.Oral Surg Oral Med Oral Pathol 1965; 19: 515-530.

57. NYBORG H , BRANNSTROM M . Pulp reaction to heat. J ProsDent 1968; 19: 605-612.

58. BERLUCCHI G, BUCHTEL HA. Some trends in the neurologicalstudy of learning. In: Gazzaniga MS, Blakemore C, eds.Handbook of psycho biology. New York: Academic Press,1975; 481-498.

59. THOMPSON RF, GLANZMAN DS. Neural and behavioral mech-anisms of habituation and sensitization. In: Tighe TJ, LeatonRN, eds. Habituation: perspectives from child developmentanimal behavior and neurophysiology, Hillsdale: Erlbaum,1976; 49-93.

60. KENSHALO DR, HOLMES G E , WOOD P B . Warm and cold

thresholds as a function of rate of stimulus temperaturechange. Pen Psychophys 1968; 3: 81-84.

61. ADRIANSEN H , GYBELSJ, HANDWERKER HO, VAN HEES J,

Response properties of thin myelinated (A-delta) fibers inthe skin nerves, J Meurophysiol 1983; 49: 111-122.

62. ToREBjoRK HE, HALLIN RG. Responses in human A and C

fibres to repeated electrical intradermal stimulation. J JVeurol.Neiirosurg Psychiatry 1974; 37: 653-664.VAN HEES J, GYBELS J. G nociceptor activity in humannerve during painful and non-painful stimulation. J NeurolNeurosurg Psychiat 1981; 44: 600-607.F̂ .RREiRA SH, VANE JR. Prostaglandins: their disappearancefrom and release into the circulation. Mature 1967; 216:868-873,HAMBERG M , SAMUELSSON B. Prostaglandin endoperoxidrs.

Novel transformations of arachidonic acid in humanplatelets. Proc Nail Acad Sci 1974; 71: 3400-3404.HAMBERG M , SVENSSON J, SAMUELSSON B. Thromboxanes: a

new group of biologically active compounds derived fromprostaglandins endoperoxides, Proc jVatl Acad Sci 1975; 72:2994-2998.MoNCADA S, GRVGLEWSKI RJ, BUNTING S, VANE JR. An

enzyme isolated from arteries transforms prostaglandin endo-peroxides to an unstable substance that inhibits platelet ag-gregation. .^''ature 1976; 263: 663-665.VANE JR. Inhibition of prostagiandin synthesis as a mechan-isms of action for aspirin-like drugs. .Nature (New Biol) 1971;231: 232-235.BERGSTROM S, Prostaglandins and related compounds - bio-regulators with clinical application. Ai:ta Phcirm Tax. 1977:41: (suppl IV) p. 12.AHLBERG F K . Influence of local noxious heat stimulation onthe sensory nerve activity in thefeline dental pulp. Acta Physi-ol Scand 1978; 103: 71-80,AHLBERG FK. Dose-dependent inhibition of sensory nerveactivity in the feline dental pulp by anti-inflammatory drugs.Acta Physiol Scand 1978; 102: 434-440.HANDWERKF.R H . Pain producing substances. In: KosterlitzHW, Terenius LY. eds. Pain and society. Dahlem Konferen-zen, Weinheim: Verlag Chemie, 1980.RosENTHAL SR. Histamine as the chemical mediator forreferred pain. In: Kenshalo DR, cd. I he skin senses. Spring-field: Thomas, 1968; 480-498.RosENTHAL SR, Histamine as the chemical mediator forcutaneous pain. J Jnv Derm 1977; 69: 98- 105,KANAKA R , SCHAIBLE H - G , SCHMIDT RF. Activation of fme

articular afferent units by bradykinin. Brain Res 1985; 327:81-90.DELLOW PG, ROBERTS ML. Bradykinin application to den-

tine: a study of a sensory receptor mechanism. Aust Dent J1966; //.- 384-387.OLGART L. Excitation of intradental sensory units by phar-macological agents. Acta Physiol Scand 1974; 92: 48-55.KROEGER DC, KRIVOY WA. In: Structure and function of

biologically active peptide; discussion following E. W, Hor-ton, the role of bradykinein in the peripheral nervous systcni-Ann ^' Y Acad Sci 1963; 104: 256.

ANDERSON DJ, NAYLER MN. Chemical excitants of pain inhuman dentine and dental pulp. Arch Oral Biol 1962; 7:413-415.ANDERSON DJ, CURWEN M P , HOWARD LV. The sensitivity of

human dentin. J Dent Res 1958; 37: 669-677.NARHI M V O . The characteristics of intradental sensory unitsand their responses to stimulation. J Dent Res 1985; 64:564-571.STERANKA L R , MANNING DC, DEHAAS GJ, et al. Bradykinin

as a pain mediator; receptors are localized to sensory neuronsand antagonists have analgesic actions. Proc .Natl Acad Sci1988; 55(9): 3245-9.BURGESS PR, PERL ER. Myelinated afferent fibres ri-sponding specifically to noxious stimulation of the skin. JPhysiol 1967; 190: 541-562.FERREIRA SH. Prostaglandins, aspirin-like drugs and anal-gesia. .Nature 1972; 240: 200-203.TUCKETT RP, FRANZEN O , SKOLNICK R , WEI JY. Histamii^e

208

inflammatian & dental pain

iontophoresis into the skin. A reliable method for inducing neurons to the spinal cord and interact in spinal behavioralpruritus (itch). M'euroscience 1987; 22 {Suppl): s720. responses of the rat. .Vewrcic Z,eH 1984; 52.- 199-204.

lib. VENGE P, DAHL R , FREDENS K, HALLGREN R, PETERSON G. 88. FRANZEN O , HALLGREN R, VENGE P, AHLQUIST M . Inflam-

Eosinophil cationic proteins (ECP) and EPX9 in health and matory pain and eosinophil cationic (ECP) in patients withdisease. In: Yoshida T, Torisu M, eds. Immunobiology of ankylising spondylitis (Mb Bechterew). (Submitted),eosinophil. New York: Elsevier, 1983; 163-178. 89. LEVINE J, CODERRE, T, BASBAUM A. The peripheral ner\'ous

87, WIESENFELD-HALLINZ, HOKFELTT, LUNDBERGJ, FoRSSMANN system and inflammatory process. In: Dubner R, GebhartW, REINECHE M , TSCHOPP F, FISHER J. Immunoreactive calci- G, Bond M, eds. Proceedings of the Vth World Congress ontonin gene-related peptide and substance P coexist in sensory Pain. New York: Elsevier 1988: 33-43.

nt