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Habituation to bearable experimental pain elicited by tooth pulp electrical stimulation
Pain, 11 (1981) 185--200 Elsevier/North-Holland Biomedical Press
185
HABITUATION TO BEARABLE EXPERIMENTAL PAIN ELICITED BY TOOTH PULP ELECTRICAL STIMULATION
MIGUEL CONDES-LARA, JOSE M. CALVO and AUGUSTO FERNANDEZ-GUARDIOLA Unidad de Investigaciones Cerebrales, lnstituto Nacional de Neurologga y Neurocirugia and Facultad de Psicolog(a, Universidad Nacional Autdnoma de Mdxico, Mexico (Mexico)
(Received 6 October 1980, accepted 5 May 1981)
SUMMARY
Stimulation (1/10 sec, 1--2 msec) of the tooth pulp of volunteers was carried out for 120 min at an intensity that produced bearable pain. Cortical evoked potentials, electroencephalographic activity, electromyograms of the superciliary and masseter muscles and galvanic skin response were recorded. Every 30 min, without suspending the stimulation, the subjects were questioned with respect to the sensations accompanying the stimuli. A progressive decrease in all polygraphic responses was obsen,ed which coincided with a decrease in the reported sensation of pain. This effect could be reversed by applying heterosensorial stimulatioa (questioni~lg). It is suggested that this is a phenomenon of habituation to pain since dishabituation, potentiation of habituation, and habituation to dishabituation were found.
INTRODUCTION
Habituation is a general process which gives rise to a decrease in the behavioral response to all modalities of sensory stimulation, particularly when long periods of intermittent stimulation are employed. There is reliable evidence that it is a central process [10,20,24,35] and correlated electroencephalographic (EEG) activity [2,37,41] and evoked responses [9,14,15, 26,27,36,38,39] have been described. Habituation should be distinguished from other processes which also give rise to dimimshed behavioral responses Please send correspondence to: Dr. Augusto Fern~indez-Guardiola, Unidad de Investigaciones Cerebrales, Instituto Nacional de Neurologia, Insurgentes Sur 3877, Mexico, D.F. (14410). 0304-3959/81/0000---0000/$02.50 © 1981 Elsevier/North-Holland Biomedical Press
186 arid evoked potentials (EP) such as transmission fatigue or receptor adaptation. In order to make this distinction, Thompson and Spencer have proposed various criteria gathered from the early literature on habituation [42 ]. Among these, the most commonly used is the presence of dishabituation by other heterosensorial stimuli or by the suspension and resumption of the stimulation. Another criterion is that "the weaker the stimulus, the more rapid and/or more pronounced is habituation; strong stimuli may yield no significant habituation" [42]. Our group has demonstrated that the paralysis accompanying mydriasis in the cat interferes with the process of sensory habituation to luminous stimuli [14], which is in agreement with the above statement since in this case, the stimuli which reach the retina are more intense than those encountered under physiological conditions. Nevertheless, even under these conditions of extremely intense and prolonged stimulation, we have found habituation and dishabituation at the cortical level. Similar results have been described in the rat [ 15]. Thus, it is possible that habituation exists ever, for stimuli of great intensity which provoke a strong behavioral response, such as nociceptive stimuli. In one of the first papers on this phenomenon, Hern~ndez-Pebn and BrustCarmona reported that the evoked responses to nociceptive and tactile stimuli in the gracilis and cuneate nuclei could be inhibited by stimulation of the reticular formation [ 25 ]. However, these authors noted that "the inhibition less often observed for nociceptive impulses than for tactile impulses falis in line with the well known difficulty for excluding pain sensation out of the span of attention" [25, p. 296]. It is significant that they too do not completely discard the possibility of habituation to pain. In order to elucidate the phenomenon of habituation to pain it is necessary to utilize an experimental model of nociceptive stimuli which are pulsatile, periodic, uniform and measuri~ble, and which do not lesion the tissues. Experimental evidence in man indicates that pain can be produced by thermal, electrical, osmotic or chemical stimulation of the dentin or dental pulp [1,4,31,33]. This method has been used by Chatrian et al. who implanted electrodes to stimulate the teeth of volunteers with the object of studying acute pain [4]. Using signal averaging procedures, they demonstrated that reliable evoked potentials can be recorded from the scalp in response to brief electrical shocks delivered to the tooth pulp through implanted electrodes, as was previously found using stronger currents [40]. Harkins and Chapman established a positive relationship between the subjective reports of sensation and the amplitude of brain evoked responses upon stimulatiag the tooth pulp [23 ]. The expeAments described here were carried out in order to determine if electrical stimulation of the pulpal nerves in man produces (1) only pain sensation, (2) measurable behavioral components, (3)changes in the amplitude of cerebral evoked potentials during a long period of stimulation, and {4) possible habituation to pain measured by electrographic, behavioral and subjective responses.
187 METHODS
8ubiects Five male volunteer subjects with a mean age of 29 years who presented enamel caries were used in this study. After removing the caries, two AgC1 electrodes, isolated except for the tip, were inserted in order to carry out bipolar stimulation of the tooth pulp (Fig. 1). The cavity was covered with dental cement and precautions were taken so that no saliva came in contact with the electrodes. This procedure permitted four of the subjects to participate in two experimental sessions on successive days. Subsequently, the electrodes were removed, the state of the dental pulp was radiographically examined, and the teeth were restored•
Recording EEG electrodes were attached to the following locations: F3--C3, FT--T~, F4--C4, Fs--T4 and O!--O2. Electrodes were also placed for bipolar recording of the masseter (EMGm) and superciliary (EMGs) muscles, galvanic skin response (GSR), electrocardiogram (ECG), respiration (ENG), and plethysmogram (PSG). The O1--O2 channel, besides being recorded, was also passed through a wide band AC preamplifier integrator. Variations in the ECG frequency were measured with an ECG tachograph. The EEG channels, the EMGm and EMGs signals, and a synchronous pulse given 100 msec before the stimuli were recorded on magnetic tape {Ampex
Fig. 1. Radiograph showing two electrodes implanted for the bipolar stimulation of the tooth pulp of a volunteer.
188
PR 2200) and later analyzed with a Nicolet 1072 transient averaging computer. Evoked potentials (average of 32 stimuli) were recorded during the entire testing period. EMG activity was also averaged and the GSR was measured every 30 sec.
Procedure Subjects lay quietly in a semi-dark soundproof room equipped with twoway sound and were asked to remain with their eyes closed. A control polygraphic recording of all variables was made for 30 min. Subsequently, several series of 8 stimuli each (1 per 10 sec, 1--2 msec) of increasing voltage were giv2n using a Grass $88 stimulator and isolating unit in order to identify the sensory and pain thresholds. Once the pain threshold had been determined, the intensity was increased on the average of 200/~A, an amount that approximated 10% of the difference between the intensities of the sensory and pain thresholds. After establishing this intensity, repetitive stimuli (1 per 10 sec) were continuously applied for 120 min. Every 30 min the subjects were questioned for a maximum of 2 rain with respect to the sensations accompanying the stimuli ~180 stimuli/30 min) at the beginning, middle and end of the previous 30 min period. Electrical stimulation was not suspended during questioning and the subject did not change position. After 120 min, stimulation was suspended for a period of 4 min, the light was turned on~ and the subjects were again questioned. Subsequently, a series of 50 stimuli was applied under the same conditions as before. A scale of sensation was constructed on the basis of the subjective responses: (1) Absence of sensation: no sensation reported. (2) Variable light sensation: undefinable sensations or those such as tingling, not perceived with every stimulus. (3) Variable sensation: diverse sensations of different intensities such as pricking, pinching and throbbing, perceived with every stimulus but not described as painful. (4) Variable pain: some stimuli perceived as painful, others not. (5) Bearable pain: all stimuli reported as painful and of different intensity and duration. (6) Uniform bearable p a i n all stimuli perceived as bearable pain of the same intensity and duration. RESULTS
Identification of thresholds During the search for the sensory and pain thresholds, verbal reports were obtained of sensations such as light touch, heat, strong touch, vibration, and pain of different intensity and duration. In no case were the subjects stimulated at intensities beyond those which produce bearable pain. Sensation was restricted to the tooth that was stimulated and no reflex sensations arising
189
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Fig. 2. Polygraphic recording m a d e while the i n t e n s i t y of t o o t h pulp stimulation was increased. T h e first five channels are the EEG recordings made at the locations referred to according to the 10-20 I n t e r n a t i o n a l Classification; EMGs, e l e c t r o m y o g r a m o f the superciliary muscle ipsilateral to t h e site of s t i m u l a t i o n ; EMGm, e l e c t r o m y o g r a m of the masseter muscle; ST, stimulus artifact; GSR, galvanic skin response; EKG (= ECG), electrocardiogram tachograph recording; f O l - - O 2 , integrated frequency and voltage of O1--O2 EEG; PSG, p l e t h y s m o g r a m ; ENG, e l e c t r o p n e u m o g r a m . Arrow indicates the m o m e n t that the voltage of the stimuli is increased. T h e interval b e t w e e n stimuli was 10 sec.
in other locations were reported. The duration of the painful sensation was reported to be several seconds in some cases, but was generally much less. As the intensity of the stimulus was increased, the sensation of pain was accompanied by changes in the physiological variables. Fig. 2 shows a polygraphic recording during which the intensity of stimulation was increased and the subjective report passed from variable sensation to pain. The following phenomena were observed: changes in EMGm and EMGs activities which corresponded to facial contractions; a decrease in skin resistance; and alterations in the ECG, occipital EEG rhythms, PSG, and in the frequency and amplitude of respiration.
190
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Fig. 3. Average (8 stimuli) potentials evoked in response to different intensities of electrical stimulation. The verbal reports we~'e classified in the following manner: 1, absence of sensation (0.9 mA); 2, variable light ~ensation (1.5 mA); 3, variable sensation (2.1 mA); 4, bearable pain (3.5 mA). A, F3--C3 EEG; B, ]74--C4 EEG. e, stimulus artifact. Calibrations: 50 pV, 200 msec.
During the initial (threshold) period in which a series of 8 stimuli were repeatedly given, each of greater intensity than the last, the EEG activity w a s analyzed before, during and after the stimuli in order to average the EPs. There was a positive correlation between the peak to peak amplitude of the potentials evoked by the different intensities of stimulation and the verbal reports of the sensations provoked by the stimuli (Fig. 3).
Repetitive stimulation EEG (Fig. 4). EEG activity was visually evaluated during the first 100 stimuli of the experiment CA) and during the 100 stimuli that followed the three questioning periods (B, C, D) in each of the 9 experiments carried out. Plots of occurrence were constructed from these data and regression lines were drawn. Three EEG patterns could be distinguished: (1)wakefulness, beta and alpha rhythms; (2) somnolence, appearance of alpha rhythms associated with stimuli (paradoxical alpha) and theta rhythms; and (3) sleep, theta and delta rhythms interspersed with spindles (14--16 cps). The regression lines were negative for pattern (1) while those for patterns (2) and (3) were positive. Thus, the decrease in the occurrence of wakefulness (1) was due to the increase in somnolence (2) during the first 100 stimuli of the experiment CA). In (B), (C) and (D), wakefulness decreased and sleep (3) increased. This decrease in wakefulness was blocked by the questioning periods when the pattern characteristic of arousal reappeared. Evoked potentials. Peri-st~mulus EEG activity (100 msec before and 8 0 0 msec after) was analyzed by averaging consecutive series of 32 EPs during repetitive stimulation, The latencies (Table I) and amplitude of each component of the EPs were meas~lred. Fig. 5 shows the EPs and their variations
191
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during repetitive stimulation, consisting of a progressive decrease in the peak to peak amplitude. This decrease in the amplitude of the EPs was blocked by the questioning periods. The amplitude of components N I and P~ showed great variability and no significant changes. Component N2 displayed the most significant decrease (P < 0.001) during the course of the experiment; that is, following each dishabituation by questioning, N2 showed a progressively greater tendency to decrease in the subsequent 30 min period (Fig. 6). In no case did the N2
TABLE I CHARACTERISTICS
OF EVOKED
POTENTIAL
COMPONENTS
Temporal characteristics (msec) of components (NI, Pl, N2, P2) of average potentials evoked by painful stimulation of the dental pulp. N = number of mean evoked potentials (average of 32 stimuli) used for the analysis.
X s'D. S.E. N
Nl
Pt
N2
P2
30.4 7.6 0.9 64
99.4 10.1 0.9 74
160.4 19.8 1.9 75
237.4 19.9 2.4 73
192
400
'
m sec
Fig. 5. Evoked potentials recorded in a subject during the stimulation o f the left inferior first molar. Each trace represents an average of 32 stimuli recorded: A, during the first stimuli of the experiment; B, before the first questioning period (30 min of repetitive stimulation); C, immediately after the first questioning period; D, before the second questioning period (60 min); E, after the second questioning period, e, stimulus artifact.
components of the potentials recorded immediately after questioning show a significant difference in amplitude from those initially recorded at the beginning of the experiment (A). These decreases in N2 were accompanied by decreases in the P2 component, although they were not always parallel. In the first half hour of the experiment (A), the amplitude of the N2 component did not decrease while P2 decreased significantly at 24 min (P < 0.01) and 30 min (P < 0.001) (Fig. 6). GSR. A graph was constructed from the variations in GSR obtained over 5 experiments. The temporal sequence of this variable was averaged for the control situation (no stimulation}, the period of threshold localization, and for the 120 min of nociceptive stimulation (Fig. 7). The lowest resistances were recorded during the search for the sensory and pain thresholds, the first stimuli of the 120 min period, and immediately after each questioning. A progressive increase in skin resistance was found during the periods besween questioning. This increase, similar to t~he pattern of decrease in the N2 and P2 components of the EPs, was more rapid as the experiment proceeded. EMGs and EMGm. Stimulation of the tooth pulp at intensities above the pain threshold caused an increase in the frequency of discharge in the EMGs, with a latency of 150 msec and a duration of 1--3 sec. With succes-
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Fig. 6. Variations in the amplitude of the N2 (upper graph) and P2 (lower graph) components of the potentials evoked by tooth pulp stimulation. Each point represents the mean of 128 potentials recorded in 4 subjects (32/subject). The changes in amplitude + S.E. are represented as percentages of the amplitude of the components recorded in response to the first stimuli of the experiment. The inset (upper right) shows an average evoked response (mean of 32 stimuli) with the nomenclature used for each component (N l, P1, N2, P2). The arrows (Cl, C2, C3, C4) indicate the time at which the subjects were questioned (every 30 min). Interrogation caused the decrease in amplitude to be interrupted; values similar to the initial ones were reestablished.
sive stimuli, this response tended to decrease, but reappeared spontaneously and also in response to questioning (Fig. 8). EMGm activity (Fig. 9) showed a sudden decrease after stimulation (20 + 5 msec latency) with a duration of 100 msec, followed by a tonic increase in activity that in some cases was longer than 1 sec. The tonic increase was preceded by a facial contraction at the end of the deactivation period. This phasic response tended to be more pronounced after each questioning period as the experiment proceeded, despite the general decrease in muscle tone.
Subjective responses Volunteers were interrogated in a non-suggestive manner every 30 min with respect to the sensations provoked by the initial, intermediate and final stimuli received in the period prior to questioning (Table II). The reports
194 GSR I n= 5 S s I= S.E.
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Fig. 7. Histo~am of the average galvanic skin response (GSR) -+ S.E. of 5 subjects during the following periods: A, contro! (no stimulation); B, localization of ~ensory and pain thresholds; Cl, C2, C3, first, second and third questioning periods: respectively, during which stimulation was continued (1 per 10 sec); C4, suspension (interrogation) and subsequent resumption of stimulation.
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Fig. 9. Peri-stimulus histograms of EMGm activity. Each trace corresponds to an average of 40 stimuli. A, first 30 min of repetitive stimulation; B, C, D, following the first, second and third interrogations, respectively; E, after the suspension and resumption of stimulation at the end of the experiment. 1, first stimuli of the experiment (A) or after each questioning period; 2, 3, second (41--80) and third (81--120) series of stimuli at the beginning of the experiment (A) or after each questioning period. Ordinates: frequency of discharge; abscissae: time of analysis (800 msec). Arrow: stimulus signal.
obtained in the course of 7 experiments (a total of 84 subjective responses) were evaluated according to the scale described in the Procedure section. On 12 occasions, the subjects reported that the intermediate stimuli or those given just before questioning were of the same intensity as the initial ones of a particular period. In all others (n = 72), the initial stimuli were perceived as being more intense. The frequency of the sensations provoked by tooth pulp stimulation are listed in Table II. Concerning those stimuli (10, 20, 30 rain) which correspond to the first questioning period (C~), absence of sensation was reported only once, while uniform bearable pain was described on 8 occasions; C2 (40, 50, 60 rain): absence of sensation (n = 2), uniform bearable pain (n = 7); C~ (70, 80, 90 rain): absence of sensation (n = 4), uniform bearable pain
Uniform Bearable Variable Variable Variable Absence
bearable pain pain pain sensation light sensation o f sensation
Sensations
5 2
1 3 2 1 1 1
2 2 1 2 1
4
40
30
10
20
C2
C1
Minutes
1 2 1 2 1
50
2 2
2 1
60
1
2 1 1 2
70
C3
CI---C4 represent the questioning periods. N = 7 subjects with a total of 84 responses.
A N A L Y S I S OF THE V E R B A L R E P O R T S
TABLE II
1 2 1
3
80
2 2
2 1
90
1
2 2 2
100
C4
2
2 1 2
110
3
1 2
1
120
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197 (n = 2); C4 (100, 110, 120 min): absence of sensation (n = 5), uniform bearable pain (n = 3). From these data, we c~n generalize that less sensation was reported more frequently as the experiment progressed, while the more intense sensations diminished.
Summary of results The blocking of the alpha rhythm which constitutes an orientation response, alterations in the amplitude of the N2 and P2 components of the EPs, changes in skin conductance, and the intensity with which the superciliary muscle contracts and the masseter muscle is inhibited are responses ~sociated with the painful perception of tooth pulp stimulation. All the responses to pain, including the verbal reports of painful sensation, tended to decrease with repetitive stimulation, reappearing immediately after, and ix some cases during, the questioning periods. DISCUSSION In these experiments, both painful and non-painful sensations were described in response to tooth pulp stimulation. There is evidence suggesting that both types of sensation originate in the tooth pulp and not ;,n the peridental tissue [21,31]. In our experiments using bipolar stimulation, the electrodes were firmly implanted in the dentin and isolated to prevent contact with saliva in order to assure that only the afferents of the tooth pulp were stimulated. In man, the verbal report of pain (experimental or pathological) is the strongest evidence of this perceptual experience. Hardy et al. [22] have suggested the term "experience of pain" to cover all the effects of nociceptive stimulation: (a) the reaction prior to painful stimulation -- the threat that the stimulation will produce a disagreeable sensation; (b) the local reaction at the site where the stimulus is applied; (c) the sensation of tho stimulus; and (d) the emotional reaction to the sensation of the stimulus. Gracely et al. [16--18] have called the sensation of the stimulus (c) the "sensory descriptors" and the emotional reaction (d) the "affective descriptors to pain". McGlashen et al. [32] have reported that the affective descriptors to pain do not necessarily reflect the intensity of the stirr:ulation or the extent of tissue damage. In order to measure pain precisely, we have proposed a method similar to that of Hardy et al. [22], combining both verbal reports and the measurement of a large number of physiological parameters (GSR, EEG, EMG, ECG, EP) [12,13]. In studies of experimental pain in animals as well as in man, different methods of measuring pain have been employed. Stimulation of the tooth pulp in cats [29,34] and monkeys [19] provokes a jaw opening reflex (JOR). This response has been used to measure the intensity of experimental pain [19,29]. Recently, it has been demonstrated that stimulation of the tooth pulp in man inhibits the masseter muscle [31], considered to be a response similar to the JOR [6]. The fact that inhibition of the masseter
198 muscle and contractions of the superciliary muscle were found in our experiments indicates that the intensity of stimulation exceeded the sensory threshold [ 31]. In this study, there was a correlation between all the physiological variables and the verbal reports, a finding that permits the former to be related to the experience of pain, although not all the variables are specific for pain. The recordings of the GSR and heart and respiration rates indicate that they are not specifically associated with the experience of pain but rather reflect the global state of arousal of an individual [28]. However, the potentials evoked by painful stimuli appear to be specific, as it is impossible to obtain this type of response upon tooth pulp stimulation in patients who display a congenital absence of sensitivity to pain [5 ]. The blockage of the alpha rhythm, the presence of an EEG pattern of somnolence, the disappearance of the GSR, and the decrease in the EMG responses are indicative of a general depression of the state of wakefulness in our subjects during the course of the experiment, and suggest the development of the phenomenon of habituation, generally reported to be accompanied by a progressive deactivation of the reticular formation and a slowing of cortical rhythms [ 3,11,24 ]. Habituation can be subjectively defined as the abolition or dimunition of the perception of a given stimulus and has been traditionally measured by changes in the arousal reaction recorded in the EEG [41], alterations in the amplitude and morphology of EPs [24,26], changes in brain electrical activity (background}, or by behavioral means [43]. One of the most important criteria to establish that these changes are due to habituation and not to adaptation or transmissi-n fatigue is the appearance of the process of dishabituation, due to heterosensorial stimulation or changes in the frequency of stimulation [7,8]. We consider that habituation to bearable pain is demonstrated in our experiments since without suspending the nociceptive stimuli, heterosensorial and psychic stimulation as represented by verbal questioning produce a clear increase in the response previously depressed by the repetitive stimuli. This increase is frequently accompanied by the reappearance of tbe sensation of pain. Two other phenomena characteristic of habituation are also present. First, habituation of the responses to pain occurs more rapidly as the experiment proceeds {with successive questioning periods, see Fig. 7 for example). This has been termed the "potentiation of habituation" by Thompson and Spencer [42] and has been described by Konorski for the orienting response [30 ]. Furthermore, the phenomenon of habituation to dishabituation is present as can be seen in the verbal reports (Table II) and in the amplitude of the EPs, particularly component N2 {Fig. 6). Nevertheless, it is necessary to point out that the GSR, while showing potentiation of habituation, does not give evidence of habituation to dishabituation; thus, after each questioning period,, the GSR attains similar levels. This might indicate a differential effect ~nong the responses and a lowered specificity of the GSR. In the case of bearable experimental pain, the decrease of the responses to painful stimuli may be adaptive in the Darwinian sense, since once the
199
organism is alerted, this reaction could lose its significance. This might be so especially under our experimental conditions in which the subjects are normal young volunteers who received stimuli of brief duration and bearable intensity, who did not associate the stimuli with any present pathology, and who had the certainty that the pain would disappear without a trace. It is of interest to point out that those clinical cases of spontaneously disappearing and reappearing pain could be due to the phenomenon of habituation and dishabituation. This possibility could open new perspectives in the investigation of nociception. REFERENCES 1 Anderson, D.J., Pain from dentine and pulp, Brit. med. Bull., 31 (1975) 111--114. 2 Apelbaum, J., Silva, E.E., Frick, O. and Segundo, J.P., Specificity and biasing of arousal reaction habituation, Electroenceph. clin. Neurophysiol., 12 (1960) 829--840. 3 Cavaggioni, A., Giannelli, G. and Santibafiez-H. G., Effects of repetitive photic stimulation on responses evoked in the lateral geniculate body and the visual cortex, Arch. ital. Biol., 97 (1959) 266--275. 4 Chatria, G.E., Canfield, R.C., Knauss, T.A. and Lettich, E., Cerebral responses to electrical tooth pulp stimulation in man. An objective correlate of acute experimental pain, Neurology (Minneap.), 25 (1975) 745--757. 5 Chatrian, G.E., Farrell, D.F., Canfield, R.C. arid Lettich, E., Congenital insensitivity to noxious stimuli, Arch. Neurol. (Chic.), 32 (1975) 141--145. 6 Cond~s-Lara, M., Estimulaci6n Nociceptiva Experimental, Thesis, Universidad Nacional Aut6noma de M~xico, Mexico City, 1978. 7 Cond~s-Lara, M., Calvo, J.M. y Fern~ndez-Guardiola, A., Estimulaci6n nociceptiva experimental en el hombre, Bol. Inst. Estud. m~d. biol. Univ. nac. M~x., 30 (1978) 140. 8 Cond~s-Lara, M., Dfez-Martfnez, S. y Fern~nde~-Guardiola, A., Habituaei6n al dolor experimental, Paper presented at the XXII Congreso Nacional de Ciencias Fisiol6gicas, Aguascalientes, Mexico, August, 1979. 9 Cruikshank, R.M., Human occipital brain potentials as effected by intensity-duration variables of visual stimulation, J. exp. Psychol., 21 (1937) 625--641. 10 Dodge, R., Habituation to rotation, J. exp. Psychol., 6 (1923) 1 - 3 6 . 11 Fern~ndez-Guardiola, A., Harmony, T. and Rold~n, E., Modulation of visual input by pupillary mechanisms, Electroenceph. clin. Neurophysiol., 16 ( 1964 ) 259--268. 12 Fern~ndez-Guardiola, A., Calvo, J.M., CondOs, M. y Dfez-Martfnez, S., Estudio neurofisiol6gico en el gato y poligr~ifico en el hombre: valoraci6n del efecto de la floctafenina sobre el sistema nervioso central, Medicina (M~x.), 56 (1976) 352--362. 13 Fern~ndez-Guardiola, A., Ostrosky, F., CondOs, M., Zapata, A., Soils, H. y Contreras, C.M., Umbral al dolor t~rmico cut~neo en el hombre: modificaciones producidas por la pirazolona, Medicina (M~x.), 54 (1974) 367--374. 14 Fern~ndez-Guardiola, A., Rold~n, R.E., Fanjul, M.L. and Castells, C., Role of the pupillary mechanism in the process of habituation of the visual pathways, Electroenceph, clin. Neurophysiol., 13 (1961) 564--576. 15 Garcia-Austt, E., Influence of the states of awareness upon sensory evoked potentials, Electroenceph. clin. Neurophysiol., Suppl. 24 (1963) 76--89. 16 Gracely, R.H., Dubner, R. and McGrath, P.A., Narcotic analgesia: fentanyl reduces the intensity but not the unpleasantness of painful tooth pulp sensations, Science, 203 (1979) 1261--1263. 17 Gracely, R.H., McGrath, P. 'and Dubner, R., Ratio scales of sensory and affective verbal pain descriptors, Pain, 5 (1978) 5--18. 18 Gracely, R.H., McGrath, P. and Dubner, R., Validity and sensitivity of ratio scales of sensory and affective verbal pain descriptors: manipulation of affect by diazepam,
200 Pain, 5 (1978) 19--29. 19 Ha, H., Wu, R.S., Contreras, R.A. and Tan, E.-C., Measurement of pain threshold by electrical stimulation of tooth pulp afferents in the monkey, Exp. Neurol., 61 (1978) 260--269. 20 Hagbarth, K.-E. and Kerr, l~.I.B.,Central influences on spinal afferent conduction, J. Neurophysiol., 17 (1954) 295--307. 21 Hannan, A.G., Sui, W. and Tom, J., A comparison of monopolar and bipolar pulp testing, J. Canad. dent. Assoc., 40 (1974) 124--128. 22 Hardy, J.D., Wolff, H.G. and Goodell, H., Pain -" controlled and uncontrolled, Science, 117 (1953) 164--165. 23 Harkins, S.W. and Chapman, C.R., Cerebral evoked potentials to noxious dental stimulation: relationship to subjective pain report, Psychophysiology, 15 (1978) 248--252. 24 Hermindez-PeAn, R., Central mechanisms controlling conduction along central sensory pathways, Acta neurol, lat.-amer., 1 (1955} 256--264. 25 Herndndez-Pe6n, R. and Brust-Carmona, H., Inhibition of tactile and nociceptive spinal evoked potentials in the cat during distraction, Acta neurol, lat.-amer., 7 (1961) 289--298. 26 Hern~indez-Pe6n, R., Guzm~in-Flores, C., Alcaraz, M. and Fernhndez-Guardiola, A., Photic potentials in the visual pathway during attention and photic habituation, Fed. Proc., 15 (1956) 91--92. 27 Hern~indez-Pe6n, R., Scherrer, H. and Jouvet, M., Modifica~io::~ of electric activity in cochlear nucleus during "attention" in unanesthetized cats, ~cience, 123 (1956) 331--332. 28 Hilgard, E.R., Pain as puzzle for psychology and physiology, A~~er. J. Psychol., 24 (1969) 103---113. 29 Keller, O., Vyklick:p, L. and Sykovd, E., Reflexes from A5 and A0l trigeminal afferents, Brain Res., 37 (1972) 330--332. 30 Konorski, J., Conditioned Reflexes and Neuron Organization, Cambridge University Press, Cambridge, 1948. 31 Matthews, B, Baxter, J. and Watts, S., Sensory and reflex responses to tooth pulp stimulation in man, Brain Res., 113 (1976) 83--94. 32 McGlashen, T.H., Evans, F.J. and Arne, M.T., The nature of hypnotic analgesia and placebo response to experimental pain, Psychosom. Med., 31 (1969} 227--246. 33 Mumford, J.M. and Bowsher, D., Pain and protopathic sensibility. A review with particular reference to the teeth, Pain, 2 (1976) 223--244. 34 Oliveras, J.L., Redjemi, F., Guilbaud, G. and Besson, J.M. Analgesia induced by electrical stimulation of the inferior centralis nucleus of the raphe in the cat, Pain, 1 (1975) 139--145. 35 Pavlov, I.P., Conditioned Reflexes, Dover, New York, 1960. 36 Picton, T.W., Hillyard, S.A. and Galambos, R., Habituation and attention in the auditory system. In: W.D. Keidel and W.D. Neff (Eds.), Handbook of Sensory Physiology, Vol. 5, Springer, Berlin, 1976, pp. 343--389. 37 Rheinberger, M.B. and Jasper, H.H., The electrical activity of the cerebral cortex in the unanesthetized cat, Amer. J. Physiol., 119 (1937) 186--196. 38 Rust, J., Habituation and the orienting response in the auditory c•:tical evoked potential, Psychophysiology, 14 ( 1977 ) 123--126. 39 Salamy, A. and McKean, C.M., Habituation and dishabituation of cortical and brain stern evoked potentials, Int. J. Neurosci., 7 (1977) 175--182. 40 Schmidt, J., Die Beeinflussung der langsamen Hirnrindenpotentiale des Menschen nach elektrischer Zahnreizung durch Analgetika, Acta biol. reed. germ., 24 (1970} 361--368. 41 Sharpless, S. and Jasper, H.H., Habituation of the arousal reaction, Brain, 17 (1956) 655--680. 42 Thompson, R.F. and Spencer, W.A., Habituation: a model phenomenon for the study of neuronal substrates of behavior, Psychol. Rev., 73 (1966) 16--43. 43 Thorpe, W.H., Learning and Instinct in Animals, Methuen, London, 1956.
185
HABITUATION TO BEARABLE EXPERIMENTAL PAIN ELICITED BY TOOTH PULP ELECTRICAL STIMULATION
MIGUEL CONDES-LARA, JOSE M. CALVO and AUGUSTO FERNANDEZ-GUARDIOLA Unidad de Investigaciones Cerebrales, lnstituto Nacional de Neurologga y Neurocirugia and Facultad de Psicolog(a, Universidad Nacional Autdnoma de Mdxico, Mexico (Mexico)
(Received 6 October 1980, accepted 5 May 1981)
SUMMARY
Stimulation (1/10 sec, 1--2 msec) of the tooth pulp of volunteers was carried out for 120 min at an intensity that produced bearable pain. Cortical evoked potentials, electroencephalographic activity, electromyograms of the superciliary and masseter muscles and galvanic skin response were recorded. Every 30 min, without suspending the stimulation, the subjects were questioned with respect to the sensations accompanying the stimuli. A progressive decrease in all polygraphic responses was obsen,ed which coincided with a decrease in the reported sensation of pain. This effect could be reversed by applying heterosensorial stimulatioa (questioni~lg). It is suggested that this is a phenomenon of habituation to pain since dishabituation, potentiation of habituation, and habituation to dishabituation were found.
INTRODUCTION
Habituation is a general process which gives rise to a decrease in the behavioral response to all modalities of sensory stimulation, particularly when long periods of intermittent stimulation are employed. There is reliable evidence that it is a central process [10,20,24,35] and correlated electroencephalographic (EEG) activity [2,37,41] and evoked responses [9,14,15, 26,27,36,38,39] have been described. Habituation should be distinguished from other processes which also give rise to dimimshed behavioral responses Please send correspondence to: Dr. Augusto Fern~indez-Guardiola, Unidad de Investigaciones Cerebrales, Instituto Nacional de Neurologia, Insurgentes Sur 3877, Mexico, D.F. (14410). 0304-3959/81/0000---0000/$02.50 © 1981 Elsevier/North-Holland Biomedical Press
186 arid evoked potentials (EP) such as transmission fatigue or receptor adaptation. In order to make this distinction, Thompson and Spencer have proposed various criteria gathered from the early literature on habituation [42 ]. Among these, the most commonly used is the presence of dishabituation by other heterosensorial stimuli or by the suspension and resumption of the stimulation. Another criterion is that "the weaker the stimulus, the more rapid and/or more pronounced is habituation; strong stimuli may yield no significant habituation" [42]. Our group has demonstrated that the paralysis accompanying mydriasis in the cat interferes with the process of sensory habituation to luminous stimuli [14], which is in agreement with the above statement since in this case, the stimuli which reach the retina are more intense than those encountered under physiological conditions. Nevertheless, even under these conditions of extremely intense and prolonged stimulation, we have found habituation and dishabituation at the cortical level. Similar results have been described in the rat [ 15]. Thus, it is possible that habituation exists ever, for stimuli of great intensity which provoke a strong behavioral response, such as nociceptive stimuli. In one of the first papers on this phenomenon, Hern~ndez-Pebn and BrustCarmona reported that the evoked responses to nociceptive and tactile stimuli in the gracilis and cuneate nuclei could be inhibited by stimulation of the reticular formation [ 25 ]. However, these authors noted that "the inhibition less often observed for nociceptive impulses than for tactile impulses falis in line with the well known difficulty for excluding pain sensation out of the span of attention" [25, p. 296]. It is significant that they too do not completely discard the possibility of habituation to pain. In order to elucidate the phenomenon of habituation to pain it is necessary to utilize an experimental model of nociceptive stimuli which are pulsatile, periodic, uniform and measuri~ble, and which do not lesion the tissues. Experimental evidence in man indicates that pain can be produced by thermal, electrical, osmotic or chemical stimulation of the dentin or dental pulp [1,4,31,33]. This method has been used by Chatrian et al. who implanted electrodes to stimulate the teeth of volunteers with the object of studying acute pain [4]. Using signal averaging procedures, they demonstrated that reliable evoked potentials can be recorded from the scalp in response to brief electrical shocks delivered to the tooth pulp through implanted electrodes, as was previously found using stronger currents [40]. Harkins and Chapman established a positive relationship between the subjective reports of sensation and the amplitude of brain evoked responses upon stimulatiag the tooth pulp [23 ]. The expeAments described here were carried out in order to determine if electrical stimulation of the pulpal nerves in man produces (1) only pain sensation, (2) measurable behavioral components, (3)changes in the amplitude of cerebral evoked potentials during a long period of stimulation, and {4) possible habituation to pain measured by electrographic, behavioral and subjective responses.
187 METHODS
8ubiects Five male volunteer subjects with a mean age of 29 years who presented enamel caries were used in this study. After removing the caries, two AgC1 electrodes, isolated except for the tip, were inserted in order to carry out bipolar stimulation of the tooth pulp (Fig. 1). The cavity was covered with dental cement and precautions were taken so that no saliva came in contact with the electrodes. This procedure permitted four of the subjects to participate in two experimental sessions on successive days. Subsequently, the electrodes were removed, the state of the dental pulp was radiographically examined, and the teeth were restored•
Recording EEG electrodes were attached to the following locations: F3--C3, FT--T~, F4--C4, Fs--T4 and O!--O2. Electrodes were also placed for bipolar recording of the masseter (EMGm) and superciliary (EMGs) muscles, galvanic skin response (GSR), electrocardiogram (ECG), respiration (ENG), and plethysmogram (PSG). The O1--O2 channel, besides being recorded, was also passed through a wide band AC preamplifier integrator. Variations in the ECG frequency were measured with an ECG tachograph. The EEG channels, the EMGm and EMGs signals, and a synchronous pulse given 100 msec before the stimuli were recorded on magnetic tape {Ampex
Fig. 1. Radiograph showing two electrodes implanted for the bipolar stimulation of the tooth pulp of a volunteer.
188
PR 2200) and later analyzed with a Nicolet 1072 transient averaging computer. Evoked potentials (average of 32 stimuli) were recorded during the entire testing period. EMG activity was also averaged and the GSR was measured every 30 sec.
Procedure Subjects lay quietly in a semi-dark soundproof room equipped with twoway sound and were asked to remain with their eyes closed. A control polygraphic recording of all variables was made for 30 min. Subsequently, several series of 8 stimuli each (1 per 10 sec, 1--2 msec) of increasing voltage were giv2n using a Grass $88 stimulator and isolating unit in order to identify the sensory and pain thresholds. Once the pain threshold had been determined, the intensity was increased on the average of 200/~A, an amount that approximated 10% of the difference between the intensities of the sensory and pain thresholds. After establishing this intensity, repetitive stimuli (1 per 10 sec) were continuously applied for 120 min. Every 30 min the subjects were questioned for a maximum of 2 rain with respect to the sensations accompanying the stimuli ~180 stimuli/30 min) at the beginning, middle and end of the previous 30 min period. Electrical stimulation was not suspended during questioning and the subject did not change position. After 120 min, stimulation was suspended for a period of 4 min, the light was turned on~ and the subjects were again questioned. Subsequently, a series of 50 stimuli was applied under the same conditions as before. A scale of sensation was constructed on the basis of the subjective responses: (1) Absence of sensation: no sensation reported. (2) Variable light sensation: undefinable sensations or those such as tingling, not perceived with every stimulus. (3) Variable sensation: diverse sensations of different intensities such as pricking, pinching and throbbing, perceived with every stimulus but not described as painful. (4) Variable pain: some stimuli perceived as painful, others not. (5) Bearable pain: all stimuli reported as painful and of different intensity and duration. (6) Uniform bearable p a i n all stimuli perceived as bearable pain of the same intensity and duration. RESULTS
Identification of thresholds During the search for the sensory and pain thresholds, verbal reports were obtained of sensations such as light touch, heat, strong touch, vibration, and pain of different intensity and duration. In no case were the subjects stimulated at intensities beyond those which produce bearable pain. Sensation was restricted to the tooth that was stimulated and no reflex sensations arising
189
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Fig. 2. Polygraphic recording m a d e while the i n t e n s i t y of t o o t h pulp stimulation was increased. T h e first five channels are the EEG recordings made at the locations referred to according to the 10-20 I n t e r n a t i o n a l Classification; EMGs, e l e c t r o m y o g r a m o f the superciliary muscle ipsilateral to t h e site of s t i m u l a t i o n ; EMGm, e l e c t r o m y o g r a m of the masseter muscle; ST, stimulus artifact; GSR, galvanic skin response; EKG (= ECG), electrocardiogram tachograph recording; f O l - - O 2 , integrated frequency and voltage of O1--O2 EEG; PSG, p l e t h y s m o g r a m ; ENG, e l e c t r o p n e u m o g r a m . Arrow indicates the m o m e n t that the voltage of the stimuli is increased. T h e interval b e t w e e n stimuli was 10 sec.
in other locations were reported. The duration of the painful sensation was reported to be several seconds in some cases, but was generally much less. As the intensity of the stimulus was increased, the sensation of pain was accompanied by changes in the physiological variables. Fig. 2 shows a polygraphic recording during which the intensity of stimulation was increased and the subjective report passed from variable sensation to pain. The following phenomena were observed: changes in EMGm and EMGs activities which corresponded to facial contractions; a decrease in skin resistance; and alterations in the ECG, occipital EEG rhythms, PSG, and in the frequency and amplitude of respiration.
190
A
B
Fig. 3. Average (8 stimuli) potentials evoked in response to different intensities of electrical stimulation. The verbal reports we~'e classified in the following manner: 1, absence of sensation (0.9 mA); 2, variable light ~ensation (1.5 mA); 3, variable sensation (2.1 mA); 4, bearable pain (3.5 mA). A, F3--C3 EEG; B, ]74--C4 EEG. e, stimulus artifact. Calibrations: 50 pV, 200 msec.
During the initial (threshold) period in which a series of 8 stimuli were repeatedly given, each of greater intensity than the last, the EEG activity w a s analyzed before, during and after the stimuli in order to average the EPs. There was a positive correlation between the peak to peak amplitude of the potentials evoked by the different intensities of stimulation and the verbal reports of the sensations provoked by the stimuli (Fig. 3).
Repetitive stimulation EEG (Fig. 4). EEG activity was visually evaluated during the first 100 stimuli of the experiment CA) and during the 100 stimuli that followed the three questioning periods (B, C, D) in each of the 9 experiments carried out. Plots of occurrence were constructed from these data and regression lines were drawn. Three EEG patterns could be distinguished: (1)wakefulness, beta and alpha rhythms; (2) somnolence, appearance of alpha rhythms associated with stimuli (paradoxical alpha) and theta rhythms; and (3) sleep, theta and delta rhythms interspersed with spindles (14--16 cps). The regression lines were negative for pattern (1) while those for patterns (2) and (3) were positive. Thus, the decrease in the occurrence of wakefulness (1) was due to the increase in somnolence (2) during the first 100 stimuli of the experiment CA). In (B), (C) and (D), wakefulness decreased and sleep (3) increased. This decrease in wakefulness was blocked by the questioning periods when the pattern characteristic of arousal reappeared. Evoked potentials. Peri-st~mulus EEG activity (100 msec before and 8 0 0 msec after) was analyzed by averaging consecutive series of 32 EPs during repetitive stimulation, The latencies (Table I) and amplitude of each component of the EPs were meas~lred. Fig. 5 shows the EPs and their variations
191
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during repetitive stimulation, consisting of a progressive decrease in the peak to peak amplitude. This decrease in the amplitude of the EPs was blocked by the questioning periods. The amplitude of components N I and P~ showed great variability and no significant changes. Component N2 displayed the most significant decrease (P < 0.001) during the course of the experiment; that is, following each dishabituation by questioning, N2 showed a progressively greater tendency to decrease in the subsequent 30 min period (Fig. 6). In no case did the N2
TABLE I CHARACTERISTICS
OF EVOKED
POTENTIAL
COMPONENTS
Temporal characteristics (msec) of components (NI, Pl, N2, P2) of average potentials evoked by painful stimulation of the dental pulp. N = number of mean evoked potentials (average of 32 stimuli) used for the analysis.
X s'D. S.E. N
Nl
Pt
N2
P2
30.4 7.6 0.9 64
99.4 10.1 0.9 74
160.4 19.8 1.9 75
237.4 19.9 2.4 73
192
400
'
m sec
Fig. 5. Evoked potentials recorded in a subject during the stimulation o f the left inferior first molar. Each trace represents an average of 32 stimuli recorded: A, during the first stimuli of the experiment; B, before the first questioning period (30 min of repetitive stimulation); C, immediately after the first questioning period; D, before the second questioning period (60 min); E, after the second questioning period, e, stimulus artifact.
components of the potentials recorded immediately after questioning show a significant difference in amplitude from those initially recorded at the beginning of the experiment (A). These decreases in N2 were accompanied by decreases in the P2 component, although they were not always parallel. In the first half hour of the experiment (A), the amplitude of the N2 component did not decrease while P2 decreased significantly at 24 min (P < 0.01) and 30 min (P < 0.001) (Fig. 6). GSR. A graph was constructed from the variations in GSR obtained over 5 experiments. The temporal sequence of this variable was averaged for the control situation (no stimulation}, the period of threshold localization, and for the 120 min of nociceptive stimulation (Fig. 7). The lowest resistances were recorded during the search for the sensory and pain thresholds, the first stimuli of the 120 min period, and immediately after each questioning. A progressive increase in skin resistance was found during the periods besween questioning. This increase, similar to t~he pattern of decrease in the N2 and P2 components of the EPs, was more rapid as the experiment proceeded. EMGs and EMGm. Stimulation of the tooth pulp at intensities above the pain threshold caused an increase in the frequency of discharge in the EMGs, with a latency of 150 msec and a duration of 1--3 sec. With succes-
193 NI 200
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sive stimuli, this response tended to decrease, but reappeared spontaneously and also in response to questioning (Fig. 8). EMGm activity (Fig. 9) showed a sudden decrease after stimulation (20 + 5 msec latency) with a duration of 100 msec, followed by a tonic increase in activity that in some cases was longer than 1 sec. The tonic increase was preceded by a facial contraction at the end of the deactivation period. This phasic response tended to be more pronounced after each questioning period as the experiment proceeded, despite the general decrease in muscle tone.
Subjective responses Volunteers were interrogated in a non-suggestive manner every 30 min with respect to the sensations provoked by the initial, intermediate and final stimuli received in the period prior to questioning (Table II). The reports
194 GSR I n= 5 S s I= S.E.
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195
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obtained in the course of 7 experiments (a total of 84 subjective responses) were evaluated according to the scale described in the Procedure section. On 12 occasions, the subjects reported that the intermediate stimuli or those given just before questioning were of the same intensity as the initial ones of a particular period. In all others (n = 72), the initial stimuli were perceived as being more intense. The frequency of the sensations provoked by tooth pulp stimulation are listed in Table II. Concerning those stimuli (10, 20, 30 rain) which correspond to the first questioning period (C~), absence of sensation was reported only once, while uniform bearable pain was described on 8 occasions; C2 (40, 50, 60 rain): absence of sensation (n = 2), uniform bearable pain (n = 7); C~ (70, 80, 90 rain): absence of sensation (n = 4), uniform bearable pain
Uniform Bearable Variable Variable Variable Absence
bearable pain pain pain sensation light sensation o f sensation
Sensations
5 2
1 3 2 1 1 1
2 2 1 2 1
4
40
30
10
20
C2
C1
Minutes
1 2 1 2 1
50
2 2
2 1
60
1
2 1 1 2
70
C3
CI---C4 represent the questioning periods. N = 7 subjects with a total of 84 responses.
A N A L Y S I S OF THE V E R B A L R E P O R T S
TABLE II
1 2 1
3
80
2 2
2 1
90
1
2 2 2
100
C4
2
2 1 2
110
3
1 2
1
120
O~
197 (n = 2); C4 (100, 110, 120 min): absence of sensation (n = 5), uniform bearable pain (n = 3). From these data, we c~n generalize that less sensation was reported more frequently as the experiment progressed, while the more intense sensations diminished.
Summary of results The blocking of the alpha rhythm which constitutes an orientation response, alterations in the amplitude of the N2 and P2 components of the EPs, changes in skin conductance, and the intensity with which the superciliary muscle contracts and the masseter muscle is inhibited are responses ~sociated with the painful perception of tooth pulp stimulation. All the responses to pain, including the verbal reports of painful sensation, tended to decrease with repetitive stimulation, reappearing immediately after, and ix some cases during, the questioning periods. DISCUSSION In these experiments, both painful and non-painful sensations were described in response to tooth pulp stimulation. There is evidence suggesting that both types of sensation originate in the tooth pulp and not ;,n the peridental tissue [21,31]. In our experiments using bipolar stimulation, the electrodes were firmly implanted in the dentin and isolated to prevent contact with saliva in order to assure that only the afferents of the tooth pulp were stimulated. In man, the verbal report of pain (experimental or pathological) is the strongest evidence of this perceptual experience. Hardy et al. [22] have suggested the term "experience of pain" to cover all the effects of nociceptive stimulation: (a) the reaction prior to painful stimulation -- the threat that the stimulation will produce a disagreeable sensation; (b) the local reaction at the site where the stimulus is applied; (c) the sensation of tho stimulus; and (d) the emotional reaction to the sensation of the stimulus. Gracely et al. [16--18] have called the sensation of the stimulus (c) the "sensory descriptors" and the emotional reaction (d) the "affective descriptors to pain". McGlashen et al. [32] have reported that the affective descriptors to pain do not necessarily reflect the intensity of the stirr:ulation or the extent of tissue damage. In order to measure pain precisely, we have proposed a method similar to that of Hardy et al. [22], combining both verbal reports and the measurement of a large number of physiological parameters (GSR, EEG, EMG, ECG, EP) [12,13]. In studies of experimental pain in animals as well as in man, different methods of measuring pain have been employed. Stimulation of the tooth pulp in cats [29,34] and monkeys [19] provokes a jaw opening reflex (JOR). This response has been used to measure the intensity of experimental pain [19,29]. Recently, it has been demonstrated that stimulation of the tooth pulp in man inhibits the masseter muscle [31], considered to be a response similar to the JOR [6]. The fact that inhibition of the masseter
198 muscle and contractions of the superciliary muscle were found in our experiments indicates that the intensity of stimulation exceeded the sensory threshold [ 31]. In this study, there was a correlation between all the physiological variables and the verbal reports, a finding that permits the former to be related to the experience of pain, although not all the variables are specific for pain. The recordings of the GSR and heart and respiration rates indicate that they are not specifically associated with the experience of pain but rather reflect the global state of arousal of an individual [28]. However, the potentials evoked by painful stimuli appear to be specific, as it is impossible to obtain this type of response upon tooth pulp stimulation in patients who display a congenital absence of sensitivity to pain [5 ]. The blockage of the alpha rhythm, the presence of an EEG pattern of somnolence, the disappearance of the GSR, and the decrease in the EMG responses are indicative of a general depression of the state of wakefulness in our subjects during the course of the experiment, and suggest the development of the phenomenon of habituation, generally reported to be accompanied by a progressive deactivation of the reticular formation and a slowing of cortical rhythms [ 3,11,24 ]. Habituation can be subjectively defined as the abolition or dimunition of the perception of a given stimulus and has been traditionally measured by changes in the arousal reaction recorded in the EEG [41], alterations in the amplitude and morphology of EPs [24,26], changes in brain electrical activity (background}, or by behavioral means [43]. One of the most important criteria to establish that these changes are due to habituation and not to adaptation or transmissi-n fatigue is the appearance of the process of dishabituation, due to heterosensorial stimulation or changes in the frequency of stimulation [7,8]. We consider that habituation to bearable pain is demonstrated in our experiments since without suspending the nociceptive stimuli, heterosensorial and psychic stimulation as represented by verbal questioning produce a clear increase in the response previously depressed by the repetitive stimuli. This increase is frequently accompanied by the reappearance of tbe sensation of pain. Two other phenomena characteristic of habituation are also present. First, habituation of the responses to pain occurs more rapidly as the experiment proceeds {with successive questioning periods, see Fig. 7 for example). This has been termed the "potentiation of habituation" by Thompson and Spencer [42] and has been described by Konorski for the orienting response [30 ]. Furthermore, the phenomenon of habituation to dishabituation is present as can be seen in the verbal reports (Table II) and in the amplitude of the EPs, particularly component N2 {Fig. 6). Nevertheless, it is necessary to point out that the GSR, while showing potentiation of habituation, does not give evidence of habituation to dishabituation; thus, after each questioning period,, the GSR attains similar levels. This might indicate a differential effect ~nong the responses and a lowered specificity of the GSR. In the case of bearable experimental pain, the decrease of the responses to painful stimuli may be adaptive in the Darwinian sense, since once the
199
organism is alerted, this reaction could lose its significance. This might be so especially under our experimental conditions in which the subjects are normal young volunteers who received stimuli of brief duration and bearable intensity, who did not associate the stimuli with any present pathology, and who had the certainty that the pain would disappear without a trace. It is of interest to point out that those clinical cases of spontaneously disappearing and reappearing pain could be due to the phenomenon of habituation and dishabituation. This possibility could open new perspectives in the investigation of nociception. REFERENCES 1 Anderson, D.J., Pain from dentine and pulp, Brit. med. Bull., 31 (1975) 111--114. 2 Apelbaum, J., Silva, E.E., Frick, O. and Segundo, J.P., Specificity and biasing of arousal reaction habituation, Electroenceph. clin. Neurophysiol., 12 (1960) 829--840. 3 Cavaggioni, A., Giannelli, G. and Santibafiez-H. G., Effects of repetitive photic stimulation on responses evoked in the lateral geniculate body and the visual cortex, Arch. ital. Biol., 97 (1959) 266--275. 4 Chatria, G.E., Canfield, R.C., Knauss, T.A. and Lettich, E., Cerebral responses to electrical tooth pulp stimulation in man. An objective correlate of acute experimental pain, Neurology (Minneap.), 25 (1975) 745--757. 5 Chatrian, G.E., Farrell, D.F., Canfield, R.C. arid Lettich, E., Congenital insensitivity to noxious stimuli, Arch. Neurol. (Chic.), 32 (1975) 141--145. 6 Cond~s-Lara, M., Estimulaci6n Nociceptiva Experimental, Thesis, Universidad Nacional Aut6noma de M~xico, Mexico City, 1978. 7 Cond~s-Lara, M., Calvo, J.M. y Fern~ndez-Guardiola, A., Estimulaci6n nociceptiva experimental en el hombre, Bol. Inst. Estud. m~d. biol. Univ. nac. M~x., 30 (1978) 140. 8 Cond~s-Lara, M., Dfez-Martfnez, S. y Fern~nde~-Guardiola, A., Habituaei6n al dolor experimental, Paper presented at the XXII Congreso Nacional de Ciencias Fisiol6gicas, Aguascalientes, Mexico, August, 1979. 9 Cruikshank, R.M., Human occipital brain potentials as effected by intensity-duration variables of visual stimulation, J. exp. Psychol., 21 (1937) 625--641. 10 Dodge, R., Habituation to rotation, J. exp. Psychol., 6 (1923) 1 - 3 6 . 11 Fern~ndez-Guardiola, A., Harmony, T. and Rold~n, E., Modulation of visual input by pupillary mechanisms, Electroenceph. clin. Neurophysiol., 16 ( 1964 ) 259--268. 12 Fern~ndez-Guardiola, A., Calvo, J.M., CondOs, M. y Dfez-Martfnez, S., Estudio neurofisiol6gico en el gato y poligr~ifico en el hombre: valoraci6n del efecto de la floctafenina sobre el sistema nervioso central, Medicina (M~x.), 56 (1976) 352--362. 13 Fern~ndez-Guardiola, A., Ostrosky, F., CondOs, M., Zapata, A., Soils, H. y Contreras, C.M., Umbral al dolor t~rmico cut~neo en el hombre: modificaciones producidas por la pirazolona, Medicina (M~x.), 54 (1974) 367--374. 14 Fern~ndez-Guardiola, A., Rold~n, R.E., Fanjul, M.L. and Castells, C., Role of the pupillary mechanism in the process of habituation of the visual pathways, Electroenceph, clin. Neurophysiol., 13 (1961) 564--576. 15 Garcia-Austt, E., Influence of the states of awareness upon sensory evoked potentials, Electroenceph. clin. Neurophysiol., Suppl. 24 (1963) 76--89. 16 Gracely, R.H., Dubner, R. and McGrath, P.A., Narcotic analgesia: fentanyl reduces the intensity but not the unpleasantness of painful tooth pulp sensations, Science, 203 (1979) 1261--1263. 17 Gracely, R.H., McGrath, P. 'and Dubner, R., Ratio scales of sensory and affective verbal pain descriptors, Pain, 5 (1978) 5--18. 18 Gracely, R.H., McGrath, P. and Dubner, R., Validity and sensitivity of ratio scales of sensory and affective verbal pain descriptors: manipulation of affect by diazepam,
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