8. Baroreceptor activity and nociception l
H. RAU, T. ELBERT and N. BIRBAUMER
1. Introduction
The arterial baroreceptors contribute to stabilize the arterial blood pressure: Increases in blood pressure lead to enhanced baroreceptor activation. This dampens sympathetic arousal and stimulates the n.vagus. As a consequence, cardiac contractility and heart rate will be lowered reflexively and blood pressure will drop to normal levels. Decreases in blood pressure, on the other hand, lead to reduced baroreceptor activity, the sympathetic nervous system is activated while the parasympathetic branch becomes inhibited, cardiac output and in turn blood pressure increases. Apart from these homoestatic effects of baroreceptor activation, accumulating evidence suggests that baroreceptors may have considerable impact on higher brain structures and thus also on behavioral processes. Such extrahomeostatic effects seem to involve more global changes in brain states like changes in the activation level or neural excitability and on activation and processing of aversive environs on the behavioral side. This chapter will concentrate on laboratory experiments investigating the latter aspect, while the fonner has been dealt with in the chapter by Elbert and Rau (this volume). The following is a brief chronological summary of the literafure on the extrahomoeostatic effects ofthe baroreceptors: - Koch [12] detected decreases in the activation level in dogs after mechanical stimulation ofthe arterial carotid baroreceptors. - Gellhorn, Yesinick, Kessler, and Hailman [11] demonstrated that convulsions in dogs and cats could be abolished through the activation ofarterial baroreceptors. - Bonvallet, Dell, and Hiebel [2] reported EEG synchronizing as response to mechanical stimulation ofthe carotid baroreceptors in animals.
In" IS research was supported by a grant from the Deutsche Forschungsgemeinschaft 152 H Rau, T. Elbert and N Birbaumer
- Nakao, Ballim, Gellhom, and Gellhom [16] discovered EEG synchronizing artel effects of pharmacological baroreceptor stimulation evoked through increments norr in blood pressure in cats. bec:: - Coleridge, Coleridge, and Rosenthal [5] demonstrated that single cell ovel activity of pyramidal cells in animals could be dampened by activation of the arterial baroreceptors. the 1 - Dworkin, Filewich, Miller, Craigmyle, and Pickering [8] reported reduced may pain avoidance in rats during pharmacological stimulation of the arterial blood evel pressure. This effect was absent when the arterial baroreceptors of the animals exci were surgically denervated. - Randich and Hartunian [17] studied the influence of pharmacologially raised blood pressure levels on tail-flick-Iatency in rats. They found a weak but reflt significant correlation between reflectory heart rate (HR) decreases and the tail pere flick-latency indicating more pronounced antinociception during conditions of cam enhanced baroreceptor activation. and - Randich and Maixner [18] observed higher pain thresholds in spontaneous beh: hypertensive rats than in normotensive rats to thermal stimuli but lower mee perception and pain thresholds to electrical stimuli. Surgical denervation of the com arterial baroreceptors had no significant effects on pain thresholds to thermal stimuli, neither in the normotensive nor in the hypertensive animals. Thresholds MOl to electrical stimuli, on the other hand, were influenced by the denervation: 1. perception and pain thresholds were decreased after the denervation in both 2. groups ofanimals without any significant group differences. - In our lab, we have obtained evidence that the modulation of pain thresholds, caused by pharmacological manipulation of the blood pressure, 3. depends on the tonic blood pressure in humans [13]. Subjects with higher blood pressure levels showed increased pain thresholds after blood pressure increases as compared to a saline placebo. The effect became reversed for subjects with normal to low tonic levels of blood pressure. Independent of blood pressure levels, however, was the influence of blood pressure manipulations on the Contingent Negative Variation (CNV), a slow cortical potential which is related 4. to cortical excitability. This electrocortical phenomenon became reduced in amplitude when blood pressure was raised by means of an a-sympathomimetic agent compared to a placebo saline infusion (see also chapter by Elbert & Rau). - In a number of studies [9,20] we and our colleagues studied the influence of mechanical stimulation of the carotid baroreceptors on brain and behavior. Dw Pertinent to this issue is the study by Elbert et a!. [9] showing increases in pain thresholds only in a group of borderline hypertensives during stimulation of the Baroreceptor activity andnociception 153
arterial baroreceptors, compared to a control condition. In a group of s normotensive subjects baroreceptor stimulation decreased pain thresholds. They became more sensitive to pain. In addition, borderline hypertensives showed an II overall higher pain threshold than normotensive subjects did. ,e Taken together, these results have shown that baroreceptor effects go beyond the blood pressure stabilizing homeostatic effects. The extrahomeostatic actions d may affect sensory intake and processing, in particular that of aversive or painful d events and also may include a modulation of the indices of arousal and neuronal Is excitability. Such observations were the basis for Dworkin [6] to formulate a psychopsychological model of essential hypertension. Briefly, the model ofDworkin [6, 8] states that activation ofthe baroreceptor Y It reflex arc, by its central nervous inhibitory effects, leads to reduction in the 1 perception ofpain and stress. The inhibitory ef!ect of baroreceptor activation as )f caused by blood pressure increases acts as a reinforcing stimulus which rewards and strengthens further enhancements in blood pressure. A number of factors,
LS behavioral and genetic, may interact to specify the extent to which the proposed
~r mechanism consitutes a risk factor for hypertension in any given individual. The .e contributing factors are summarized in the Venn diagramm (Fig. 1). 11 ls Model for learned hypertension (according to Dworkin [6]): 1. There needs to be a chronic source ofaversive stimulation or stress. h 2. The perceived aversiveness constitutes the risk more than physical charateristics of the stimulation (e.g. subjective intensity rather than the n physical intensity ofa noise). -,> 3. There exists a c possibly acquired - predisposition to learn changes in blood d pressure under aversive stimulation. In the previous experiments, some of the subjects learned to produce far greater increases in blood pressure than others. Also if other, more effective responses, to cope with an aversive 'e condition are available, they may be learned first, and the blood pressure e symptom may never fully emerge. d 4. There may be a genetically determined distribution of baroreceptor n reinforcement sensitivities in a given population. Those deriving greater c behavioral advantage from this mechanism ate more likely to use it.
e On the basis of the recent results, some of which were obtained after r. Dworkin has formulated his model, we already could clarify the last point: n e 154 H Rau, T. Etberl andN Birbaumer
chronic exposure Sf to noxious stimulation
n< st bI
r------el, I fu I aversiveness of bl noxious stimulation ba I th E) wl
ba ex th,
Fig. 1: Venn diagram offactors contributing to the risk for developing hypertension according to the model ofDworkin (1988). 2. Assume for a subject the dampening effect ofbaroreceptors on the perception and processing of aversive situations is particularly strong. Then his risk for the Ce development of hypertension should be particularly high. Consequently, subjects in who display increased sensitivity to baroreceptor manipulations are more likely tha to have already elevated blood pressure levels before entering the laboratory. We ph; have consistently observed such a relationship in our studies [9, 13]. del This view receives support by earlier studies employing the neck cuff rat stimulation. Mancia et al. [14] demonstrated that stimulation of the carotid in baroreceptors produces differential heart rate responding in both normotensives COl and hypertensives. The heart rate decelerations in response to stimulation ofthe dec carotid baroreceptors (by neck suction) were significantly more pronounced in ave hypertensives than in norrnotensives. Inhibition ofthe baroreceptors, on the other pai hand, resulted in stronger heart rate accelerations in normotensives than in col hypertensives. Obviously, baroreceptors of hypertensives seem to be more pre aY< Baroreceptor activity andnociception 155
sensitive to (simulated) blood pressure increases while baroreceptors of normotensives are more sensitive to a decline in blood pressure. Thus, the baroreflex fulfills its homeostatic requirement. In hypertensives it tends to dampen primarily further blood pressure enhancements while it protects normotensives relatively more against a threatening drop in blood pressure. We should, however, not forget that the baroreflex may be inhibited through higher brain structures with descending fibers to the brain stem. Assuming that pain thresholds during baroreceptor stimulation are primarily elevated in subjects with sensitive or strongly responding baroreceptors, the findings ofMancia et al. [14] might explain why subjects with tonically elevated blood pressure levels tolerate more intense pain, particularly when their baroreceptors are stimulated. In the natural environment, this would imply that the perception ofaversive events may be suppressed by raises in blood pressure. Exposed to chronic aversive events or stress, a viscious circle catches the ones who responded with blood pressure enhancements. In the next section, we will further stabilize the experimental basis for the baroreceptor hypothesis of pain modulation. Then we will present new experimental procedures and results providing the basis for the revised form of the model.
2. Critical evaluation ofDworkins baroreceptor-pain studies
Central to Dworkins hypothesis [6] which assigns operant mechanisms a key role in the genesis of hypertension is one of his own investigations [8]. It indicated that rats avoid pain to a lesser degree when blood pressure was raised pharmacologically as compared to a placebo saline condition. Surgical denervation ofthe arterial baroreceptors abolished this effect. In this experiment, f rats had to run on a treadwheel to avoid noxious trigeminal stimulation. Changes l in heart rate, which were induced reflexively by blood pressure increases, were correlated with the amount of avoidance acitivity. The greater the heart rate ~ decelerations (indicating stronger baroreceptor activation), the less effective 1 ~ avoidance behavior appeared. In order to test the hypothesis that the changes in r pain avoidance activity are mediated by baroreceptors, Dworkin and his rJ. colleagues denervated the arterial baroreceptors in a control group and, as e predicted, the dampening effect of the alpha-sympathomimetic agent on the avoidance measures was no longer observable. The conclusion ofthe authors was 156 H Rau, T Elbert and N Birbaumer that their experimental results demonstrated unequivocally the influence of sho baroreceptors on nociception. foll Dworkin et al. considered the possibility that the heart rate changes elicited har. by the baroreflex in intact animals (decelerations up to 160 bpm) might account wit for the impaired running performance. The question now arises: Is it possible that difJ the intact rats were simply unable to avoid the pain by running, as their cardiac see output was low, and consequently the blood supply to the muscles dropped, while nociceptive processes remained unchanged? If it was true that reduced cardiac evr output, initiated by the intact baroreflex to the blood pressure enhancement, would not allow the organism to engage in high physical acitivity, then the results Ac from Dworkin et al. study [8] could be trivial: Blood pressure elevation did not ser produce bradycardia after surgical denervation of baroreceptors and thus would the not interfere with strong physical activity. As a consequence, avoidance behavior fen would have persisted in the control animals. The Dworkin et al. [8] study does ab! not allow to determine, which one of either hypothesis, the trivial one or the we baroreceptor-pain-hypothesis, should be accepted. dUi The Dworkin et al. study is surely not the only one which is ambiguous in its in outcome. Another example is the one by Randich and Maixner [18], as their de] results were different for the thermal and the electrical pain. In order to test a) the hypothesis of baroreceptor activation and pain int perception interaction and b) the hypothesis of the contribution of this postulated baJ process to the genesis of hypertension, we perofrmed further experiments ar< employing mechanical baroreceptor stimulation in man. rm str ce: 3. Mechanical baroreceptor stimulation and bicycle ergometry sli co In medical practice, a bicycle ergometer test is frequently used to assess the ps individual risk for the later development of hypertension (e.g. the Franz test; [10]). In the standard test situation, the patient has to cycle with a work load of w. 50, 60, 70, 80, 90 and 100 watts, one minute for each particular load. Heart rate, w: systolic and diastolic blood pressure were continually monitored during three in periods: baseline (3 min), bicycling (5 min) and 5 minute recovery period. People be at risk can be identified on the basis of the time course of the diastolic blood in pressure during work load and subsequent recovery. The higher the diastolic p~ blood pressure raises during and after work load, referred to the baseline, the su more "exercise-positive" is the cardiovascular response of the individual. In a b~ b~ follow-up study of 22 exercise-positive borderline hypertensives, Fram [10] has Baroreceptor activity and nociception 157
shown that in allofthese patients a hypertension had developed 3.8 years later. A follow-up study of 15 exercise-negative borderline hypertensives, on the other hand, has shown, that 3.6 years after the test 68.5% had blood pressure levels within the normotensive range. These follow-up studies demonstrate that the 'differentiation into the category of exercise-positive vs. exercise-negative group seems to have a prognostic value for the later development ofhypertension. We tested 56 subjects with the procedure suggested by the Franz [10] and evaluated the baroreceptor dependent pain thresholds (see also [19]) in order to examine whether both suggested risk indicators were correlated with each other. According to Franz [10], the reduced blood pressure recovery after work load serves as an indicator for hypertensive development. According to Dworkin [6, 7] the baroreceptor pain interaction predicts hypertension, too. 24 male and 22 female subjects (age ranging from 20 to 48 years, no cardiovascular abnormalities) had to perform a bicycle ergometer test. Blood pressure recordings .were taken every minute during a baseline period, the work load period, and during 5 minutes recovery. According to the criteria by Franz [10], the difference in diastolic blood pressure between the baseline and recovery was chosen as the dependent variable. After the completion of this test, pain-thresholds were determined during intervals of baroreceptor stimulation and during control conditions. Carotid barorecepto'rs were stimulated by applying a negative pressure within a cuff around the neck for periods of6 s each. This negative pressure reached about -30 mmHg and caused a greater stress across the arterial wall. Since baroreceptors are stretch receptors, they are stimulated through the application of a negative cervical pressure. Increases in cuff pressure, which reached some + 8 mmHg2 , slightly inhibited baroreceptor activity. This condition served as a control condition. 16 trials for each of the two conditions were presented in a pseudorandomized sequence. The intertrial interval ranged from 12 to 24 seconds. During the 6 second trials either a positive or a negative cuff pressure was applied. 4 seconds after the onset of the pressure change an electric current was applied to the right forearm by means of a Tursky-electrode. The current intensity increased continously for 2 seconds up to a level which was determined before the experiment individually as very painful. Subjects were asked to interrupt the current by pressing a button as soon as the electrical simulus became painful. Thus the latency ofpressing the button indicated pain tolerance. For each subject the mean difference in pain sensitivity between the condition of baroreceptor stimulation and the control condition served as an index of baroreceptor-dependent alteration in pain threshold. Positive values indicate a 158 H Rau, T. Elbert and N. Birbaumer higher pain threshold during stimulation ofthe baroreceptors as compared to the control condition, negative values a lowered pain threshold. The effect of the baroreceptor stimulation was determined by evaluating the reflectory heart rate changes during the stimulation. Heart rate clearly differentiated both conditions (p<0.001). During trials with reduced cuffpressure (baroreceptor stimulation) heart rate decreased about 6 bpm while it increased about 0.5 bpm during trials with positive cuff pressure (control condition). This effect became evident in every single subject. As predicted, the correlation between the pain index and the Franz test critera (difference in diastolic blood pressure from baseline to recovery period) came out significant (r=-.26; p<0.05), although not very strong. When, however, only those subjects are considered which are at high risk, according to the Franz criterion, then 11 of the 12 subjects also exhibited decreased pain sensitivity during baroreceptor stimulation. Figure 2 illustrates this relationship between the two . variables. Subjects with an "exercise-positive" outcome in the Franz test tended to show increased pain thresholds during baroreceptor stimulation. This result demonstrates that for healthy subjects, without any acute signs of cardiovascular disorders and without hypertension, the interindividual variation in baroreceptor-dependent pain threshold is related to the outcome ofthe bicycle Fi ergometer test. The correlation between both variables was low. It remains di questionable whether or not subjects who are on risk according to both criteria p< are those subjects with the greatest likelihood to develop hypertension. Subjects er X demonstrating a positive response in only one ofthese variables could be thought of as having a medium risk compared to subjects with negative response in both variables. Another possible interpretation arises within the framework of Dworkin's model. Most ofthe subjects who are at risk for hypertension should respond with 4 attenuated nociception during high baroreceptor input. And indeed 11 of the 12 subjects who were at risk according to the Franz criteria did so. However, not all subjects which exhibited such a nociceptive modulation should be at risk, as other s factors (like the exposure to noxious environments) have to be present. This SI would leave us with the following speculation. Subjects who frequently reduce d negative perceptions of their environment by blood pressure enhancements respond positively to the Franz test already before the hypertensive development becomes manifest. Baroreceptor activity and nociception 159
ms
+120
"'0 C ID • • O1 u • f;:2 C • L Cl • :J- Cl +60 -o:J J:: C • • • E ID • • -0:0=_ If) • ' .... • • 0 •• • J:: l- 0 • • lIlO . ID~ • • La. "'0 • • -c (]) ID ~ u u L(]) :J • -0 -60 • c 0 ID '0 a l- • • .. a..o • •
-16 -8 o +8 +16 mmHg high risk low risk for development of hypertension
Fig. 2: Negative correlation between baroreceptor dependent changes in pain threshold (Y-axis: difference in pain interruption delay between baroreceptor stimulation and control condition; a positive value indicates longer latencies during stimulation 'of the baroreceptors and, hence, enhanced pain thresholds). X-axis: exercise responses of diastolic blood pressure according to the Franz (1986) test. Each asterix represents one subject.
4. A new method for stimulating baroreceptors including a placebo condition
Studies using mechanical baroreceptor stimulation with the cuff technique, suffered from one serious methodological flaw. Subjects could easily differentiate the stimulation (negative cuff pressure) from epoches when there was no or a positive cuff pressure. Most subjects identified the stimulation condition as the one changing bodily reactions more effectively, and hence it is conceivable that the stimulation was more distractive than the "control" condition. The reported effects might therefore result from this difference. 160 H Rau, T. Elbert andN Birbaumer -:; ":i .,' Recently, we have developed an improved technique of cervical pressure manipulation which allows to stimulate the carotid baroreceptors and the application of an adaequate placebo condition3. Thus we could set up experiments, the results of which could not be confounded with distraction or other psychological effects differentiating stimulation and control condition. Like most receptors, baroreceptors are not only sensitive to the level of pressure but also to the rate of change. Therefore a very short negative cuff pressure burst during the systolic phase of the cardiac cycle should be more effective in stimulating carotid baroreceptors than the same pressure change within the diastolic phase. A systolic negative pressure burst should add to the internal blood pressure increment to a large dilation of the carotid arteries. A diastolic cuffpressure burst, on the other hand, prolongs only this dilation ofthe arteries which has been initiated by the internal systolic pulse wave. Figure 3 explains the procedure. Given, that baroreceptors are more sensitive to changes in dilation of the arterial wall than to prolongation of the dilation reached, the fIrst case (systolic negative and diastolic positive cuff pressure application) should stimulate baron:ceptors more effectively. The second ca<;e (systolic positive and diastolic negative cuff pressure application), however, may have a smaller stimulatory power to the baroreceptors than the first one has. This device has two advantages. First, it allows doubleblind settings, and second it applies identical physical stimulation during both conditions (cuff-pressure changes of same duration and same intensity). Only the phase of stimulation within the cardiac cycle differentiates both kinds of external manipulations4. In the present experiment, the duration of each stimulation depended upon the length of the last baseline cardiac cycle. Both negative and positive pressure bursts had a duration of a half inter-beat-interval minus 100 msec. With this algorithm, the duration ofpressure bursts varied between individuals and between Fig. puIs, trials, but it did not differ between positive and negative pressure bursts. duril We have employed PRES in two studies. In thest: experiments the carotid and, baroreceptors were stimulated and unloaded by the PRES technique (systolic negative and diastolic positive pressure as stimulatory condition and diastolic negative with systolic positive pressure as control condition). Both conditions stim were employed in a pseudorandomized sequ~nce. Heart rate responses to both dec( PRES conditions were compared in order to determine the effects of the pres stimulations applied. As illustrated in Figure 4, heart rate clearly differentiates hear the two conditions (F(1,19)=51.0; p ECG 135 mmHg carotid 80 pulse wave +---f--,/ cuff o u c =0 -20 pressure 0·- U tn>.::J 135 iJ) iJ) 80 200 1000ms Fig. 3: A model ofthe function ofPRES: after a certain delay from the R-wave ofthe ECG the pulse pressure within the carotid arteria reaches its maximum. Cuff pressure manipulations during different phases of the cardiac cycle lead to different changes of the transmural pressure and, hence, baroreceptor acitvation. Condition 1 (systolic negative cuff pressure, diastolic positive cuff pressure) stimulates the carotid baroreceptors and produces reflectpry heart rate deceleration. Condition 2 (systolic positive cuff pressure, diastolic negative cuff pressure) tends to inhibit carotid baroreceptor activity and produces reflectory heart rate acceleration. All subjects were asked for their sensation of different conditions of the baroreceptor stimulation. None of the subjects could 162 H Rau, T. E/bert and N. Birbaumer differentiate the two conditions nor did anyone detect that the rhythm of positive 5. I and negative pressure bursts applied was triggered by his or her own heart. To tt furth< contr , "'~~"~."" ..•.... hypo ~ ..... be 10 ... ~...../ . ... ~ . and J SecoJ (eN' durin reduc cond: in Ell of th 2 3 4 5 6 small time [seconds I diast< S•off andb inhibition F furthc stimulation applil the ti for 1< 1 baror mani] thed pseuc durin 2 3 4 5 6 7 inten time [seconds I ratin! S•off in fro four t jJ (systc Fig 4: a: Grand mean (~=20) ofHR changes during systolic suction (baroreceptor stimulation) contrl and during diastolic suction (control condition). b: Grand mean (n=20) ofCNV (Fz) during systolic suction and during diastolic suction. F The a Baroreceptor activity and nociception 163 5. Pain perception, pain evoked potentials and PRES:5 To test the connection between baroreceptor activation and pain perception, a further experiment using PRES for stimulation of carotid baroreceptors and control condition including electrical finger stimulation was set up. It was hypothesized, that subjective pain ratings and pain evoked EEG potentials would be lower, when the pain stimulus was applied during baroreceptor stimulation and higher, when the pain stimulus was applied during the control condition. Secondly, it was hypothesized that a negative variation of the EEG potential (CNV) would occur during the whole 6 s interval (the cuffwas active for 6 s and during this interval 4 pain stimuli were presented). This brain wave should be reduced in amplitude under the stimulation condition, compared to the control condition. Data from additional studies supporting this hypothesis are presented in Elbert and Rau (in this volume). Thirdly, it was hypothesized that (independent of the external baroreceptor stimulation) the perceived aversiveness would be smaller when the pain stimulus was presented during systole as compared to diastole. During systole the pulse wave dilates the arteries in the carotid sinuses and hence stimulates baroreceptors more than during diastole. For pain stimulation the method by Bromm and his coworkers ([3] and further refined by Miltner et al. [15]) was used. A brief electrical pulse was applied with a current intensity ranging from 70 to 900 !lA intracutaneously to the tip of the middle finger of the non-dominant hand. The bipolar pulse lasted for 10 ms and current intensity was held constant within subjects. The electrical stimulus was presented during both types of manipulations of . baroreceptor firing (systolic suction and diastolic suction). During the manipulations, the pain stimulus was applied either during the systolic or during the diastolic phase of the cardiac cycle. All four conditions were employed in a pseudorandom order. Each of them comprised a 6 second stimulation period during which the cuff was active. Four pain stimuli were presented during that interval. Their intensity was kept constant and adjusted as painful according to a rating procedure. After each trial a visual scale appeared on the computer screen in front ofthe subject. Subjects were asked to rate the global pain intensity ofthe four electrical simuli presented during the previous trial. An ANOVA was calculated comprising two within subjects factors: "pain" (systolic vs. diastolic pain presentation) and "baromodulation" (stimulation vs. control, i.e. systolic vs diastolic suction). For painrati~gs, the effect "pain" reached significance (F(1,19)=7.8; p=O.Ol). The application ofthe pain stimulus within systole was rated as less painful than 164 H Rau, T Elbert andN Birbaumer when it was presented during the diastole. Neither the effect "baromodulation" nor the interaction reached significance. In addition, the EEG evoked potentials at Cz and pz differed with respect to the different types ofbaroreceptor modulation. The peak-to-peak measure (NI 50 P260) showed a smaller amplitude during baroreceptor stimulation (pz: F(l,19)=6.0; p N differences. U The evoked potential showed no significant differences between systolic or -4 -2 -- -- inhibition stimulation > 0 ::t N.~ \ UCO \ "- ~-i , 1 \ Ctt! 2 2.0 \ ___.J/ 8.E "'I -02 \ / xenID- / o ell 4 / >0> IDe 1 ro / ~ () / ( 6 I / f I 8 ~ "- J '-./ 10 , " 0 100 200 300 400 600 time (msec J Fig. 5: Grand mean (n=20) of evoked potentials (Cz) during baroreceptor stimulation and control condition. 6. Concluding remarks A critical inspection of the studies exammmg relations between baroreceptor acitvation and the processing of painful stimuli teaches us that such connections do exist but probably not as firm linkages. Our previous studies [9, 13] indicate that tonic blood pressure level is one crucial variable determining the kind of relations in a particular subject. Only subjects with higher blood pressure levels showed antinociception during baroreceptor stimulation as compared to the control condition. The data ofthe present experiment using the Franz test showed that not only the tonic blood pressure but also phasic blood pressure responses to physical stress are correlated with the baroreceptor - pain interaction. This indicates that the mechanism which allows the baroreceptors to inhibit pain sensation might be involved in the development ofhypertension. This would lend i I f 166 H Rau, T. Elbert andN Birbaumer support only to one aspect of Dworkin's model [6]. Baroreceptor dependent alterations in pain perception are not the consequence but probably one condition which facilitates development ofhypertension via negative reinforcement. These findings open new perspectives for further research. It seems worthwile studying furhter conditions which bring pain inhibiting effects of baroreceptor activity into action. APPENDIX 2 While a negative pressure presses the cuff onto the skin, and thus automatically tightens gaps betwen cuff and tissue, an excess pressure increases such gaps and thus causes air leakage. Therefore high positive pressures are technically more difficult to accomplish. 3 The technique was developed together with Barry Dworkin, Bertram Geiger, and Wemer Lutzenberger. 4 The method has been described more detailled elsewhere [21]. A short technical description is given in the following. Using a motor of a vacuum cleaner and 4 valves, which could be opened and closed by electromagnets very rapidely (computer driven), we constructed a device, which allows us to apply the above described principle in human subjects: R-waves from the ECG trigger the valves (with software driven delays) and cuff pressure changes from 200 msec (or [ : variable) duration can be applied to the neck in each phase of a cardiac cycle. In order to increase the effectiveness of the method, not only negative cuff pressure bursts were applied but also positive cuff pressure bursts. The active condition [~ (barostimulation) consisted of a systolic negative pressure burst of about 200 msec duration and was followed by a positive pressure burst of the same duration. The control condition used reversed series: during systole a positive pressure burst, [1 1 which tends to inhibit the dilation of the arteries, was applied and followed by a [1 negative pressure burst of the same duration during the diastole. We will refer to this method as "PRES" (cardiac phase related external suction). (1: 5 While a negative pressure presses the cuff onto the skin, and thus automatically tightens gaps between cuff and tissue, an excess pressure increases such gaps and [1~ thus causes air leakage. Therefore high positive pressures are technically more difficult to accomplish. 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