Baroreceptor Stimulation Alters Pain Sensation Depending on Tonic Blood Pressure

It has been hypothesized that activation of the baroreceptor reflex arc, by its central nervous inhibitory effects, is involved in an operant learning mechanism of blood pressure elevation. The present study investigated the effects of mechanical stimulation of the baroreceptors in the carotid sinus on pain threshold and electrical brain activity in two groups of humans with different tonic blood pressure levels. In normotensives, baroreceptor stimulation lowered pain threshold as compared to a control condition, while borderline hypertensives tolerated more intense electric stimulation when baroreceptors were activated. A marked reduction of the contingent negative variation in anticipation of the aversive stimulation accompanied baroreceptor stimulation, probably a consequence of baroreceptor afferent impulses exerted via brainstem centers to cerebral cortex. The distribution of the potential change across the scalp depended on the tonic blood pressure, indicating differences in brain functioning between normotensives and borderline hypertensives. The present results suggest that the hypothesis of an operantly-conditioned blood pressure elevation under stress may be valid only in subjects with a predisposition for essential hypertension.     

Nociception and baroreceptor stimulation in hypertension-prone men and women

We examined the effects of baroreceptor stimulation on nociceptive responding in men and women with a positive or negative parental history of hypertension. The effects of three baroreceptor conditions (stimulation, inhibition, and control) on subjective pain and nociceptive responding were evaluated during electrocutaneous sural nerve stimulation. Pain ratings were lower in men with positive parental history relative to men with negative parental history, but this difference was not found in women. Both stimulatory and inhibitory baroreceptor conditions were associated with reduced pain reports compared to the control condition. There were no significant differences in nociceptive responding as a function of parental history of hypertension. Although this study confirms a link between hypoalgesia and risk for hypertension in men, it does not support the hypothesis that this attenuated pain perception is due to enhanced baroreceptor activity.     

Arterial baroreceptor reflex control of heart rate in two species of turtle

Attempts were made to stimulate an arterial baroreceptor reflex in anesthetized and conscious pond turtles. In turtles anesthetized with either alpha-chloralose or pentobarbital, occlusion of the ascending or descending aortas produced no reflex heart rate (HR) changes. In pentobarbital-anesthetized turtles, direct electrical or mechanical stimulation of potential baroreceptor sites along the central aortic arches and carotid arteries produced no significant changes in either HR or blood pressure (BP). Occlusion of the common carotid arteries also produced no HR or BP changes. Intravenously administered nitroglycerin lowered BP but caused no reflex tachycardia in anesthetized turtles. Phenylephrine and angiotensin elevated BP in the anesthetized turtle but caused no reflex bradycardia. In conscious turtles phenylephrine increased BP and nitroglycerin decreased BP. Neither response produced a statistically significant HR change, although HR tended to decrease transiently with phenylephrine and increase with nitroglycerin. These HR changes were abolished by atropine. Rapid intra-arterial infusion of 6% dextran transiently raised BP but caused no reflex bradycardia. These experiments suggest that cardiovascular regulation in the turtle is accomplished without a major contribution from arterial baroreceptor reflexes.     

Effects of PRES baroreceptor stimulation on thermal and mechanical pain threshold in borderline hypertensives and normotensives

Prior studies have noted a pain relieving effect of baroreceptor stimulation and of higher tonic blood pressure in animals and humans. The present study used a new technique for the controlled, noninvasive stimulation of human carotid baroreceptors (PRES). PRES baroreceptor manipulation was delivered to both normotensive subjects (n= 11) and medication-free labile hypertensive subjects (n= 10) during both thermal and mechanical pain. Consistent with prior research, hypertensives had a higher threshold for thermal pain than did normotensives. PRES baroreceptor manipulation had no significant effect on thermal pain threshold for either group. For the mechanical pain model, the opposite results were obtained; group pain threshold did not differ, but there was a significant PRES baroreceptor stimulation effect of increasing pain threshold for both groups. Results are discussed in terms of specific features of the stimuli, dampening of pain in hypertensives, and adaptation to pain.     

Blood pressure, gender, and parental hypertension are factors in baseline and poststress pain sensitivity in normotensive adults

We studied 38 men and 36 women to learn whether a brief speech stressor reduced normotensive humans thermal pain sensitivity, whether baseline and poststress pain threshold and tolerance varied with blood pressure (BP) and hemodynamic measures, and whether these relations differed by gender and parental hypertension (PH). PH-women with low resting BPs had lower baseline pain tolerance than did all other groups (ps < .05), and this group alone exhibited stress-induced analgesia (ps = .008). In women, pre- and poststress pain tolerance varied directly with rest and stress BP (ps < .05). In men, BP and pain measures were not related, but high cardiac index during stress was associated with low baseline pain tolerance (p < .01). The present findings support the hypothesis that pain sensitivity and cardiac stress response share a common mechanism, but they yield little support for the hypothesis that analgesic responses to acute stress contribute to hypertension etiology via an instrumental learning process. We are grateful to Robin Campbell for her technical assistance and to Dr. Alan L. Hinderliter for his assistance in screening volunteers for participation in this study. This research was supported by Grant R01-HL3t533 from the National Health, Lung, and Blood Institute, Bethesda, MD     

The Effect of Modification of Baroreceptor Activity on Reaction Time

The Laceys' hypothesis that baroreceptor stimulation has a direct effect on performance was tested by experimental manipulation of baroreceptor activity while subjects performed reaction time tests. Baroreceptor activity was altered by varying external cervical pressure and hence carotid sinus transmural pressure. The physiological effects of the baroreflex on heart rate and pulse transit time (a measure which generally correlates well with blood pressure) were seen both when baroreceptor stimulation was increased and when it was decreased. However, no difference in reaction time was found between the two conditions, therefore failing to support the Laceys' hypothesis.     

Effects of artificial and natural baroreceptor stimulation on nociceptive responding and pain

The arterial baroreflex may mediate hypertensive hypoalgesia. Carotid baroreceptors can be artificially stimulated by neck suction and inhibited by compression. Effects of brief neck suction and compression on nociceptive responding and pain were studied in 25 normotensive adults. The sural nerve was electrocutaneously stimulated at threshold intensity during systole or diastole combined with neck suction, neck compression, or no pressure. Nociceptive responding was indexed by electromyographic activity elicited in the biceps femoris. Participants rated the intensity of sural stimulation. Although artificial baroreceptor stimulation (suction) did not affect nociceptive responding, baroreceptor inhibition (compression) reduced pain ratings. In contrast, natural baroreceptor stimulation during systole reduced nociceptive responding compared to diastole, but did not affect pain ratings. The data provide partial support for baroreflex modulation of pain.     

Modulation of the human nociceptive flexion reflex across the cardiac cycle

Carotid baroreceptor stimulation has been shown to dampen pain. This study tested, in 40 normotensive adults, the hypothesis that pain is lower during systole when arterial baroreceptor stimulation is maximal than diastole when stimulation is minimal. The sural nerve was stimulated electrocutaneously to obtain a nociceptive flexion reflex (NFR) threshold, and then stimulation was delivered for 28 trials at 100% NFR threshold at seven intervals after the R-wave. Nociceptive responding was indexed by electromyographic (EMG) activity elicited in the biceps femoris. Significant variations in EMG activity occurred across the cardiac cycle, with less activity midcycle, indicating that the NFR response was attenuated during systole compared to diastole. Stimulation of baroreceptors by natural changes in blood pressure during the cardiac cycle dampened nociception, and accordingly, the data support the arterial baroreflex mechanism of hypertensive hypoalgesia.     

Relationship between baroreceptor cardiac reflex sensitivity and pain experience in normotensive individuals.

In the present study, the relationship between cardiac baroreceptor function and the perception of acute pain was investigated in 60 normotensive subjects. Baroreceptor reflex sensitivity was determined using the sequence method based on continuous blood pressure recordings. A cold pressor test was used for pain induction. Visual analogue scales and a questionnaire were applied in order to quantify sensory and affective pain experience. Moderated multiple regression analysis revealed an inverse relationship between baroreceptor reflex sensitivity assessed during painful stimulation and the intensity of experienced pain. This relationship was moderated by resting blood pressure, with decreasing blood pressure being accompanied by a decrease in the magnitude of the association. Furthermore, resting blood pressure was inversely related to pain intensity. The inverse association between baroreceptor reflex sensitivity and pain experience is discussed as reflecting the well-established pain-inhibiting effect of baroreceptor activity. The finding that this relationship was less pronounced in the case of lower blood pressure suggests that baroreceptor-mediated pain attenuation is reduced in this population.     

Baroreceptor stimulation alters cortical activity

The arterial baroreceptors constitute an essential sensory link for the short-term regulation of blood pressure and may also influence higher cortical function. The present study was undertaken to evaluate previous reports of such a cortical influence under conditions of psychologically controlled, mechanical baroreceplor stimulation. This control was achieved by use of PRES (phase-related external suction), a modified neck suction technique. PRES applies short suction bursts that have a different impact on baroreceptors depending on their timing within the cardiac cycle and has the advantage that subjects cannot easily discriminate between conditions of stimulation and inhibition. Electroencephalograms were recorded from 22 subjects during PRES manipulations. A surface-negative shift of about 10 μV developed during the cuff manipulations. Over frontal-central regions, this shift was smaller during baroreceptor stimulation than during inhibition. These data provide support for the proposal that baroreceptor activation influences cortical activity.     

Effects of cardiopulmonary baroreceptor activation on pain may be moderated by risk for hypertension

Cardiopulmonary baroreceptor stimulation may modulate pain, though the literature is much smaller than research showing that sinoaortic baroreceptor stimulation can buffer pain. To examine the possibility that risk for established high blood pressure may moderate the effects of cardiopulmonary baroreceptor stimulation on pain, 22 borderline hypertensive and 18 normotensive men participated in a laboratory experiment. Group differences in blood pressure were documented by 24-h ambulatory blood pressure recording. Ratings of the intensity of acute heat pain were influenced by both group membership and leg position. Passive elevation of the legs, a technique that stimulates cardiopulmonary baroreceptors, reduced ratings of heat pain though only among borderline hypertensives. Alteration of pain sensitivity may reflect the development of the hypertensive process.     

Psychophysiology of arterial baroreceptors and the etiology of hypertension.

Arterial baroreceptors are sensitive to blood pressure dependent blood vessel dilation. They play a key role in the short term regulation of blood pressure. Their impact on psychological and psychophysiological aspects is of increasing interest. The review focuses on experimental techniques for the controlled baroreceptor manipulation. Results from the application of these techniques show that baroreceptor activation influences the cardiovascular system as well as central nervous functioning: Behavioral and electrophysiological measures of arousal, low level reflexes and pain responses are modulated through baroreceptor manipulation. The observation of an overall dampening ('barbiturate like') effect of baroreceptor activity led Dworkin et al. formulate the theory of learned hypertension: Subjects might experience blood pressure dependent baroreceptor activation as stress and pain relieving. High blood pressure periods become negatively reinforced. Phasic high blood pressure might develop as a coping strategy. Data from a longitudinal human study supporting this theory are reported.     

Family history of hypertension,exercise training,and reactivity to stress in rats

In this study we sought to assess the role of exercise training on blood pressure (BP) reactivity to tailshock stress in rats with varying family histories of hypertension. Exercise training consisted of swimming 90 min per day in isothermic water for either 2, 6, or 10 months, beginning at 2 months of age. Control subjects were age-matched and did not exercise daily. Rats with either zero (Wistar-Kyoto), 1 (borderline hypertensive), or 2 (spontaneously hypertensive) hypertensive parents were studied. At the appropriate age, femoral artery catheters were implanted and rats were studied at rest and in response to a 20-min stress session. Exercise training reduced basal BP, especially in rats with a positive family history that were exercised for the longest duration. Reactivity to stress was actually significantly enhanced in trained rats. Thus, these data do not support the reactivity hypothesis, but suggest several reasons why the literature has been so inconsistent. The discussion emphasizes the importance of basal, rather than phasic, BP responses resulting from exercise training. Research for this article was supported by National Institutes of Health (NIH) Grant No. HL19680 to James E. Lawler and NIH Grant No. HL34878 to Ronald H. Cox     

Blood pressure changes validate phase related external suction,a controlled method for stimulation of human baroreceptors

Summary Phase related external suction (PRES), a new controlled method for manipulating activity in human baroreceptors, applies precisely timed bursts of suction and pressure within the cardiac cycle through an external neck cuff. Seven healthy adult men participated in 32 pseudo-random trials of baroreceptor stimulation and inhibition. Blood pressure was assessed both intra-arterially and with a noninvasive device. In the present study, PRES baroreceptor stimulation elicited invasively measured blood pressure decreases of about 2.5 mmHg (0.33 kPa) and heart rate decreases of about 5 beats · min^–1, while baroreceptor inhibition increased invasively measured blood pressure by about 1.5 mmHg (0.20 kPa) and heart rate about 2.5 beats · min^–1. It was concluded that PRES is an effective method for baroreceptor manipulation with weaker size effect but better control of nonspecific factors in human subjects than other baroreceptor manipulation techniques. The noninvasive blood pressure measurement device was less sensitive to experimental variation than was the invasive device.     

Sensory detection thresholds are modulated across the cardiac cycle: Evidence that cutaneous sensibility is greatest for systolic stimulation

The visceral afferent feedback hypothesis proposes that sensorimotor function is impaired by cortical inhibition associated with increased baroreceptor activation. This study is the first to examine the effects of naturally occurring variations in baroreceptor activity across the cardiac cycle on cutaneous sensory detection thresholds. In each trial, an electrocutaneous stimulus was delivered to the index finger at one of three intervals (0, 300, 600 ms) after the R-wave of the electrocardiogram. Separate interleaving up-down staircases were used to determine the 50% detection threshold for each R-wave to stimulation interval. Cutaneous sensory detection thresholds were lower for stimuli presented at R+300 ms than R+0 ms or R+600 ms. The finding that cutaneous sensibility was greater when stimulated during systole than diastole may be accounted for by a modified afferent feedback hypothesis.     

Adaptation of the human carotid baroreceptor-cardiac reflex.

1. Four intensities of neck suction were applied for 5 sec in healthy young men to determine the time course of decay of carotid baroreflex sinus node inhibition. 2. Peak responses occurred at about 1-25 sec after the onset of baroreceptor stimulation and were proportional to the intensity of stimulation. 3. Responses declined steadily during the remaining period of stimulation; the rate of decay of sinus node inhibition was decribed well by a power function and was proportional to the intensity of baroreceptor stimulation. 4. beta-adrenergic blockade did not alter the rate of decay of abroreflex sinus node inhibition. 5. These results suggests that adaptation of the integrated baroreceptor-cardiac reflex occurs in man and follows the same time course as adaptation of individual baroreceptor units an experimental animals.     

Rabbit classical eyeblink conditioning is altered by brief cerebellar cortical stimulation

A pair of studies examined how cortical intracerebellar stimulation (ICS) affects eyeblink conditioning in the rabbit. Rabbits were implanted with chronic bipolar stimulating electrodes in the cell body layers of cerebellar lobule H-VI. Brief (40 ms) trains of intracranial stimulation (100 Hz, 250 microA) were delivered during training trials [forward pairings of a tone-conditioned stimulus (CS) with an air puff unconditioned stimulus (US)]. In Experiment 1, the onset of ICS varied randomly within sessions. US-onset-coincident ICS proved detrimental to the maintenance of conditioning [measured as the percentage of trials on which conditioned responses (CRs) were made] compared to ICS that ended 60 ms before US onset. Based on these findings, a second experiment compared a group trained with ICS consistently delivered at US onset to groups trained with ICS consistently delivered either at CS onset or between the two stimuli, as well as to unstimulated control subjects. Animals receiving CS- or US-coincident ICS learned slowest, whereas animals receiving middle stimulation learned more quickly than all other groups. In both Experiments 1 and 2, highly trained animals produced blinks in direct response to the stimulation. These data are discussed in terms of a new hypothesis concerning interactions between cerebellar cortex and the deep cerebellar nuclei during eyeblink conditioning--a rebound from inhibition hypothesis.     

Influence of low- and high-pressure baroreceptors on plasma renin activity in humans

We evaluated effects of the low- and high-pressure baroreceptors on plasma renin activity (immunoassay) using graded lower body suction (LBS) in six healthy men. LBS at -10 and -20 mmHg for 10 min decreased central venous pressure without changing arterial pressure and thereby presumably reduced low- but not high-pressure baroreceptor inhibition of renin release. LBS at these levels produced forearm vasoconstriction, but did not increase renin. LBS at -40 mmHg decreased central venous and arterial pulse pressure and thus reduced both low- and high-pressure baroreceptor inhibition. LBS at this level produced forearm vasoconstriction and tachycardia and increased renin from 2.1 +/- 0.4 (mean +/- SE to 7.4 +/- 1.4 ng.ml-1.h-1 (P less than 0.05). In summary, reduction in low-pressure baroreceptor inhibition in humans did not increase renin in the presence of physiological tonic inhibition from high-pressure baroreceptors. Increases in renin did not occur until there was combined reduction of high- and low-pressure baroreceptor inhibition on plasma renin activity.     

Reactions to pain among subjects high and low in dental fear

Differential pain tolerance might account for the diversity of reactions commonly seen in response to stressful medical and dental procedures. College students reporting themselves either highly fearful or nonfearful of dental work were compared in several aspects of their reactions to dental and nondental pain. The two groups did not differ in pain threshold or pain tolerance assessed during tooth pulp stimulation or during electrical stimulation of the forearm. High-dental fear subjects, however, retrospectively rated tooth shock (but not arm shock) more painful than low-fear subjects. High-fear subjects also showed significantly greater affective reactions assessed via the Anxiety Differential during both tolerance tests, with the group differences greater in magnitude during tooth shock than arm shock.This research was supported by USPHS Grant DE-04976 from the National Institute of Dental Research awarded to the first author.     

Human investigations into the exercise pressor reflex

During exercise, neural input from skeletal muscles reflexly maintains or elevates blood pressure (BP) despite a maybe fivefold increase in vascular conductance. This exercise pressor reflex is illustrated by similar heart rate (HR) and BP responses to electrically induced and voluntary exercise. The importance of the exercise pressor reflex for tight cardiovascular regulation during dynamic exercise is supported by studies using pharmacological blockade of lower limb muscle afferent nerves. These experiments show attenuation of the increase in BP and cardiac output when exercise is performed with attenuated neural feedback. Additionally, there is no BP response to electrically induced exercise with paralysing epidural anaesthesia or when similar exercise is evoked in paraplegic patients. Furthermore, BP decreases when electrically induced exercise is carried out in tetraplegic patients. The lack of an increase in BP during exercise with paralysed legs manifests, although electrical stimulation of muscles enhances lactate release and reduces muscle glycogen. Thus, the exercise pressor reflex enhances sympathetic activity and maintains perfusion pressure by restraining abdominal blood flow, while brain, skin and muscle blood flow may also become affected because the reflex 'resets' arterial baroreceptor modulation of vascular conductance, making BP the primarily regulated cardiovascular variable during exercise.