Relation Between Systemic Hypertension and Pain Perception David S. Sheps,
Edith E. Bragdon, MA, T. Flint Gray III, MD, Martha Ballenger, James E. Usedom, MD, and William Maixner, DDS, phD
MD, MSPH,
To test the hypotfiesis that hypertension diminishes pain mn, a study was made that evaluated the rektion between arterial blood pressure and thermal pain peroeption In human subjects. The average mean arterial pressure in all 20 men studied (l0 hypertensive, 10 normotensive) proved to be signtfkantly related to both thermal pain threshold (p = 0.05) and tolerance (p = 0.003). The difference between normotensive and hypettenslve groups in baseline and posttestplasmalevelsof~endorphh~wasalso signifkant (p = 0.02) and indicated an itieractlon betwen endogenous opidds and blood pressure. Other recent studfes of hypertension in relatlon to hypalgesia were also revkwed. An increased pain threshold was found in hypertensive versus nonwWwhf e rats. In cats, electrical stimulation of vagal afkrent nerves (cardiopulmonary baroreceptors) suppresses nodcepthre responses, and both pharmacologic elevation of blood pressure and vascular volume expansion produce anthwciperception. Together wtth preliminary Rndkgs in human studies, these results indkate an Itieractlon between pain-controllng and cardiovascular regulatory functions that is probably medlated by the bawweceptor system. (Am J Cardid 1552;70:3FbF)
From the University of North Carolina School of Medicine, Chapel Hill, North Carolina. Supported in part by Cooperative Agreement CR817643 between the University of North Carolina and the Environmental Protection Agency and in part by grants from the National Heart, Lung, and Blood Institute (HL-38168 and HL47477), the National Institutes of Health (RR00046), and from the National Institute of Dental Research (DE-07509 and DE-08013). Address for reprints: David S. Sheps, MD, Division of Cardiology/CB #7075, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27.599-7075.
Ah
number of experimental findings in animals demonstrate an association between ypertension and diminished sensitivity to noxious stimuli. Several investigators have reported an increased thermal pain threshold in hypertensive versus normotensive rats, as measured by the hot plate technique.1-3 Interestingly, this hypalgesia is reversed by the opioid antagonist naloxone,29 which implies that the relation between blood pressure and pain perception is at least partly modulated by endogenous opioids. Elevated mechanical pain thresholds have also been seen in spontaneously hypertensive rats.4 Studies in humans, although less extensive than in animals, also appear to link hypalgesia and elevated blood pressure. For example, Zamir and Shubers and Ghione et al6 demonstrated higher pain thresholds’ in hypertensive subjects than in normotensive controls in response to electrical stimulation of tooth pulp.
METHODS Although the assessment of pain perception with electrical and mechanical stimuli has provided useful information, it has not been clarified whether hypertension diminishes pain perception evoked by procedures that selectively stimulate nociceptive afferents. An alternative approach is to apply noxious thermal stimuli that selectively activate peripheral nociceptors. Sensitivity to thermal pain can be measured with a computer-controlled, hand-held thermal probe that a technician places on the volar forearm of a research subject. In our laboratory, investigators have delivered thermal stimuli ranging from 43” to 50°C in 0.5”C steps of 5 seconds each. Subjects were instructed to report when they first perceived the stimulus as painful (threshold) and again when they perceived the stimulus as intolerable (tolerance); at the latter point, the device was removed. Three ascending series of thermal stimuli were delivered to 3 separate loci on the volar forearm, and the average temperature A SYMPOSIUM: MECHANISMS FOR MYOCARDIAL PROTECTION
3F
91
TABLE I Properties
Carotid sinus
IX
of Mechanoreceptors
t Arterial pressure
Associated
sensitive and specific immunoreactive for p endorphin concentrations.
with
1 Sympathetic tone t Parasympathetic tone A EEG synchronization J “Sham rage” behavior i Somatomotor (? analgesia)
reflexes
Aortic arch
X
t Arterial pressure
J Sympathetic tone T Parasympathetic tone
Cardiopulmonary region
X
T Vascular volume t Central venous pressure
J Sympathetic tone T Parasympathetic tone A EEG synchronization J Somatomotor reflexes (? analgesia)
Opiates Nicotine Veratrum alkaloids Serotonin Capsaicin
technique
RESULTS In all subjects, the average mean arterial pressure during testing was significantly related (by regression analysis) to both the thermal pain threshold (r = 0.44; p = 0.05) and tolerance (r = 0.635; p = 0.003) (Fi gure 1). The baseline and posttest plasma levels of p endorphin in the normotensive group were significantly different from those of the hypertensive group (p = 0.02). However, a direct relation between pain perception and circulating endorphin levels was not observed, possibly because of the small size of our sample.
DISCUSSION These findings not only provide further evidence of a relation between hypertension and diminished pain perception, but also support the existence of a specific interaction between the values associated with threshold and tolerance endogenous opioid system and pain-blood preswere determined. We used this technique to test thermal pain sure regulatory systems. The nature of this interaction has not been well explored, but it may be perception in 20 nonmedicated men (mean age mediated by the baroreceptor system of cardiovas34 & 13 years) of whom 10 were hypertensive cular regulation.1-3,8 (blood pressure 2 140/90) and 10 normotensive.7 The baroreceptor reflex arcs are activated by Blood pressure was continuously monitored by an stimulation of mechanoreceptors (Table I): presautomated cuff during testing. Blood samples were sure receptors, located in the carotid sinus and drawn at baseline after a rest period and immedi- aortic arch, whose afferents travel via cranial nerves ately after testing, and were assayed by a highly IX and X; and volume receptors, located in the cardiopulmonary region, whose afferents travel via cranial nerve X (the vagus). The pressure recep52tors are sensitive to increased arterial pressure, whereas the volume receptors are sensitive to increases in vascular volume. The baroreceptors respond to these stimuli by decreasing sympathetic tone. Also, the activation of these visceral afferents alters central nervous system excitability, promoting electroencephalographic synchronization, b sleeplike behavior, a suppression of “sham rage,” 3 46-. and behavioral responses consistent with analgeEEG= electroencephalographic; t = increase; 1 = decrease;A = change. Adapted from Pm Finn Dent SOC.‘~
.-c
0.
a” 44-
0
sia
422
100 110 120 70 80 90 Average mean arterial pressure (mm W
average mean art&al prerFlwRE l. Relationsum (mm Hg) daring thmnal paln perception testing and tolerance to thermal paln (“C) In 2C nomndcateul men
(c = 0.83b; p = 0.003). 4F
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
8-11
Electric stimulation of vagal afferent nerves in cats has been shown to suppress nociceptive reflexes-for instance, inhibiting the normal response of dorsal horn neurons to painful stimuli in their Similarly, pharmacologic elevareceptive fields. 9~12 tion of blood pressure8y11(for example, by phenylephrine) and cardiovascular volume expansion13induce attenuation of the tail-flick reflex (an index of algesia) in animals. The enhanced cardiopulmonary baroreceptor activity associated with hypertension may mediate NOVEMBER
16. 1992
the hypalgesia found in hypertensive subjects.14J5 tivity, and a number of measures of pain percepIn support of this hypothesis, the hypalgesia found tion fluctuate in response to opioid production. in hypertensive rats can be attenuated by interrup- Further, the results of our study furnish prelimition of the right cervical vagus nerve and, con- nary evidence that hypertensive subjects exhibit versely, is enhanced by increasing vascular volume enhanced levels of circulating endorphins and diminished sensitivity to noxious thermal stimuli. and central venous pressure.13 Although the role of endogenous opioids in the Hence, endogenous opioids may be one of many integration of the pain and cardiovascular regula- factors that contribute to the relation between tory systems is not yet clear, their participation is blood pressure and sensitivity to pain. suggested by a number of facts. First, various sites within the central nervous system that are involved in arterial blood pressure regulation also contain REFERENCES L Zamir N, Simantov R, SegaI M. Pain sensitivity and opioid activity in opioid receptors and are known to mediate analge- genetic&y and experimentaIiyhypertensiverats. Emin Res 1980,184:29%310. sia, which in some instances is reversible by nalox- 2. SaavedraJM. NaIoxone reversible decreasein pain sensitivity in young and spontaneouslyhypertensiverats. Bruin Res 1981;20924%249. one. Next, injection of l3 endorphin into the nu- 3.adult Maimer W, Tow KB, Brody MJ, Gebhart GF, Long JP. Factors intluenccleus tractus solitarii, which receives afferent fibers ing the altered pain perception in the spontaneouslyhypertensiverat. Bruin Res from the vagus, decreases arterial blood pressure 1982;237:137-145. Chipkin RE, Latranyi MB. Subplantar yeast injection induces a nonand heart rate in rats, an effect that can be blocked 4.naloxone reversible antinociception in spontaneouslyhypertensive rats. Emin by prior administration of naloxone.16 Further, Res 1984;303:16. recent evidence suggests that endogenous opioids 5. Zamir N, Shuber E. Altered pain perception in hypertensive humans.Brain Ra 1980;201:471-474. may act peripherally as well as in the central 8. Ghione S, Rosa C, Mezzasahna L, Panattoni E. Arterial hypertension is 1988,12:491-497. nervous system to blunt the activation of pain associatedwith hypalgesiain humans.Hyetim 7. Gray TF, ShepsDS, Ballenger MN, Miller PF, Humphrey CB, Usedom JE, reflexes in animals, in part by stimulating cardio- Koch GG, Maimer W. Hypertension is associatedwith diminished pain pcrceppulmonary vagal afferents.17J8 tion and elevated p endorphm levels. (Abstr.) Circulation 1991;84:11-481. The antinociceptive effects that accompany 8. Randich A, Maimer W. Interactions between cardiovascularand pain regusystems.Ntw-osci Biobehav Rev 1984;8:34>367. blood pressure elevation may eventually contribute latory 9. Maimer W. Interactionsbehveencardiovawdar and pain modulatory systems: to the development of essential hypertension.3j8 physiological and pathophysiological implications. J Cardiovasc Efectmphysiol 1991;2(suppl):s3-Sl2. The consequent relief from aversive sensations l0. Maimer W. Autonomic and somatosensoryinteractions: physiological and that are evoked by environmental stressors may pathophysiologicalimplications.m Finn Dtzf Sot 1989;85:39.%407. invoke conditioning mechanisms that gradually iL Randich A, Maimer W. The role of sinoaortic and cardiopulmonary baroreceptor reflex arcs in nociception and stress-inducedanalgesia.Am N Y modify the short-term coping pattern of acute Acad Sci 1986;467:385401. blood pressure reactivity into chronic disease.Such IZ.Thies R, Foreman RD. Descending inhibition of spinal neurons in the cardiopulmonary region by electrical stimulation of vagaI afferent nerves.Bmin mechanisms may utilize endogenous opioids as Res 1981;207:17~183. part of a reward system. l3. Maimer W, Randich A. Role of the right vagaI nerve trunk in antinocicep CONCWSION
An association between hypertension and hypalgesia has been well described in animals and tentatively demonstrated in human subjects, although its nature remains largely unknown. Evidence from electrophysiologic, pharmacologic, and behavioral research suggests that this relation reflects an interface between cardiovascular and pain-regulating functions of the baroreceptor system. Endogenous opioids influence baroreflex ac-
tion. Emin Ra 1984;298:374-377. l4. Mark AL, Kerber RE. Augmentation of cardiopulmonary baroreflex control of forearm vascular resistance in borderline hypertension. mrrnsion 19Q439-46. IS. Ricksten SE, Noresson E, Thor&n P. Inhibition of renal sympatheticnewe trafTic from cardiac receptors in normotensive and spontaneouslyhypertensive rats.Acta Physiol Stand 1979;106:17-22. 18. DeJong W, Petty m Sitsen JMA. Role of opioid peptides in brain mechanismsregulating blood pressure.Chest 1983;83(supplto no. 2):306-308. 17. Randich A, Maimer W. [D-AIa2]-methionine enkephalmamidereflexively inducesantinociception by activating vagal afferents. Phamuzcol Btixhm Behav 1984;21:441-448. 18. Randich A, Thurston CL, Ludwig PS, Tiierman MR, Gebhart GF. Antintiception and cardiovascularresponsesproducedby intravenousmorphine: the role of vagal afferents. Bmin Res 1991;543:25&270.
A SYMPOSIUM:
MECHANISMS
FOR MYOCARDIAL
PROTECTION
SF
Edith E. Bragdon, MA, T. Flint Gray III, MD, Martha Ballenger, James E. Usedom, MD, and William Maixner, DDS, phD
MD, MSPH,
To test the hypotfiesis that hypertension diminishes pain mn, a study was made that evaluated the rektion between arterial blood pressure and thermal pain peroeption In human subjects. The average mean arterial pressure in all 20 men studied (l0 hypertensive, 10 normotensive) proved to be signtfkantly related to both thermal pain threshold (p = 0.05) and tolerance (p = 0.003). The difference between normotensive and hypettenslve groups in baseline and posttestplasmalevelsof~endorphh~wasalso signifkant (p = 0.02) and indicated an itieractlon betwen endogenous opidds and blood pressure. Other recent studfes of hypertension in relatlon to hypalgesia were also revkwed. An increased pain threshold was found in hypertensive versus nonwWwhf e rats. In cats, electrical stimulation of vagal afkrent nerves (cardiopulmonary baroreceptors) suppresses nodcepthre responses, and both pharmacologic elevation of blood pressure and vascular volume expansion produce anthwciperception. Together wtth preliminary Rndkgs in human studies, these results indkate an Itieractlon between pain-controllng and cardiovascular regulatory functions that is probably medlated by the bawweceptor system. (Am J Cardid 1552;70:3FbF)
From the University of North Carolina School of Medicine, Chapel Hill, North Carolina. Supported in part by Cooperative Agreement CR817643 between the University of North Carolina and the Environmental Protection Agency and in part by grants from the National Heart, Lung, and Blood Institute (HL-38168 and HL47477), the National Institutes of Health (RR00046), and from the National Institute of Dental Research (DE-07509 and DE-08013). Address for reprints: David S. Sheps, MD, Division of Cardiology/CB #7075, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27.599-7075.
Ah
number of experimental findings in animals demonstrate an association between ypertension and diminished sensitivity to noxious stimuli. Several investigators have reported an increased thermal pain threshold in hypertensive versus normotensive rats, as measured by the hot plate technique.1-3 Interestingly, this hypalgesia is reversed by the opioid antagonist naloxone,29 which implies that the relation between blood pressure and pain perception is at least partly modulated by endogenous opioids. Elevated mechanical pain thresholds have also been seen in spontaneously hypertensive rats.4 Studies in humans, although less extensive than in animals, also appear to link hypalgesia and elevated blood pressure. For example, Zamir and Shubers and Ghione et al6 demonstrated higher pain thresholds’ in hypertensive subjects than in normotensive controls in response to electrical stimulation of tooth pulp.
METHODS Although the assessment of pain perception with electrical and mechanical stimuli has provided useful information, it has not been clarified whether hypertension diminishes pain perception evoked by procedures that selectively stimulate nociceptive afferents. An alternative approach is to apply noxious thermal stimuli that selectively activate peripheral nociceptors. Sensitivity to thermal pain can be measured with a computer-controlled, hand-held thermal probe that a technician places on the volar forearm of a research subject. In our laboratory, investigators have delivered thermal stimuli ranging from 43” to 50°C in 0.5”C steps of 5 seconds each. Subjects were instructed to report when they first perceived the stimulus as painful (threshold) and again when they perceived the stimulus as intolerable (tolerance); at the latter point, the device was removed. Three ascending series of thermal stimuli were delivered to 3 separate loci on the volar forearm, and the average temperature A SYMPOSIUM: MECHANISMS FOR MYOCARDIAL PROTECTION
3F
91
TABLE I Properties
Carotid sinus
IX
of Mechanoreceptors
t Arterial pressure
Associated
sensitive and specific immunoreactive for p endorphin concentrations.
with
1 Sympathetic tone t Parasympathetic tone A EEG synchronization J “Sham rage” behavior i Somatomotor (? analgesia)
reflexes
Aortic arch
X
t Arterial pressure
J Sympathetic tone T Parasympathetic tone
Cardiopulmonary region
X
T Vascular volume t Central venous pressure
J Sympathetic tone T Parasympathetic tone A EEG synchronization J Somatomotor reflexes (? analgesia)
Opiates Nicotine Veratrum alkaloids Serotonin Capsaicin
technique
RESULTS In all subjects, the average mean arterial pressure during testing was significantly related (by regression analysis) to both the thermal pain threshold (r = 0.44; p = 0.05) and tolerance (r = 0.635; p = 0.003) (Fi gure 1). The baseline and posttest plasma levels of p endorphin in the normotensive group were significantly different from those of the hypertensive group (p = 0.02). However, a direct relation between pain perception and circulating endorphin levels was not observed, possibly because of the small size of our sample.
DISCUSSION These findings not only provide further evidence of a relation between hypertension and diminished pain perception, but also support the existence of a specific interaction between the values associated with threshold and tolerance endogenous opioid system and pain-blood preswere determined. We used this technique to test thermal pain sure regulatory systems. The nature of this interaction has not been well explored, but it may be perception in 20 nonmedicated men (mean age mediated by the baroreceptor system of cardiovas34 & 13 years) of whom 10 were hypertensive cular regulation.1-3,8 (blood pressure 2 140/90) and 10 normotensive.7 The baroreceptor reflex arcs are activated by Blood pressure was continuously monitored by an stimulation of mechanoreceptors (Table I): presautomated cuff during testing. Blood samples were sure receptors, located in the carotid sinus and drawn at baseline after a rest period and immedi- aortic arch, whose afferents travel via cranial nerves ately after testing, and were assayed by a highly IX and X; and volume receptors, located in the cardiopulmonary region, whose afferents travel via cranial nerve X (the vagus). The pressure recep52tors are sensitive to increased arterial pressure, whereas the volume receptors are sensitive to increases in vascular volume. The baroreceptors respond to these stimuli by decreasing sympathetic tone. Also, the activation of these visceral afferents alters central nervous system excitability, promoting electroencephalographic synchronization, b sleeplike behavior, a suppression of “sham rage,” 3 46-. and behavioral responses consistent with analgeEEG= electroencephalographic; t = increase; 1 = decrease;A = change. Adapted from Pm Finn Dent SOC.‘~
.-c
0.
a” 44-
0
sia
422
100 110 120 70 80 90 Average mean arterial pressure (mm W
average mean art&al prerFlwRE l. Relationsum (mm Hg) daring thmnal paln perception testing and tolerance to thermal paln (“C) In 2C nomndcateul men
(c = 0.83b; p = 0.003). 4F
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
8-11
Electric stimulation of vagal afferent nerves in cats has been shown to suppress nociceptive reflexes-for instance, inhibiting the normal response of dorsal horn neurons to painful stimuli in their Similarly, pharmacologic elevareceptive fields. 9~12 tion of blood pressure8y11(for example, by phenylephrine) and cardiovascular volume expansion13induce attenuation of the tail-flick reflex (an index of algesia) in animals. The enhanced cardiopulmonary baroreceptor activity associated with hypertension may mediate NOVEMBER
16. 1992
the hypalgesia found in hypertensive subjects.14J5 tivity, and a number of measures of pain percepIn support of this hypothesis, the hypalgesia found tion fluctuate in response to opioid production. in hypertensive rats can be attenuated by interrup- Further, the results of our study furnish prelimition of the right cervical vagus nerve and, con- nary evidence that hypertensive subjects exhibit versely, is enhanced by increasing vascular volume enhanced levels of circulating endorphins and diminished sensitivity to noxious thermal stimuli. and central venous pressure.13 Although the role of endogenous opioids in the Hence, endogenous opioids may be one of many integration of the pain and cardiovascular regula- factors that contribute to the relation between tory systems is not yet clear, their participation is blood pressure and sensitivity to pain. suggested by a number of facts. First, various sites within the central nervous system that are involved in arterial blood pressure regulation also contain REFERENCES L Zamir N, Simantov R, SegaI M. Pain sensitivity and opioid activity in opioid receptors and are known to mediate analge- genetic&y and experimentaIiyhypertensiverats. Emin Res 1980,184:29%310. sia, which in some instances is reversible by nalox- 2. SaavedraJM. NaIoxone reversible decreasein pain sensitivity in young and spontaneouslyhypertensiverats. Bruin Res 1981;20924%249. one. Next, injection of l3 endorphin into the nu- 3.adult Maimer W, Tow KB, Brody MJ, Gebhart GF, Long JP. Factors intluenccleus tractus solitarii, which receives afferent fibers ing the altered pain perception in the spontaneouslyhypertensiverat. Bruin Res from the vagus, decreases arterial blood pressure 1982;237:137-145. Chipkin RE, Latranyi MB. Subplantar yeast injection induces a nonand heart rate in rats, an effect that can be blocked 4.naloxone reversible antinociception in spontaneouslyhypertensive rats. Emin by prior administration of naloxone.16 Further, Res 1984;303:16. recent evidence suggests that endogenous opioids 5. Zamir N, Shuber E. Altered pain perception in hypertensive humans.Brain Ra 1980;201:471-474. may act peripherally as well as in the central 8. Ghione S, Rosa C, Mezzasahna L, Panattoni E. Arterial hypertension is 1988,12:491-497. nervous system to blunt the activation of pain associatedwith hypalgesiain humans.Hyetim 7. Gray TF, ShepsDS, Ballenger MN, Miller PF, Humphrey CB, Usedom JE, reflexes in animals, in part by stimulating cardio- Koch GG, Maimer W. Hypertension is associatedwith diminished pain pcrceppulmonary vagal afferents.17J8 tion and elevated p endorphm levels. (Abstr.) Circulation 1991;84:11-481. The antinociceptive effects that accompany 8. Randich A, Maimer W. Interactions between cardiovascularand pain regusystems.Ntw-osci Biobehav Rev 1984;8:34>367. blood pressure elevation may eventually contribute latory 9. Maimer W. Interactionsbehveencardiovawdar and pain modulatory systems: to the development of essential hypertension.3j8 physiological and pathophysiological implications. J Cardiovasc Efectmphysiol 1991;2(suppl):s3-Sl2. The consequent relief from aversive sensations l0. Maimer W. Autonomic and somatosensoryinteractions: physiological and that are evoked by environmental stressors may pathophysiologicalimplications.m Finn Dtzf Sot 1989;85:39.%407. invoke conditioning mechanisms that gradually iL Randich A, Maimer W. The role of sinoaortic and cardiopulmonary baroreceptor reflex arcs in nociception and stress-inducedanalgesia.Am N Y modify the short-term coping pattern of acute Acad Sci 1986;467:385401. blood pressure reactivity into chronic disease.Such IZ.Thies R, Foreman RD. Descending inhibition of spinal neurons in the cardiopulmonary region by electrical stimulation of vagaI afferent nerves.Bmin mechanisms may utilize endogenous opioids as Res 1981;207:17~183. part of a reward system. l3. Maimer W, Randich A. Role of the right vagaI nerve trunk in antinocicep CONCWSION
An association between hypertension and hypalgesia has been well described in animals and tentatively demonstrated in human subjects, although its nature remains largely unknown. Evidence from electrophysiologic, pharmacologic, and behavioral research suggests that this relation reflects an interface between cardiovascular and pain-regulating functions of the baroreceptor system. Endogenous opioids influence baroreflex ac-
tion. Emin Ra 1984;298:374-377. l4. Mark AL, Kerber RE. Augmentation of cardiopulmonary baroreflex control of forearm vascular resistance in borderline hypertension. mrrnsion 19Q439-46. IS. Ricksten SE, Noresson E, Thor&n P. Inhibition of renal sympatheticnewe trafTic from cardiac receptors in normotensive and spontaneouslyhypertensive rats.Acta Physiol Stand 1979;106:17-22. 18. DeJong W, Petty m Sitsen JMA. Role of opioid peptides in brain mechanismsregulating blood pressure.Chest 1983;83(supplto no. 2):306-308. 17. Randich A, Maimer W. [D-AIa2]-methionine enkephalmamidereflexively inducesantinociception by activating vagal afferents. Phamuzcol Btixhm Behav 1984;21:441-448. 18. Randich A, Thurston CL, Ludwig PS, Tiierman MR, Gebhart GF. Antintiception and cardiovascularresponsesproducedby intravenousmorphine: the role of vagal afferents. Bmin Res 1991;543:25&270.
A SYMPOSIUM:
MECHANISMS
FOR MYOCARDIAL
PROTECTION
SF
