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Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity
Pain 82 (1999) 311±317
Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity Luigina Guasti*, Giovanni Gaudio, Danilo Zanotta, Paola Grimoldi, Maria Rosaria Petrozzino, Fabio Tanzi, Andrea Bertolini, Anna Maria Grandi, Achille Venco Chair of Internal Medicine, Department of Clinical and Biological Sciences, Faculty of Medicine, University of Insubria, Viale Borri 57, Varese, Italy Received 20 January 1999; accepted 1 March 1999
Abstract Introduction: The aim of this study was to determine whether the degree of blood pressure elevation and/or a genetic predisposition to hypertension have a major role in determining a reduced pain perception in hypertensives. The reasons underlying the relationship between blood pressure elevation and pain perception mechanisms are not completely understood. Methods: One hundred and four untreated hypertensive patients (65 subjects with and 39 without a positive parental history of hypertension) together with a control group of 42 subjects (20 normotensive offspring of normotensive parents, and 22 normotensive offspring of hypertensive parents) were submitted to standard blood pressure evaluation, 24-h blood pressure monitoring and dental pain perception evaluation. Results: Both pain threshold and tolerance were found to be higher in hypertensive than normotensive subjects (P , 0:0001 and P , 0:015, respectively). Positive signi®cant correlations were found between both 24-h systolic and diastolic pressure and the pain perception variables. When a 2 £ 2 ANOVA test was performed, factoring for the effects of both blood pressure status and family history of hypertension on pain sensitivity, a signi®cant effect was revealed only for blood pressure status. Moreover, after controlling for blood pressure by a covariate analysis, no signi®cant difference was found between the subjects with or without hypertensive parents as regards pain perception variables. Conclusions: Pain sensitivity is correlated to blood pressure levels whereas the parental history of hypertension per se does not affect the pain perception pattern. Thus, the degree of blood pressure elevation, more than a genetic predisposition to hypertension may in¯uence the mechanisms leading to hypalgesia in hypertension. q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Blood pressure; Hypertension, essential; Parental history of hypertension; Pain threshold; Analgesia
1. Introduction Since the late 1970s there has been an increase in experimental evidence of hypertension-related hypalgesia (Zamir and Segal, 1979; Dworkin et al., 1979; Ghione, 1996). Most of the animal studies have reported that various forms of hypertension were associated with a behavioural evidence of hypalgesia (Zamir and Segal, 1979; Saavedra, 1981; Maixner et al., 1982; Wendel and Bennet, 1981; Sisten and de Jong, 1983). A study on spinal nociceptive transmission in SHR and WKY rats con®rmed an inhibition of the sensory function in hypertension (Randich and Robertson, 1994). In humans, a reduced pain perception has been described in subjects with increased blood pressure values, in essential hypertensive patients and in hypertensives with coronary artery disease (Zamir and Shuber, 1980; Ghione et al., 1985, 1988; Vignocchi et al., 1989; Sheps et al., 1992; * Corresponding author. Tel.: 139-0332-278-273; fax. 139-0332-265586.
Rosa et al., 1994; Guasti et al., 1995a,b; Krittayaphong et al., 1996; Falcone et al., 1997; Shef®eld et al., 1997). Various techniques have been used to test experimental pain perception in hypertensive patients (Zamir and Shuber, 1980; Ghione et al., 1985, 1988; Vignocchi et al., 1989; Sheps et al., 1992; Rosa et al., 1994; Guasti et al., 1995a,b). The tooth pulp stimulation allows the pain threshold to be quanti®ed as the intensity of test current linearly increases. Moreover, possible interferences from pressure, touch and thermal sensitivity are avoided due to the fact that dental pulp contains ®bers which are presumed to transmit painful sensation only (Anderson et al., 1973; Azerad and Woda, 1977). Dental pain perception has been more closely correlated with the 24-h ambulatory blood pressure than with blood pressure measured before pain perception evaluation, indicating a role for sustained blood pressure in the modulation of pain sensitivity (Guasti et al., 1995a). However, some peculiar aspects of the relationship between hypalgesia and hypertension are still unknown. In particular, it is not clear whether hypalgesia is secondary to blood
0304-3959/99/$20.00 q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. PII: S 0304-395 9(99)00059-7
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pressure elevation or both depend on common factors, possibly genetically linked. Only a few authors have looked for a possible association between the parental history of hypertension and the pain perception pattern, with con¯icting results (Ghione et al., 1988; France et al., 1991, 1994; Stewart and France, 1996; Page and France, 1997). The aim of this study was to investigate whether the reduced sensitivity to pain associated with hypertension depends on the degree of blood pressure elevation and/or is related to a genetically transmitted pattern linked to the predisposition to hypertension. 2. Methods One hundred and four consecutive hypertensive patients with documented positive (n 65) or negative (n 39) family history of hypertension were studied together with a control group of 42 normotensive subjects (22 offsprings of hypertensive parents; 20 offsprings of normotensive parents). As for inclusion criteria, all the subjects had the following characteristics: male sex, age between 30 and 50 years, documented positive or negative parental history of hypertension, no assumption of any therapy and/or pharmacological wash-out for at least three weeks before the study, a dental formula suitable for the pulpar test (no caries, abrasions, ®llings, marked periodontal diseases), no concomitant diseases (diabetes, obesity, cardiac or pulmonary diseases, neurologic or psychiatric disorders), no secondary forms of hypertension as indicated by a routine examination, no competitive sport activities, and informed consent to the study. All the subjects were submitted to dental pain perception evaluation and 24-h ambulatory blood pressure monitoring. The hypertensive patients were recruited among our out-patient population whereas the normotensives were evaluated during a general clinical check-up among Italian Post Of®ce Employees. The parental history of hypertension was assessed as follows: negative family history was established when both parents were living and showed blood pressure , 140=90 mm Hg or when medical records showed repeatedly normal blood pressure values during the last three years of life; positive family history was assessed when at least one parent was living and had blood pressure $ 140=90 mm Hg and/or at least one parent had a history of chronic antihypertensive treatment. The hypertensive and normotensive subjects did not differ as regards mean age (41 ^ 7 and 42 ^ 7 years, respectively) and body mass index (24:7 ^ 1:9 and 25 ^ 2 Kg/m 2, respectively). The study was approved by the Ethical Committee of our Department. 2.1. Pulpar test Dental pain sensitivity was investigated in all the subjects between 9.00 and 10.00 am, after a 30-min rest in a supine and comfortable position. As previously reported (Guasti et al., 1995a,b), the experimental pain was induced by means
of a pulpar tester (MEDI-tester, MEDIC-AL) which delivers automatic intermittent bursts of test current of linearly increasing intensity (from 0 to 0.03 mA; voltage: 6500 mV; frequency: 5 Hz). As the intensity of test current increases, a number from 0 to 80 (relative Units -rU-) appears on a display not visible to the subjects under examination. The stimulator was applied on the enamel surface of the tooth through a metal cilinder (inner diameter: 0.9 mm) with an electrode paste to improve contact. The operator's hand was placed on the lips of the subject to close the circuit. Three teeth were evaluated in each subject (two upper incisors and one inferior incisor), and the data reported refer to the mean value of the three. Dental pain threshold was de®ned as the minimal intensity of test current that elicited a pulp sensation. The subjects were previously instructed to raise the right hand as the pain threshold occurred. The stimulation was then interrupted and re-applied immediately afterwards to determine pain tolerance (intensity of test current at the time when the subject asked for the test to be stopped). All the subjects were asked not to smoke nor to eat chocolates or drink teas, coffees, cola-containing substances or alcoholic beverages during the previous 12 h. All the subjects completed the test on three teeth although they knew that dental pain evaluation could have been interrupted any time. 2.2. Blood pressure measurements 2.2.1. Pre-pain testing blood pressure During the rest period preceding the pulpar test, blood pressure was automatically measured every 3 min by a Hewlett Packard 78352A recorder. The values of blood pressure and heart rate measured immediately before the pulpar test are referred to as `pre-pain testing blood pressure and heart rate'. Before pain testing, if the value obtained differed more than 5 mm Hg from the previous measure, another measure was taken until two were close. 2.2.2. Ambulatory blood pressure All the subjects performed a non-invasive blood pressure monitoring after pain perception evaluation. As described previously (Guasti et al., 1995a), a TAKEDA TM2421 (A and D Co) set to take one measure every 15 min for a 24-h period was used. This instrument has a combined auscultatory and oscillometric method to minimize errors. The test quality was good (.80% valid measurements) in 137 subjects; 9 subjects repeated the test successfully the day after. A computerized program did the reading and editing of the data (Guasti et al., 1995a). The 24-h, day-time (7am to 10pm), night-time (10pm to 7am) values of systolic and diastolic blood pressure were taken into consideration in subsequent analysis. All the hypertensive patients showed a day-time blood pressure $ 140 and/or 90 mm Hg whereas normotensives had day-time blood pressure , 140=90 mmHg.
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analysis of covariance was performed (2 groups: subjects with a positive family history vs. subjects with a negative history) using the 24 h blood pressure as covariate and both pain threshold and tolerance as dependent variable. Relations among variables were investigated by linear regression analysis. The statistical analysis was performed using the GB Stat v.6.5 program. A P value ,0.05 was considered to be signi®cant. 3. Results 3.1. Blood pressure measurements Fig. 1. Bar graph showing dental pain threshold and tolerance (expressed in natural logarithm of relative Units, ln rU). A signi®cant difference was found between the two groups of normotensives (solid bars) and hypertensives (open bars) regarding both pain threshold (P , 0:0001) and tolerance (P , 0:015).
2.3. Statistical analysis Data are presented as mean values ^ standard deviations. Since the variances of pain perception variables were not homogeneous, pain threshold and tolerance values were transformed to natural logarithm (ln). After the transformation, no other signi®cant differences among variables were detected by a Cochran's test. The variables were compared by the Mann Whithney U test (pain sensitivity variables) and Student t-test (haemodynamic variables).A one-way ANOVA and the post-hoc Student-Newman- Keuls test were used to compare the pain sensitivity values among the four groups of normotensives with and without a positive family history of hypertension and hypertensives with and without hypertensive parents. Moreover, the results of the pain perception evaluation were analyzed by a 2 £ 2 ANOVA test factoring for the effects of both blood pressure status (normotensives vs. hypertensives) and family history of hypertension (positive vs. negative). Furthermore, a
In normotensives, the mean 24-h blood pressure (122 ^ 8=77 ^ 8 mm Hg), day-time (127 ^ 8=80 ^ 8 mm Hg), and night-time blood pressure (113 ^ 11=70 ^ 9 mm Hg) were signi®cantly lower than those in the hypertensive group (24-h arterial pressure: 145 ^ 13=92 ^ 9 mm Hg; day-time pressure: 151 ^ 13=96 ^ 9 mm Hg, and nighttime pressure: 130 ^ 16=83 ^ 12 mm Hg) (P , 0:0001). The 24-h heart rate was 73 ^ 7 beats/min in normotensives and 76 ^ 10 in hypertensive patients (P , 0:05). Pre-pain testing blood pressure, too, was higher in hypertensive patients (133 ^ 12=82 ^ 11 vs. 150 ^ 18=94 ^ 15 mm Hg, P , 0:0001), whereas pre-pain testing heart rate was similar in the two groups (70 ^ 13 and 71 ^ 11 beats/min, ns, in normotensives and hypertensives, respectively). 3.2. Dental pain perception Pain sensitivity was different in normotensive and hypertensive subjects, both dental pain threshold and tolerance being higher in the hypertensive group (pain threshold: 3:039 ^ 0:267 ln rU vs. 3:254 ^ 0:273 ln rU in normotensive and hypertensive subjects, respectively: P , 0:0001; pain tolerance: 3:521 ^ 0:383 ln rU vs. 3:708 ^ 0:384 ln rU: P , 0:015) (Fig. 1). A signi®cant association was found between pain threshold and pain tolerance (r 0:70, P , 0:0001) (Fig. 2). Pain perception variables were associated with 24-h and baseline blood pressure values. Pain threshold was correlated to 24-h systolic (r 0:41, P , 0:0001), 24-h diastolic (r 0:31; P , 0:0001), pre-pain testing systolic (r 0:26; P , 0:0015) and diastolic pressure (r 0:25; P , 0:002). Pain tolerance was signi®cantly associated with 24-h systolic blood pressure (r 0:24; P , 0:005), 24-h diastolic pressure (r 0:17; P , 0:05), and pre-pain testing systolic blood pressure (r 0:16; P , 0:05). 3.3. Family history of hypertension and pain sensitivity
Fig. 2. Scatterplot showing the positive signi®cant correlation (146 subjects) between dental pain threshold and tolerance expressed in natural logarithm of relative Units (ln rU) (r 0:70, P , 0:0001).
The normotensive and hypertensive subjects were grouped according to the family history of hypertension and blood pressure and pain sensitivity variables of the following four groups were compared: (1) normotensives with a negative family history of hypertension, (2) normo-
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Table 1 Haemodynamic variables in the groups of normotensive and hypertensive subjects with and without a positive parental history of hypertension a NPH24-h SPB (mm Hg) 24-h DBP (mm Hg) 24-h HR (beats/min) Baseline SBP (mm Hg) Baseline DBP (mm Hg) Baseline HR (beats/min)
NPH 1
HPH-
HPH 1
122 ^ 9 123 ^ 6 143 ^ 13 146 ^ 13 75 ^ 8 78 ^ 8 91 ^ 9 93 ^ 9 73 ^ 5 72 ^ 8 78 ^ 10 74 ^ 10 132 ^ 8 135 ^ 15 148 ^ 16 151 ^ 19 82 ^ 8 82 ^ 13 95 ^ 13 94 ^ 15 69 ^ 12 71 ^ 13 72 ^ 11 70 ^ 11
a NPH- indicates normotensives with a negative parental history of hypertension, NPH1 indicates normotensives with a positive parental history, HPH- indicates hypertensives with a negative history, HPH1 indicates hypertensives with a positive family history of hypertension; SBP indicates systolic blood pressure, DBP diastolic blood pressure and HR indicates heart rate.
tensive offspring of hypertensive parents, (3) hypertensive patients with normotensive parents and (4) hypertensives with a positive parental history of hypertension (Table 1). The ANOVA test indicated a signi®cant difference among the groups in 24-h and pre-pain testing systolic and diastolic pressure, and in pain threshold (P , 0:001). The StudentNewman-Keuls test showed that each group of normotensive subjects differed from each group of hypertensive patients as regards blood pressures (P , 0:01) and pain threshold (P , 0:05). However, similar values were found between the two groups of normotensives and between the two groups of hypertensive patients, regardless of their family history. Pain tolerance did not signi®cantly differ among the groups (P 0:067) (Fig. 3). The two factor ANOVA test revealed signi®cant effects on pain sensitivity for blood pressure status (F 13:267, P 0:0003 and F 5:053, P 0:0253 for pain threshold
and tolerance, respectively) while family history had no signi®cant effects (F 1:450, P 0:2294 and F 0:585, P 0:4448 for pain threshold and tolerance, respectively). Moreover, ANCOVAs were computed to evaluate the relationship between the genetic status and pain sensitivity, after controlling for blood pressure values. Twenty four hour systolic pressure served as the covariate, thus removing any effect of blood pressure. After controlling for blood pressure, no signi®cant difference was observed in the groups of subjects with and without a positive family history of hypertension (F 0:051, P 0:8201, and F 0:012, P 0:9134, entering pain threshold and tolerance, respectively, as dependent variable). 4. Discussion Hypalgesia has been almost consistently reported in hypertensive patients. In humans, various techniques, such as cutaneous electrical and thermal stimulation, and tooth pulp stimulation have been used to induce experimental pain, with similar results. Increased pain threshold and tolerance have been described in patients with hypertension when compared with normotensive subjects, together with a signi®cant correlation between pain sensitivity and baseline blood pressure (Ghione, 1996). Our group has previously shown that the 24-h blood pressure is more closely correlated with pain threshold and tolerance than blood pressure measured by standard sphygmomanometer (Guasti et al., 1995a). This study performed on a large patient population con®rms the relation between blood pressure and sensitivity to pain, and indicates a relevant role of sustained, tonic blood pressure in activating the mechanisms related to pain perception, being the correlation between 24h systolic blood pressure and pain threshold the closest association found. Some authors have pointed out that the timing between blood pressure elevation and hypalgesia are not always strictly connected (Saavedra, 1981; Wendel and Bennet, 1981; Sisten and de Jong, 1983; Guasti et al., 1995b). One study indicated the persistence of hypalgesia in renal hypertensive rats for a few days after blood pressure was reduced by the removal of the constricted kidney (Zamir and Segal, 1979). Possibly, interactions between blood pressure and pain sensitivity occur through activation of long-term pattern mechanisms. 4.1. Parental history of hypertension and sensitivity to pain
Fig. 3. Bar graph showing dental pain threshold and tolerance (natural logarithm of relative Units, ln rU) in the following four groups of subjects: normotensive subjects with a negative parental history of hypertension (solid bars), normotensive offspring of hypertensive parents (hatched bars), hypertensive patients with a negative parental history of hypertension (open bars), and hypertensives with a positive history. Pain threshold significantly differed among the groups (P , 0:001), while pain tolerance did not (P 0:067 ns).
A role for a genetic linkage between blood pressure and pain sensitivity has been suggested. In favour of this hypothesis a behavioural evidence of hypalgesia has been described in newborn SHR rats when compared with WKY rats, before a relevant blood pressure rise in the hypertensive strain (Sisten and de Jong, 1983). Furthermore, the endogenous opiate system, which has a primary role in pain perception modulation (Basbaum and Fields, 1978; Fields, 1984), has been shown to have different responses
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to stress in normotensives with or without hypertensive parents (Fontana et al., 1994). On the other hand, some authors have found that hypertension was associated with reduced sensitivity to pain both in genetically hypertensive rats and in experimentally induced hypertension (Saavedra, 1981; Maixner et al., 1982; Wendel and Bennet, 1981). Moreover, the change in pain sensitivity was not a function of the method used to induce hypertension and both renal clip and DOCA salt induced hypertension were effective in reducing pain perception (Zamir et al., 1980). At last, in normotensive rats, the ®nding of a lower pain sensitivity in the Dahl hypertension-sensitive versus hypertension-resistant strain has been associated with the slightly higher blood pressure levels observed in the ®rst line (Friedman et al., 1984). In humans, one previous report on experimental pain induced by a dental pulp stimulator did not describe any difference in pain threshold and tolerance in subjects which were subgrouped according to parental history of hypertension (Ghione et al., 1988). On the contrary, a group of investigators has consistently reported the presence of hypalgesia in normotensive offspring of hypertensive parents as compared with the group without a positive history after cold pressor test, forearm ischemia and electrical stimulation over the sural nerve (France et al., 1991; Stewart and France, 1996; Page and France, 1997). In our population study of 104 hypertensive patients and 42 normotensives, similar pain perception patterns were found in subjects with similar blood pressure levels, regardless of their family history of hypertension. However, since there was a trend towards both higher blood pressure values and reduced sensitivity to pain in the subjects with a positive parental history of hypertension, a covariate analysis was performed. After controlling for 24-h systolic blood pressure, no signi®cant difference was found between the two groups of subjects with and without a positive familiar history of hypertension, as regards pain perception variables. Moreover, the 2 £ 2 ANOVA test indicated signi®cant effects on pain sensitivity only for blood pressure status and not for the parental history. The normotensive subjects with hypertensive parents tend to have both resting blood pressure higher than normotensives without a positive family history of hypertension, and an increased haemodynamic reactivity to various forms of stimuli (Watt et al., 1983; Widgren et al., 1992). Since the relationship between blood pressure and pain sensitivity has been extended to the normotensive subjects (Bruehl et al., 1992; McCubbin and Bruehl, 1994), this confounding factor might have in¯uenced the results previously reported in normotensives on the association between a genetic predisposition to hypertension and pain sensitivity. If a genetic link exists between blood pressure and the pain modulating system, the actual expression of this effect is possibly dependent upon the development of elevated blood pressure. Since the mean age of the subjects in the present study is more elevated than the one reported by France (Stewart and France,
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1996), it is also possible that the subjects who had inherited the predisposition to hypertension had already become hypertensive in our population study. Alternatively, the presence of overt hypertension may be a stronger stimulus to hypalgesia and it may be able to suppress other hypothetical in¯uences operating in normotensives. Finally, since no women were tested as for inclusion criteria, it has to be acknowledged that the results here reported may not apply to both genders. In a previous study, France and coworkers found a signi®cant difference in venipuncture pain rating between subjects with and without a parental history of hypertension only in women with 0-1 previous blood donation whereas the other groups of males and experienced females did not show any difference (France et al., 1994). 4.2. Possible mechanisms linking blood pressure and pain perception Although not entirely understood, a close relationship exists between cardiovascular modulation and pain perception pathways. Previous studies have suggested an association between barore¯ex sensitivity and pain perception in normotensive and hypertensive subjects (Dworkin et al., 1979; Maixner et al., 1982; Elbert et al., 1988; Droste et al., 1994). Baroreceptor function manipulation and anatomical interruption of the neural arc integrity may in¯uence pain sensitivity (Maixner and Randich, 1984; Randich and Maixner, 1986; Meller et al., 1990). A group of investigators has focused on the relationship between baroreceptor stimulation and pain sensitivity in normotensive subjects (Dworkin et al., 1994). This comprehensive study using the PRES (phase-related external suction) technique showed that a painful stimuli was rated as less intense when delivered during the maximal baroreceptor stimulation (i.e. when suction was added to systolic pressure). Besides, central mechanisms acting independently of or through sympathetic nervous system activation may link pain perception and blood pressure levels. Within various structures of the central nervous system, the autonomic network was found to share anatomic areas and functional pathways with the nociceptive system (Feuerstein and Siren, 1987; Ghione, 1996). In hypertension, some of these intercorrelations may be altered as has been evidenced by experimental studies which have demonstrated differences between SHR and WKY as regards opioid receptor distribution or receptor subtypes, involved in antinociception (Zamir et al., 1980, 1981; Feuerstein et al., 1983; Jin and Rockhold, 1991). Moreover, differences in the reactivity to central sympathetic activation by opioids or changes in peripheral opioid function have also been described in hypertensive animals (Feuerstein et al., 1983; Wong and Ingenito, 1993; Di Bona and Jones, 1994). An involvement of the opiate system in hypertension-related hypalgesia has been suggested in pilot studies by the use of naloxone which tended to normalize pain threshold in SHR rats (Zamir and Segal, 1979; Saavedra, 1981). Circulating endogenous
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opioid peptides seem to increase in hypertension (Sheps et al., 1992; Guasti et al., 1996) and a signi®cant correlation between plasma beta-endorphin levels and both blood pressure and pain sensitivity has been described recently in hypertensive patients (Guasti et al., 1996). Increased sustained blood pressure may be the stimulus that leads to endogenous opiate system activation and then to hypalgesia, possibly through baroreceptor stimulation. In conclusion this study con®rms a reduced pain perception in hypertensive patients and shows a close correlation between pain sensitivity and 24-h blood pressure in a large number of subjects. The mechanisms leading to hypalgesia in hypertension seem to be dependent upon the development of elevated blood pressure whereas the parental history of hypertension does not affect pain sensitivity per se. Thus, the degree of blood pressure elevation, more than a genetic predisposition to hypertension may in¯uence the pain perception pattern associated with hypertension. References Anderson SA, Ericson T, Holmgren E, Lindquist G. Electroacupunture: effect on pain threshold measured with electrical stimulation of the tooth. Brain Res 1973;63:393±396. Azerad J, Woda A. Sensation evoked by bipolar intrapulpar stimulation in man. Pain 1977;4:145±152. Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis. Ann Neurol 1978;4:451±462. Bruehl S, Carlson CR, McCubbin JA. The relationship between pain sensitivity and blood pressure in normotensives. Pain 1992;48:463±467. Di Bona GF, Jones SJ. Role of endogenous peripheral opioid mechanisms in renal function. J Am Soc Nephrol 1994;4:1792±1797. Droste C, Kardos A, Brody S, Greenlee MW, Roskamm H, Rau H. Baroreceptor stimulation: pain perception and sensory thresholds. Biol Psychol 1994;37:101±113. Dworkin B, Filewich R, Miller N, Craigmyle N, Pickering T. Baroreceptor activation reduces reactivity to noxious stimulation: implications in hypertension. Science 1979;205:1299±1301. Dworkin BR, Elbert T, Rau H, Birbaumer N, Pauli P, Droste C. Central effects of baroreceptor activation in humans: attenuation of skeletal re¯exes and pain perception. Proc Natl Acad Sci USA 1994;91:6329± 6333. Elbert T, Rockstroh B, Lutzenberger W, Kessler M, Pietrowsky R. Baroreceptor stimulation alters pain sensation depending on tonic blood pressure. Psychophysiology 1988;25:25±29. Falcone C, Auguadro C, Sconocchia R, Angoli L. Susceptibility to pain in hypertensive and normotensive patients with coronary artery disease. Hypertension 1997;30:1279±1283. Feuerstein G, Zerbe RL, Faden AI. Opiate receptors and cardiovascular control in conscious SHR and WKY rats. Hypertension 1983;5:663±671. Feuerstein G, Siren AL. The opioid peptides: a role in hypertension? Hypertension 1987;9:561±565. Fields HL. Neurophysiology of pain and pain modulation. Am J Med 1984;77:2±8. Fontana F, Bernardi P, Pich EM, Capelli M, Bortoluzzi L, Spampinato S, Canossa M. Endogenous opioid system and atrial natriuretic factor in normotensive offspring of hypertensive parents at rest and during exercise test. J Hypertens 1994;12:1285±1290. France C, Ditto B, Adler P. Pain sensitivity in offspring of hypertensives at rest and during barore¯ex stimulation. J Behav Med 1991;14:513±525. France C, Adler PS, France J, Ditto B. Family history of hypertension and pain during blood donation. Psychosom Med 1994;56:52±60.
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Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity Luigina Guasti*, Giovanni Gaudio, Danilo Zanotta, Paola Grimoldi, Maria Rosaria Petrozzino, Fabio Tanzi, Andrea Bertolini, Anna Maria Grandi, Achille Venco Chair of Internal Medicine, Department of Clinical and Biological Sciences, Faculty of Medicine, University of Insubria, Viale Borri 57, Varese, Italy Received 20 January 1999; accepted 1 March 1999
Abstract Introduction: The aim of this study was to determine whether the degree of blood pressure elevation and/or a genetic predisposition to hypertension have a major role in determining a reduced pain perception in hypertensives. The reasons underlying the relationship between blood pressure elevation and pain perception mechanisms are not completely understood. Methods: One hundred and four untreated hypertensive patients (65 subjects with and 39 without a positive parental history of hypertension) together with a control group of 42 subjects (20 normotensive offspring of normotensive parents, and 22 normotensive offspring of hypertensive parents) were submitted to standard blood pressure evaluation, 24-h blood pressure monitoring and dental pain perception evaluation. Results: Both pain threshold and tolerance were found to be higher in hypertensive than normotensive subjects (P , 0:0001 and P , 0:015, respectively). Positive signi®cant correlations were found between both 24-h systolic and diastolic pressure and the pain perception variables. When a 2 £ 2 ANOVA test was performed, factoring for the effects of both blood pressure status and family history of hypertension on pain sensitivity, a signi®cant effect was revealed only for blood pressure status. Moreover, after controlling for blood pressure by a covariate analysis, no signi®cant difference was found between the subjects with or without hypertensive parents as regards pain perception variables. Conclusions: Pain sensitivity is correlated to blood pressure levels whereas the parental history of hypertension per se does not affect the pain perception pattern. Thus, the degree of blood pressure elevation, more than a genetic predisposition to hypertension may in¯uence the mechanisms leading to hypalgesia in hypertension. q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Blood pressure; Hypertension, essential; Parental history of hypertension; Pain threshold; Analgesia
1. Introduction Since the late 1970s there has been an increase in experimental evidence of hypertension-related hypalgesia (Zamir and Segal, 1979; Dworkin et al., 1979; Ghione, 1996). Most of the animal studies have reported that various forms of hypertension were associated with a behavioural evidence of hypalgesia (Zamir and Segal, 1979; Saavedra, 1981; Maixner et al., 1982; Wendel and Bennet, 1981; Sisten and de Jong, 1983). A study on spinal nociceptive transmission in SHR and WKY rats con®rmed an inhibition of the sensory function in hypertension (Randich and Robertson, 1994). In humans, a reduced pain perception has been described in subjects with increased blood pressure values, in essential hypertensive patients and in hypertensives with coronary artery disease (Zamir and Shuber, 1980; Ghione et al., 1985, 1988; Vignocchi et al., 1989; Sheps et al., 1992; * Corresponding author. Tel.: 139-0332-278-273; fax. 139-0332-265586.
Rosa et al., 1994; Guasti et al., 1995a,b; Krittayaphong et al., 1996; Falcone et al., 1997; Shef®eld et al., 1997). Various techniques have been used to test experimental pain perception in hypertensive patients (Zamir and Shuber, 1980; Ghione et al., 1985, 1988; Vignocchi et al., 1989; Sheps et al., 1992; Rosa et al., 1994; Guasti et al., 1995a,b). The tooth pulp stimulation allows the pain threshold to be quanti®ed as the intensity of test current linearly increases. Moreover, possible interferences from pressure, touch and thermal sensitivity are avoided due to the fact that dental pulp contains ®bers which are presumed to transmit painful sensation only (Anderson et al., 1973; Azerad and Woda, 1977). Dental pain perception has been more closely correlated with the 24-h ambulatory blood pressure than with blood pressure measured before pain perception evaluation, indicating a role for sustained blood pressure in the modulation of pain sensitivity (Guasti et al., 1995a). However, some peculiar aspects of the relationship between hypalgesia and hypertension are still unknown. In particular, it is not clear whether hypalgesia is secondary to blood
0304-3959/99/$20.00 q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. PII: S 0304-395 9(99)00059-7
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pressure elevation or both depend on common factors, possibly genetically linked. Only a few authors have looked for a possible association between the parental history of hypertension and the pain perception pattern, with con¯icting results (Ghione et al., 1988; France et al., 1991, 1994; Stewart and France, 1996; Page and France, 1997). The aim of this study was to investigate whether the reduced sensitivity to pain associated with hypertension depends on the degree of blood pressure elevation and/or is related to a genetically transmitted pattern linked to the predisposition to hypertension. 2. Methods One hundred and four consecutive hypertensive patients with documented positive (n 65) or negative (n 39) family history of hypertension were studied together with a control group of 42 normotensive subjects (22 offsprings of hypertensive parents; 20 offsprings of normotensive parents). As for inclusion criteria, all the subjects had the following characteristics: male sex, age between 30 and 50 years, documented positive or negative parental history of hypertension, no assumption of any therapy and/or pharmacological wash-out for at least three weeks before the study, a dental formula suitable for the pulpar test (no caries, abrasions, ®llings, marked periodontal diseases), no concomitant diseases (diabetes, obesity, cardiac or pulmonary diseases, neurologic or psychiatric disorders), no secondary forms of hypertension as indicated by a routine examination, no competitive sport activities, and informed consent to the study. All the subjects were submitted to dental pain perception evaluation and 24-h ambulatory blood pressure monitoring. The hypertensive patients were recruited among our out-patient population whereas the normotensives were evaluated during a general clinical check-up among Italian Post Of®ce Employees. The parental history of hypertension was assessed as follows: negative family history was established when both parents were living and showed blood pressure , 140=90 mm Hg or when medical records showed repeatedly normal blood pressure values during the last three years of life; positive family history was assessed when at least one parent was living and had blood pressure $ 140=90 mm Hg and/or at least one parent had a history of chronic antihypertensive treatment. The hypertensive and normotensive subjects did not differ as regards mean age (41 ^ 7 and 42 ^ 7 years, respectively) and body mass index (24:7 ^ 1:9 and 25 ^ 2 Kg/m 2, respectively). The study was approved by the Ethical Committee of our Department. 2.1. Pulpar test Dental pain sensitivity was investigated in all the subjects between 9.00 and 10.00 am, after a 30-min rest in a supine and comfortable position. As previously reported (Guasti et al., 1995a,b), the experimental pain was induced by means
of a pulpar tester (MEDI-tester, MEDIC-AL) which delivers automatic intermittent bursts of test current of linearly increasing intensity (from 0 to 0.03 mA; voltage: 6500 mV; frequency: 5 Hz). As the intensity of test current increases, a number from 0 to 80 (relative Units -rU-) appears on a display not visible to the subjects under examination. The stimulator was applied on the enamel surface of the tooth through a metal cilinder (inner diameter: 0.9 mm) with an electrode paste to improve contact. The operator's hand was placed on the lips of the subject to close the circuit. Three teeth were evaluated in each subject (two upper incisors and one inferior incisor), and the data reported refer to the mean value of the three. Dental pain threshold was de®ned as the minimal intensity of test current that elicited a pulp sensation. The subjects were previously instructed to raise the right hand as the pain threshold occurred. The stimulation was then interrupted and re-applied immediately afterwards to determine pain tolerance (intensity of test current at the time when the subject asked for the test to be stopped). All the subjects were asked not to smoke nor to eat chocolates or drink teas, coffees, cola-containing substances or alcoholic beverages during the previous 12 h. All the subjects completed the test on three teeth although they knew that dental pain evaluation could have been interrupted any time. 2.2. Blood pressure measurements 2.2.1. Pre-pain testing blood pressure During the rest period preceding the pulpar test, blood pressure was automatically measured every 3 min by a Hewlett Packard 78352A recorder. The values of blood pressure and heart rate measured immediately before the pulpar test are referred to as `pre-pain testing blood pressure and heart rate'. Before pain testing, if the value obtained differed more than 5 mm Hg from the previous measure, another measure was taken until two were close. 2.2.2. Ambulatory blood pressure All the subjects performed a non-invasive blood pressure monitoring after pain perception evaluation. As described previously (Guasti et al., 1995a), a TAKEDA TM2421 (A and D Co) set to take one measure every 15 min for a 24-h period was used. This instrument has a combined auscultatory and oscillometric method to minimize errors. The test quality was good (.80% valid measurements) in 137 subjects; 9 subjects repeated the test successfully the day after. A computerized program did the reading and editing of the data (Guasti et al., 1995a). The 24-h, day-time (7am to 10pm), night-time (10pm to 7am) values of systolic and diastolic blood pressure were taken into consideration in subsequent analysis. All the hypertensive patients showed a day-time blood pressure $ 140 and/or 90 mm Hg whereas normotensives had day-time blood pressure , 140=90 mmHg.
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analysis of covariance was performed (2 groups: subjects with a positive family history vs. subjects with a negative history) using the 24 h blood pressure as covariate and both pain threshold and tolerance as dependent variable. Relations among variables were investigated by linear regression analysis. The statistical analysis was performed using the GB Stat v.6.5 program. A P value ,0.05 was considered to be signi®cant. 3. Results 3.1. Blood pressure measurements Fig. 1. Bar graph showing dental pain threshold and tolerance (expressed in natural logarithm of relative Units, ln rU). A signi®cant difference was found between the two groups of normotensives (solid bars) and hypertensives (open bars) regarding both pain threshold (P , 0:0001) and tolerance (P , 0:015).
2.3. Statistical analysis Data are presented as mean values ^ standard deviations. Since the variances of pain perception variables were not homogeneous, pain threshold and tolerance values were transformed to natural logarithm (ln). After the transformation, no other signi®cant differences among variables were detected by a Cochran's test. The variables were compared by the Mann Whithney U test (pain sensitivity variables) and Student t-test (haemodynamic variables).A one-way ANOVA and the post-hoc Student-Newman- Keuls test were used to compare the pain sensitivity values among the four groups of normotensives with and without a positive family history of hypertension and hypertensives with and without hypertensive parents. Moreover, the results of the pain perception evaluation were analyzed by a 2 £ 2 ANOVA test factoring for the effects of both blood pressure status (normotensives vs. hypertensives) and family history of hypertension (positive vs. negative). Furthermore, a
In normotensives, the mean 24-h blood pressure (122 ^ 8=77 ^ 8 mm Hg), day-time (127 ^ 8=80 ^ 8 mm Hg), and night-time blood pressure (113 ^ 11=70 ^ 9 mm Hg) were signi®cantly lower than those in the hypertensive group (24-h arterial pressure: 145 ^ 13=92 ^ 9 mm Hg; day-time pressure: 151 ^ 13=96 ^ 9 mm Hg, and nighttime pressure: 130 ^ 16=83 ^ 12 mm Hg) (P , 0:0001). The 24-h heart rate was 73 ^ 7 beats/min in normotensives and 76 ^ 10 in hypertensive patients (P , 0:05). Pre-pain testing blood pressure, too, was higher in hypertensive patients (133 ^ 12=82 ^ 11 vs. 150 ^ 18=94 ^ 15 mm Hg, P , 0:0001), whereas pre-pain testing heart rate was similar in the two groups (70 ^ 13 and 71 ^ 11 beats/min, ns, in normotensives and hypertensives, respectively). 3.2. Dental pain perception Pain sensitivity was different in normotensive and hypertensive subjects, both dental pain threshold and tolerance being higher in the hypertensive group (pain threshold: 3:039 ^ 0:267 ln rU vs. 3:254 ^ 0:273 ln rU in normotensive and hypertensive subjects, respectively: P , 0:0001; pain tolerance: 3:521 ^ 0:383 ln rU vs. 3:708 ^ 0:384 ln rU: P , 0:015) (Fig. 1). A signi®cant association was found between pain threshold and pain tolerance (r 0:70, P , 0:0001) (Fig. 2). Pain perception variables were associated with 24-h and baseline blood pressure values. Pain threshold was correlated to 24-h systolic (r 0:41, P , 0:0001), 24-h diastolic (r 0:31; P , 0:0001), pre-pain testing systolic (r 0:26; P , 0:0015) and diastolic pressure (r 0:25; P , 0:002). Pain tolerance was signi®cantly associated with 24-h systolic blood pressure (r 0:24; P , 0:005), 24-h diastolic pressure (r 0:17; P , 0:05), and pre-pain testing systolic blood pressure (r 0:16; P , 0:05). 3.3. Family history of hypertension and pain sensitivity
Fig. 2. Scatterplot showing the positive signi®cant correlation (146 subjects) between dental pain threshold and tolerance expressed in natural logarithm of relative Units (ln rU) (r 0:70, P , 0:0001).
The normotensive and hypertensive subjects were grouped according to the family history of hypertension and blood pressure and pain sensitivity variables of the following four groups were compared: (1) normotensives with a negative family history of hypertension, (2) normo-
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Table 1 Haemodynamic variables in the groups of normotensive and hypertensive subjects with and without a positive parental history of hypertension a NPH24-h SPB (mm Hg) 24-h DBP (mm Hg) 24-h HR (beats/min) Baseline SBP (mm Hg) Baseline DBP (mm Hg) Baseline HR (beats/min)
NPH 1
HPH-
HPH 1
122 ^ 9 123 ^ 6 143 ^ 13 146 ^ 13 75 ^ 8 78 ^ 8 91 ^ 9 93 ^ 9 73 ^ 5 72 ^ 8 78 ^ 10 74 ^ 10 132 ^ 8 135 ^ 15 148 ^ 16 151 ^ 19 82 ^ 8 82 ^ 13 95 ^ 13 94 ^ 15 69 ^ 12 71 ^ 13 72 ^ 11 70 ^ 11
a NPH- indicates normotensives with a negative parental history of hypertension, NPH1 indicates normotensives with a positive parental history, HPH- indicates hypertensives with a negative history, HPH1 indicates hypertensives with a positive family history of hypertension; SBP indicates systolic blood pressure, DBP diastolic blood pressure and HR indicates heart rate.
tensive offspring of hypertensive parents, (3) hypertensive patients with normotensive parents and (4) hypertensives with a positive parental history of hypertension (Table 1). The ANOVA test indicated a signi®cant difference among the groups in 24-h and pre-pain testing systolic and diastolic pressure, and in pain threshold (P , 0:001). The StudentNewman-Keuls test showed that each group of normotensive subjects differed from each group of hypertensive patients as regards blood pressures (P , 0:01) and pain threshold (P , 0:05). However, similar values were found between the two groups of normotensives and between the two groups of hypertensive patients, regardless of their family history. Pain tolerance did not signi®cantly differ among the groups (P 0:067) (Fig. 3). The two factor ANOVA test revealed signi®cant effects on pain sensitivity for blood pressure status (F 13:267, P 0:0003 and F 5:053, P 0:0253 for pain threshold
and tolerance, respectively) while family history had no signi®cant effects (F 1:450, P 0:2294 and F 0:585, P 0:4448 for pain threshold and tolerance, respectively). Moreover, ANCOVAs were computed to evaluate the relationship between the genetic status and pain sensitivity, after controlling for blood pressure values. Twenty four hour systolic pressure served as the covariate, thus removing any effect of blood pressure. After controlling for blood pressure, no signi®cant difference was observed in the groups of subjects with and without a positive family history of hypertension (F 0:051, P 0:8201, and F 0:012, P 0:9134, entering pain threshold and tolerance, respectively, as dependent variable). 4. Discussion Hypalgesia has been almost consistently reported in hypertensive patients. In humans, various techniques, such as cutaneous electrical and thermal stimulation, and tooth pulp stimulation have been used to induce experimental pain, with similar results. Increased pain threshold and tolerance have been described in patients with hypertension when compared with normotensive subjects, together with a signi®cant correlation between pain sensitivity and baseline blood pressure (Ghione, 1996). Our group has previously shown that the 24-h blood pressure is more closely correlated with pain threshold and tolerance than blood pressure measured by standard sphygmomanometer (Guasti et al., 1995a). This study performed on a large patient population con®rms the relation between blood pressure and sensitivity to pain, and indicates a relevant role of sustained, tonic blood pressure in activating the mechanisms related to pain perception, being the correlation between 24h systolic blood pressure and pain threshold the closest association found. Some authors have pointed out that the timing between blood pressure elevation and hypalgesia are not always strictly connected (Saavedra, 1981; Wendel and Bennet, 1981; Sisten and de Jong, 1983; Guasti et al., 1995b). One study indicated the persistence of hypalgesia in renal hypertensive rats for a few days after blood pressure was reduced by the removal of the constricted kidney (Zamir and Segal, 1979). Possibly, interactions between blood pressure and pain sensitivity occur through activation of long-term pattern mechanisms. 4.1. Parental history of hypertension and sensitivity to pain
Fig. 3. Bar graph showing dental pain threshold and tolerance (natural logarithm of relative Units, ln rU) in the following four groups of subjects: normotensive subjects with a negative parental history of hypertension (solid bars), normotensive offspring of hypertensive parents (hatched bars), hypertensive patients with a negative parental history of hypertension (open bars), and hypertensives with a positive history. Pain threshold significantly differed among the groups (P , 0:001), while pain tolerance did not (P 0:067 ns).
A role for a genetic linkage between blood pressure and pain sensitivity has been suggested. In favour of this hypothesis a behavioural evidence of hypalgesia has been described in newborn SHR rats when compared with WKY rats, before a relevant blood pressure rise in the hypertensive strain (Sisten and de Jong, 1983). Furthermore, the endogenous opiate system, which has a primary role in pain perception modulation (Basbaum and Fields, 1978; Fields, 1984), has been shown to have different responses
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to stress in normotensives with or without hypertensive parents (Fontana et al., 1994). On the other hand, some authors have found that hypertension was associated with reduced sensitivity to pain both in genetically hypertensive rats and in experimentally induced hypertension (Saavedra, 1981; Maixner et al., 1982; Wendel and Bennet, 1981). Moreover, the change in pain sensitivity was not a function of the method used to induce hypertension and both renal clip and DOCA salt induced hypertension were effective in reducing pain perception (Zamir et al., 1980). At last, in normotensive rats, the ®nding of a lower pain sensitivity in the Dahl hypertension-sensitive versus hypertension-resistant strain has been associated with the slightly higher blood pressure levels observed in the ®rst line (Friedman et al., 1984). In humans, one previous report on experimental pain induced by a dental pulp stimulator did not describe any difference in pain threshold and tolerance in subjects which were subgrouped according to parental history of hypertension (Ghione et al., 1988). On the contrary, a group of investigators has consistently reported the presence of hypalgesia in normotensive offspring of hypertensive parents as compared with the group without a positive history after cold pressor test, forearm ischemia and electrical stimulation over the sural nerve (France et al., 1991; Stewart and France, 1996; Page and France, 1997). In our population study of 104 hypertensive patients and 42 normotensives, similar pain perception patterns were found in subjects with similar blood pressure levels, regardless of their family history of hypertension. However, since there was a trend towards both higher blood pressure values and reduced sensitivity to pain in the subjects with a positive parental history of hypertension, a covariate analysis was performed. After controlling for 24-h systolic blood pressure, no signi®cant difference was found between the two groups of subjects with and without a positive familiar history of hypertension, as regards pain perception variables. Moreover, the 2 £ 2 ANOVA test indicated signi®cant effects on pain sensitivity only for blood pressure status and not for the parental history. The normotensive subjects with hypertensive parents tend to have both resting blood pressure higher than normotensives without a positive family history of hypertension, and an increased haemodynamic reactivity to various forms of stimuli (Watt et al., 1983; Widgren et al., 1992). Since the relationship between blood pressure and pain sensitivity has been extended to the normotensive subjects (Bruehl et al., 1992; McCubbin and Bruehl, 1994), this confounding factor might have in¯uenced the results previously reported in normotensives on the association between a genetic predisposition to hypertension and pain sensitivity. If a genetic link exists between blood pressure and the pain modulating system, the actual expression of this effect is possibly dependent upon the development of elevated blood pressure. Since the mean age of the subjects in the present study is more elevated than the one reported by France (Stewart and France,
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1996), it is also possible that the subjects who had inherited the predisposition to hypertension had already become hypertensive in our population study. Alternatively, the presence of overt hypertension may be a stronger stimulus to hypalgesia and it may be able to suppress other hypothetical in¯uences operating in normotensives. Finally, since no women were tested as for inclusion criteria, it has to be acknowledged that the results here reported may not apply to both genders. In a previous study, France and coworkers found a signi®cant difference in venipuncture pain rating between subjects with and without a parental history of hypertension only in women with 0-1 previous blood donation whereas the other groups of males and experienced females did not show any difference (France et al., 1994). 4.2. Possible mechanisms linking blood pressure and pain perception Although not entirely understood, a close relationship exists between cardiovascular modulation and pain perception pathways. Previous studies have suggested an association between barore¯ex sensitivity and pain perception in normotensive and hypertensive subjects (Dworkin et al., 1979; Maixner et al., 1982; Elbert et al., 1988; Droste et al., 1994). Baroreceptor function manipulation and anatomical interruption of the neural arc integrity may in¯uence pain sensitivity (Maixner and Randich, 1984; Randich and Maixner, 1986; Meller et al., 1990). A group of investigators has focused on the relationship between baroreceptor stimulation and pain sensitivity in normotensive subjects (Dworkin et al., 1994). This comprehensive study using the PRES (phase-related external suction) technique showed that a painful stimuli was rated as less intense when delivered during the maximal baroreceptor stimulation (i.e. when suction was added to systolic pressure). Besides, central mechanisms acting independently of or through sympathetic nervous system activation may link pain perception and blood pressure levels. Within various structures of the central nervous system, the autonomic network was found to share anatomic areas and functional pathways with the nociceptive system (Feuerstein and Siren, 1987; Ghione, 1996). In hypertension, some of these intercorrelations may be altered as has been evidenced by experimental studies which have demonstrated differences between SHR and WKY as regards opioid receptor distribution or receptor subtypes, involved in antinociception (Zamir et al., 1980, 1981; Feuerstein et al., 1983; Jin and Rockhold, 1991). Moreover, differences in the reactivity to central sympathetic activation by opioids or changes in peripheral opioid function have also been described in hypertensive animals (Feuerstein et al., 1983; Wong and Ingenito, 1993; Di Bona and Jones, 1994). An involvement of the opiate system in hypertension-related hypalgesia has been suggested in pilot studies by the use of naloxone which tended to normalize pain threshold in SHR rats (Zamir and Segal, 1979; Saavedra, 1981). Circulating endogenous
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opioid peptides seem to increase in hypertension (Sheps et al., 1992; Guasti et al., 1996) and a signi®cant correlation between plasma beta-endorphin levels and both blood pressure and pain sensitivity has been described recently in hypertensive patients (Guasti et al., 1996). Increased sustained blood pressure may be the stimulus that leads to endogenous opiate system activation and then to hypalgesia, possibly through baroreceptor stimulation. In conclusion this study con®rms a reduced pain perception in hypertensive patients and shows a close correlation between pain sensitivity and 24-h blood pressure in a large number of subjects. The mechanisms leading to hypalgesia in hypertension seem to be dependent upon the development of elevated blood pressure whereas the parental history of hypertension does not affect pain sensitivity per se. Thus, the degree of blood pressure elevation, more than a genetic predisposition to hypertension may in¯uence the pain perception pattern associated with hypertension. References Anderson SA, Ericson T, Holmgren E, Lindquist G. Electroacupunture: effect on pain threshold measured with electrical stimulation of the tooth. Brain Res 1973;63:393±396. Azerad J, Woda A. Sensation evoked by bipolar intrapulpar stimulation in man. Pain 1977;4:145±152. Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis. Ann Neurol 1978;4:451±462. Bruehl S, Carlson CR, McCubbin JA. The relationship between pain sensitivity and blood pressure in normotensives. Pain 1992;48:463±467. Di Bona GF, Jones SJ. Role of endogenous peripheral opioid mechanisms in renal function. J Am Soc Nephrol 1994;4:1792±1797. Droste C, Kardos A, Brody S, Greenlee MW, Roskamm H, Rau H. Baroreceptor stimulation: pain perception and sensory thresholds. Biol Psychol 1994;37:101±113. Dworkin B, Filewich R, Miller N, Craigmyle N, Pickering T. Baroreceptor activation reduces reactivity to noxious stimulation: implications in hypertension. Science 1979;205:1299±1301. Dworkin BR, Elbert T, Rau H, Birbaumer N, Pauli P, Droste C. Central effects of baroreceptor activation in humans: attenuation of skeletal re¯exes and pain perception. Proc Natl Acad Sci USA 1994;91:6329± 6333. Elbert T, Rockstroh B, Lutzenberger W, Kessler M, Pietrowsky R. Baroreceptor stimulation alters pain sensation depending on tonic blood pressure. Psychophysiology 1988;25:25±29. Falcone C, Auguadro C, Sconocchia R, Angoli L. Susceptibility to pain in hypertensive and normotensive patients with coronary artery disease. Hypertension 1997;30:1279±1283. Feuerstein G, Zerbe RL, Faden AI. Opiate receptors and cardiovascular control in conscious SHR and WKY rats. Hypertension 1983;5:663±671. Feuerstein G, Siren AL. The opioid peptides: a role in hypertension? Hypertension 1987;9:561±565. Fields HL. Neurophysiology of pain and pain modulation. Am J Med 1984;77:2±8. Fontana F, Bernardi P, Pich EM, Capelli M, Bortoluzzi L, Spampinato S, Canossa M. Endogenous opioid system and atrial natriuretic factor in normotensive offspring of hypertensive parents at rest and during exercise test. J Hypertens 1994;12:1285±1290. France C, Ditto B, Adler P. Pain sensitivity in offspring of hypertensives at rest and during barore¯ex stimulation. J Behav Med 1991;14:513±525. France C, Adler PS, France J, Ditto B. Family history of hypertension and pain during blood donation. Psychosom Med 1994;56:52±60.
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Zamir N, Segal M. Hypertension-induced analgesia: changes in pain sensitivity in experimental hypertensive rats. Brain Res 1979;160:170±173. Zamir N, Simantov R, Segal M. Pain sensitivity and opioid activity in genetically and experimentally hypertensive rats. Brain Res 1980;184:299±310. Zamir N, Shuber E. Altered pain perception in hypertensive humans. Brain Res 1980;201:471±474. Zamir N, Segal M, Simantov R. Opiate receptor binding in the brain of hypertensive rats. Brain Res 1981;213:217±222.