Arterial Hypertension Is Associated with Hypalgesia in Humans SERGIO GHIONE, CATERINA ROSA, LORENA MEZZASALMA, AND ELISABETTA PANATTONI

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1 rteral Hypertenson Is ssocated wth Hypalgesa n Humans SERGIO GHIONE, CTERIN ROS, LOREN MEZZSLM, ND ELISBETT PNTTONI SUMMRY n assocaton between ncreased blood pressure and hypalgesa has been reported n several studes n anmals and n a few reports n humans. We nvestgated the relatonshp between hypertenson and pan percepton by comparng the response to graded electrcal stmulaton of the tooth pulp, whch s thought to represent an exclusvely nodceptve system. The test was performed wth a commercal tooth pulp tester n a large seres of subjects wth borderlne or establshed hypertenson and n three groups of normotensve controls: volunteers, nonhypertensve patents, and medcal students wth a well-establshed or no famly hstory of hypertenson. Subjects had to report when they started to feel pulp stmulaton (sensory threshold) and when ths became panful (pan threshold). Sensory and pan thresholds were obtaned as means of the measurements on four healthy, unflled teeth. Sensory thresholds were sgnfcantly hgher h subjects wth borderlne or establshed hypertenson than n two of the three normotensve groups (volunteers and normotensve patents), whereas no sgnfcant dfference was observed between the two hypertensve groups. The results for the pan threshold were qualtatvely smlar but less dear and less amenable to statstcal analyss because ths parameter could not be determned wth accuracy h a number of subjects n whom the subjectve pan threshold was above the upper range of stmulaton of the nstrument. The assocaton between Mood pressure levels and pan percepton was further confrmed by the hghly sgnfcant correlaton found for the overall data between mean arteral blood pressure and both thresholds. On the other hand, no sgnfcant correlaton was found wth heart rate and no sgnfcant effects could be detected by analyss of varance for sex, age, and famly hstory of hypertenson. Furthermore, no changes h pan senstvty were observed h a subgroup of patents studed after 3 months of duretc or ^-blockng treatment or of low salt det, despte sgnfcant reductons of arteral blood pressure. Taken together, our fndngs provde further confrmatory evdence for an ncreased tolerance to pan n hypertensve humans and suggest that ths may be a feature of arteral hypertenson rrespectve of the prevalng blood pressure levels. (Hypertenson 12: , 1988) KEY WORDS pan hypalgesa arteral hypertenson tooth pulp test SEVERL lnes of evdence ndcate that ncreased arteral blood pressure s assocated wth a decreased percepton of pan. 1 Psychophysologcal studes n the rat 2-9 have demonstrated the assocaton of hypalgesc behavor (delayed response to noxous stmul such as a hot plate, an electrc shock, or a mechancal force appled to a lmb) to arteral hypertenson. In hypertensve humans, an ncreased tolerance to pan, as assessed by the measurement of the pan threshold to graded electrcal tooth pulp stmulaton, has been reported by Zamr and Shuber 10 and confrmed n prelmnary studes by our group." l2 From the CNR Insttute of Clncal Physology (S. Ghone, C. Rosa, L. Mezzasalma) and the Dental Clnc (E. Panatton), Unversty of Psa, Psa, Italy. ddress for reprnts: Sergo Ghone, CNR Insttute of Clncal Physology, Va Sav 8, Psa, Italy. Receved October 6, 198; accepted July 2, Put nto a broader perspectve, the phenomenon of hypertenson-assocated hypalgesa may provde some nsght nto the nvolvement of the endogenous opod system(s) n the pathogeness of hypertenson. 13 In fact, several studes have demonstrated that the opate antagonst naloxone normalzes the ncrease n pan threshold n spontaneously hypertensve rats (SHR), suggestng the mplcaton of the opod peptdes n ths form of hypalgesa. Numerous bochemcal and pharmacologcal studes n expermental anmals have provded convncng evdence of the presence of opod peptdes and ther receptors n bran nucle nvolved n cardovascular control and, more generally, of a role for these neurotransmtters n cardovascular regulaton. 13 Furthermore, a role for the central opod system n the pathogeness of hypertenson n humans has been supported by the studes of Farsang and colleagues, 16-1 who showed that the 491

2 492 HYPERTENSION VOL 12, No 5, NOVEMBER 1988 anthypertensve effect of clondne nvolves an opod-medated nhbton of the central sympathetc outflow and that ths mechansm appears to be more pronounced n hypertensve patents wth hyperactvty of the adrenergc system. Because of ts smplcty, nonnvasveness, and acceptablty, tooth pulp stmulaton (a technque used n clncal dentstry for assessng pulp vtalty) s a convenent test n experments desgned to nvestgate pan mechansms. The dental pulp represents an exclusvely sensory system, 1920 and a good agreement between ntradental nerve actvty and pan percepton n response to graded stmulaton appled to the teeth has been reported The pan threshold determned by ths test s farly reproducble wthn the same ndvdual and can be altered by a varety of manpulatons known to affect pan percepton n the expermental anmal such as L-tryptophan supplementaton, acupuncture, and transcutaneous stmulaton We report the results obtaned wth ths test n a seres of 156 hypertensve and normotensve subjects. These results confrm and extend prevous prelmnary reports by us - 12 and studes by others 10 ndcatng that arteral hypertenson s assocated wth an ncreased tolerance to pan n humans. Subjects and Methods We studed 156 subjects over a perod of 2.5 years. Eghty were normotensve and 6 had ether borderlne or establshed hypertenson. The normotensve group comprsed three dfferent subgroups: normal volunteers who were recruted ether from the medcal and paramedcal staff of the hosptal (Group l) or from a selected medcal student populaton (Group 2) chosen on the bass of havng a well-establshed famly hstory of hypertenson (defned as at least one parent wth arteral hypertenson.e., havng measured hgh blood pressure levels or recevng anthypertensve treatment, or both) or no famly hstory of hypertenson (defned as blood pressure values below 140/90 mm Hg n both parents and at least three grandparents), and nonhypertensve patents (Group B) who were recruted from several outpatent clncs. TBLE 1. Characterstcs of the Subgroups Studed Normotensve Volunteers Varable ge (yr) Sex(M/F) Blood pressure (mm Hg) Heart rate (beats/mn) Famly hstory of hypertenson (n) Staff (l) (n=18) 33.1 ±8.4 (26-54) 14: /8.8 ±10.4/5. Students (2) (n=19) 23.9±1.4 (22-26) 19:0 130./5.2 ±8./ ± Values are means ± SD. ge range s shown n parentheses. ll hypertensve subjects, except two who were selected from the normal control populaton but turned out to have borderlne blood pressure values, were recruted from the same outpatent clnc. Thrty-four subjects were classfed as havng borderlne hypertenson (systolc blood pressure between 140 and 160 mm Hg or dastolc blood pressure between 90 and 95 mm Hg, or both) and 42 as havng establshed hypertenson (systolc blood pressure >160 mm Hg or dastolc blood pressure >95 mm Hg or both), accordng to World Health Organzaton recommendatons. 23 ll patents had dscontnued drug treatment at least 2 weeks before the study began, and the routne dagnostc workup excluded secondary forms of hypertenson n all but two subjects, who had renovascular hypertenson. None of the subjects had a hstory of lung dsease, stroke, dabetes, or psychatrc dsturbances. ll subjects were questoned about ther famly hstory of hypertenson and smokng habts. The major characterstcs of the varous subgroups are reported n Table 1. The procedure was explaned to all the hypertensve subjects and to Group B as representng a test that could be of some mnor utlty snce t explored a psychophysologcal aspect that mght be related to ther dsease. The procedure was explaned to all volunteers as a test to assess pan senstvty that could be of further clncal or scentfc usefulness. Before the study was ntated, the test was repeatedly performed on the nvestgators themselves and found to be readly acceptable. ll subjects were thus reassured that the test was only lghtly panful and, snce the evaluaton was gong to be performed on four teeth, that they could wthdraw ther consent at any step durng the examnaton. Nne subjects (2 normotensve and hypertensve subjects) who dsplayed extreme anxety toward the odontoatrc char and toward any odontoatrc procedure were excluded from the study. In no case was the test nterrupted, and all subjects declared themselves wllng to repeat t f requred. commercal, nonnvasve tooth pulp tester (mercan nalytc Technology, Mssoula, MT, US) was used. Ths nstrument gves automatc ntermttent bursts of electrcal stmul of negatve polarty at Patents (B) (n=43) 29.6±.2 (16-46) 32: 128.3/.0 ±12.5/.4 8.1± Borderlne (n=34) 33.1 ±10.6 (13-54) 1:1 145./94.0 ±8.3/ ± Hypertensve Establshed (n=42) 42.1 ±10.6 (16-66) 24: /10.0 ±1.0/12.6.1±

3 HYPLGESI IN HYPERTENSION/G//one et al. 493 ncreasng voltage, wth a peak output voltage rangng from 15 to 300 V and 2-Mfl load mpedance. The ntensty of the stmul, expressed n arbtrary unts (U) on a relatve scale between 0 and 80 was ndcated on a dgtal reader n the nstrument, not vsble to the subject under examnaton. The performance of the nstrument was checked every 4 months and remaned stable throughout the study. ll determnatons were done n the mornng between 0900 and 00, wth the patent sttng on an odontoatrc char, and always by the same dentst, who appled a probe to the tooth under examnaton. The subjects had to ndcate, by lftng a hand, when they started to feel pulp stmulaton (as a prcklng sensaton) and when ths became panful enough to requre the nterrupton of stmulaton, and the correspondng values on dsplay were taken as the sensory and pan thresholds. In several nstances the subjects dd not report notable pan even at the hghest stmulus ntensty of the nstrument. For these subjects n whom the pan threshold was not measurable snce t was above the upper range of stmulaton, the hghest avalable value (80 U) was arbtrarly gven. In no case was the sensory threshold above the upper range of stmulaton. In most subjects, four healthy, unflled teeth (two ncsors [the rght medal nferor and the left lateral superor] and two bcuspds [the frst rght nferor and the second left superor]) were studed, always n the same order. In 1% of the subjects n whom one tooth was not consdered healthy, only three teeth were studed. In no case were less than three teeth studed, and n all cases the average value of the measurements was used for subsequent analyss. ll measurements were done blndly (.e., wthout the dentst's knowledge of the subject's blood pressure). In all subjects heart rate and casual blood pressure were measured n the sttng poston n a quet room by an automatc recorder (Dnamap 845 Vtal Sgns Montor, Crtkon, Tampa, FL, US), and the mean of three successve measurements obtaned over 5 mnutes was used. The measurements were done 15 to 30 mnutes before the tooth pulp stmulaton test. The test was repeated after 3 months n 25 hypertensve patents; 14 were recevng anthypertensve treatment (: atenolol, 100 mg/day; : duretcs [spronolactone, 25 mg/day, and hydrochlorothazde, 25 mg/day]), and were on moderate sodum restrcton. Statstcal evaluaton was made by analyss of varance, Kruskal-Walls test, t test, Wlcoxon test, and regresson analyss, usng the SPSS (Statstcal Package for the Socal Scences) computng package (Chcago, IL, US) mplemented on an IBM 30 computer (rmonk, NY, US). Results s shown n Table 2, on average, the hghest values of sensory and pan thresholds were observed for the hypertensve subjects (borderlne and establshed), whereas varable results were obtaned n the three normotensve subgroups, the lowest values beng those of Group l (the volunteers recruted from the hosptal staff). No subjects n Group l (hosptal staff) and varous percentages of subjects n the other groups had one to four pan threshold values above the upper range. Because of the presence of these out-of-range values, the data dstrbuton of the pan threshold was not normal (Fgure 1). Therefore, dfferent statstcal technques had to be appled: one-way analyss of varance showed sgnfcant dfferences between the varous groups for the sensory threshold (F 4l36 = 8.819, p < ); for pan threshold, the equvalent nonparametrc Kruskal-Walls test also confrmed the exstence of sgnfcant dfferences between groups (ch square = 29.4, p < ). For the sensory threshold, comparson of the means by Scheffe's method (see Table 2) showed sgnfcant dfferences (p < 0.05) between the normotensve groups (l and B) on the one hand and between the borderlne and establshed hyperten- TBLE 2. Sensory and Pan Thresholds, as ssessed by Tooth Pulp Stmulaton, and Number of Out-of-Range Values n the Subgroups Studed Varable Sensory threshold (U) Pan threshold (U) No. of subjects wth pan threshold values out of range For one tooth For two teeth For three teeth For four teeth Staff (l) 29.4± ±.9 Volunteers Normotensve Students (2) 34.± ± Patents (B) 32.2±ll ± Hypertensve Borderlne Establshed 39.8±. 4O.2± ± ±13.3 Values are means ± SD. U = arbtrary unts. The horzontal lnes below the means of sensory threshold connect the homogeneous subsets obtaned wth Scheffe's multple range test; sgnfcance level: p < The test was not appled to pan threshold values (see text)

4 494 HYPERTENSION VOL 12, No 5, NOVEMBER Pan Threshold (arb. unts) FIGURE 1. Hstogram representng the frequency dstrbuton for the pan threshold (averaged over four teeth) to tooth pulp stmulaton n the 156 subjects studed. The apparent bmodal dstrbuton s due to the presence, n the hghest classes, of an ncreasng number of subjects wth one or more out-of-range values (to whch the cutoff value of 80 arbtrary unts was assgned). sve groups on the other, wth the student group occupyng an ntermedate poston. For the pan threshold, no comparson by an equvalent multple range test could be performed. When sensory and pan thresholds were correlated n the pooled data, a strong assocaton was observed between the two (r = 0.69, p < ) Mean Blood Pressure (mmhg) Heart Rate (bom) The presence of an assocaton between arteral blood pressure and pan senstvty was confrmed when the pooled data were analyzed for sgnfcant correlatons between mean arteral blood pressure and sensory (r = 0.326, p < ) and pan thresholds (r = 0.20, p < 0.001; Fgure 2, and B). On the other hand, no sgnfcant correlaton was observed wth heart rate (Fgure 2, C and D), nor was any sgnfcant effect on ether threshold found by multvarate analyss of varance for sex and age. The lack of possble nfluences on the results of age and sex dstrbuton was confrmed when age-matched and sex-matched subgroups were compared (Table 3). No effect of famly hstory was found by analyss of varance and the Kruskal- Walls test on the pooled data or when Group 2 was analyzed alone. In ths homogeneous subgroup of subjects wth ether well-establshed or no famly hstory of hypertenson, no dfference was present for sensory (35. ± 10.1 vs 33.0 ± 5.3 U) or pan thresholds (5.4 ± 16.9 vs 54.3 ± 13.4 U). Fnally, as shown n Table 4, no sgnfcant changes n sensory and pan thresholds were observed n the patents restuded after varous anthypertensve treatments, despte sgnfcant reductons of arteral blood pressure n most nstances. Dscusson The present study confrms and extends prevous observatons that n humans ncreased arteral s 0_ D 80' 0' 60 50' 40' Mean Blood Pressure (mmhg) «1M «4 t * ** * Heart Rate (bpm) FIGURE 2. Sensory and pan thresholds related to mean arteral blood pressure ( and B) and to heart rate (C and D) n the 156 subjects studed. postve sgnfcant correlaton was found for mean arteral blood pressure (r = 0.326, p < 0.000, and r = 0.20, p < 0.00, respectvely, for the sensory and pan threshold), but not for heart rate (n = 125; r = 0.084, NS, and r = 0.00, NS).

5 HYPLGESI IN HYPERTENSION/G/»one et al. 495 TBLE 3. Characterstcs, Sensory Thresholds, and Pan Thresholds of Subjects Matched for ge and Sex Hypertensve Varable ge (yr) Sex(M/F) Systolc blood pressure (mm Hg) Dastolc blood pressure (mm Hg) Heart rate (beats/mn) Sensory threshold (U) Pan threshold (U) Values are means + SD. U = arbtrary unts. Normotensve (n=16) : ±.54.06± ± ± ±18.3 Borderlne («=16) ±9.42 9: 145.5± ± ± ± Establshed (n=16) 34.5±9.15 9: ± ± ± ±.06 6f.34±12.33 blood pressure s assocated wth reduced pan percepton, as assessed by tooth pulp stmulaton. Unfortunately, a cutoff value for the pan threshold had to be assgned for a number of subjects. Ths made the estmaton of ths parameter less accurate and ts dstrbuton nonnormal, thus renderng t mpossble to apply standard technques for multple comparson. However, n ths study, as n that of Zamr and Shuber, 10 the sensory threshold to pulp stmulaton was elevated. lthough t cannot be ruled out that the percepton of other sensatons besdes pan are reduced n hypertenson, most evdence ndcates that, from a sensory pont of vew, the human tooth s an exclusvely nocceptve system and that both pan and the so-called prepan elcted by electrcal stmulaton are medated by the same type of afferents. 26 The fndng of a strong correlaton between sensory and pan thresholds observed for the pooled data s also n keepng wth a close functonal relaton of the two measurements. In ths study dfferent subgroups of normotensve subjects were nvestgated to exclude the possble confoundng effects due to the choce of control groups. Taken together, our results suggest that the dfferences observed between normotensve and hypertensve subjects were not due to the selecton of the control group, although they ndcate that nonneglgble dfferences n pan senstvty may be present between dfferent control groups. n ncreasng amount of anatomcal, physologcal, and pharmacologcal evdence supports the exstence of a relatonshp between cardovascular TBLE 4. Effect of nthypertensve Treatment on Blood Pressure and Pan Senstvty Treatment Basal 0-blocker Basal Duretcs Basal Low salt det No. of subjects rteral blood pressure (mm Hg) /100±8 146±ll*/92±6t 142±12/ ±ll/91±8t 146±/92±12 141±15/85±12 and pan regulatory systems and, n partcular, a relatonshp between arteral blood pressure and pan modulaton.' natomcal and physologcal studes have shown that the bran stem areas partcpatng n the regulaton of blood pressure and those nvolved n the modulaton of pan transmsson are closely assocated or may even partally overlap behavoral hypalgesa has been reported by several authors n SHR. 2 ~ 9 On the other hand, t s less clear whether expermentally nduced hypertenson also s assocated wth hypalgesa. In fact, varous authors have reported a reduced nocceptve responsveness n anmals after long-term 2-3 and shortterm 30 ncreases n arteral blood pressure were nduced, whereas Stsen and de Jong 8-9 dd not observe such changes n rats wth renal deoxycortcosterod acetate-salt hypertenson. lthough the underlyng mechansms responsble for ths form of hypertenson-assocated hypalgesa reman to be fully dentfed, several mportant aspects have been elucdated n recent years. The observaton that ths hypalgesa can be suppressed n the expermental anmal by naloxone, but not by ts exclusvely perpherally actng analogue, V-methyl-naloxone, 8 clearly ndcates an nvolvement of the endogenous opod systems wthn the central nervous system. However, the effect of these systems on the development and mantenance of hypertenson s less clear. 13 Interestngly, a role for the opod peptdes has been supported by several studes, both n anmals and n humans, n the medaton of the hypotensve effect nduced by central a-adrenergc receptor actvaton The relevance of these obser- Sensory threshold (U) 42±5 41±8 38±5 38±8 40±6 3±9 Pan threshold (U) 60±13 60±15 60±10 55±15 63±9 58±13 Values are means ± SD. U = arbtrary unts. *t = 4.23, p < 0.01; tf = 3.08, p < 0.02; ft = 2., p < 0.05; / = 2.6, p < 0.02 (by pared t test for arteral blood pressure and sensory threshold and by Wlcoxon test for pan threshold).

6 4% HYPERTENSION VOL 12, No 5, NOVEMBER 1988 vatons n the fndng of hypertenson-assocated hypalgesa n humans remans to be establshed. further aspect of possble mportance s represented by the role of the carotd snus and cardopulmonary baroreceptor pathways. In fact, hypalgesa can be nduced by baroreceptor actvaton n the hypertensve rat, 30 and t can be attenuated by carotd snus baroreceptor denervaton and by reducng the cardopulmonary baroreceptor afferent nput. 6 s ponted out by Zamr and Maxner 1 n a recent revew, actvaton of baroreceptor afferents may play an mportant part n hypertenson-assocated hypalgesa, and ths mechansm may represent part of an adaptve somatosensory response of the body to stressful events. Snce the majorty of patents n ths study had essental hypertenson, our study provdes no ndcaton as to whether reduced pan percepton s a characterstc feature of essental hypertenson or whether t s also present n secondary forms. On the other hand, the fndng that a reduced percepton to pan s already present n borderlne hypertenson and does not appear to ncrease n establshed hypertenson suggests that hypalgesa s not smply related to the extent of the blood pressure elevaton. The observaton that reductons of arteral blood pressure by varous treatments apparently are not assocated wth changes n pan senstvty, as observed n our study, lends support to ths suggeston. Ths fndng confrms the observatons of Stsen and de Jong, 8 who reported that the dmnshed responsveness to noxous stmul n SHR was not altered by long-term treatment wth hydralazne or captoprl, and of Morley et al., 31 who reported elevated pan tolerance to graded electrcal stmulaton of the fnger n dabetc patents treated for hypertenson and normotensve at the tme of the study, as compared wth nonhypertensve dabetcs. Furthermore, t s nterestng to observe that young SHR wth moderately elevated blood pressure levels have a smlarly reduced pan senstvty as compared wth adult SHR wth a much hgher arteral pressure. 4-6 Taken together these fndngs suggest that, at least n humans, hypalgesa s a feature of hypertenson rrespectve of the prevalng blood pressure levels. On the other hand, hypalgesa does not seem to be present n the so-called prehypertensve state. In fact, we were unable to demonstrate an assocaton between the predsposton to hypertenson (as assessed by the reported famly hstory) and hypalgesa. Whether ths observaton ndcates an actual absence of hypalgesa n hypertenson-prone subjects as compared wth non-hypertenson-prone subjects or whether t merely reflects our nsuffcent ablty to dentfy subjects predsposed to become hypertensve s unclear and requres further study. References 1. Zamr N, Maxner W. The relatonshp between cardovascular and pan regulatory systems. nn NY cad Sc 1986; 46: Zamr N, Segal M. Hypertenson-nduced analgesa: changes n pan senstvty n expermental hypertensve rats. Bran Res 199;160: Zamr N, Smantov R, Segal M. Pan senstvty and opod actvty n genetcally and expermentally hypertensve rats. Bran Res 1980;184: Saavedra JM. Naloxone reversble decrease n pan senstvty n young and adult spontaneously hypertensve rats. Bran Res 1981;209: Wendel OT, Bennett T. The occurrence of analgesa n an anmal model of hypertenson. Lfe Sc 1981 ;29: Maxner W, Touw KB, Brody MJ, Gebhart GF, Long JP. Factors nfluencng the altered pan percepton n the spontaneously hypertensve rat. Bran Res : Fredman R, Murphy D, Persons W, McCaughran J. Genetc predsposton to hypertenson, elevated blood pressure and pan senstvty: a functonal analyss. Behav Bran Res 1984;12: Stsen JM, de Jong W. Observatons on pan percepton and hypertenson n spontaneously hypertensve rats. Cln Exp Hypertens [] 1984;6: Stsen JM, de Jong W. Hypoalgesa n genetcally hypertensve rats (SHR) s absent n rats wth expermental hypertenson. Hypertenson 1983^: Zanr N, Shuber E. ltered pan percepton n hypertensve humans. Bran Res 1980^01: Ghone S, Rosa C, Panatton E, Nut M, Mezzasalma L, Gulano G. Comparson of sensory and pan threshold n tooth pulp stmulaton n normotensve man and essental hypertenson. J Hypertens 1985;3(suppl 3):S3-S5 12. Rosa C, Ghone S, Panatton E, Mezzasalma L. Comparson of pan percepton n nonnotensves and borderlne hypertensves by means of a tooth pulp stmulaton test. J Cardovasc Pharmacol 1986;8:S125-S Feuersten G, Sren L. The opod peptdes: a role n hypertenson? Hypertenson 198^: Lang RE, Bruckner UB, Kempf B, et al. Opod peptdes and blood pressure regulaton. Cln Exp Hypertens [] 1982; 4: Khachaturan H, Lews ME, Schafer MKH, Watson SJ. natomy of the CNS opod systems. Trends Neurosc 1985; 8: Farsang C, Kapocs J, Vajda L, et al. Reversal by naloxone of the anthypertensve acton of clondne: nvolvement of the sympathetc nervous system. Crculaton 1984;69: Kunos G, Farsang C, Ramrez-Gonzalez MD. 0-Endorphn: possble nvolvement n the anthypertensve effect of central alpha-receptor actvaton. Scence 1981;2: Byers MR, Neuhaus SJ, Gehrg JD. Dental sensory receptor structure n human teeth. Pan 1982;13: nderson DJ, Hannam G, Matthews B. Sensory mechansms of mammalan teeth and ther supportng structures. Physol Rev 1982,50: hlqust ML, Edwall LG, Franzn OG, Haegerstam GT. Percepton of pulpal pan as a functon of ntradental nerve actvty. Pan 1984;19: Edwall L, Olgart L. new technque for recordng of ntradental sensory nerve actvty n man. Pan 193: Seltzer S, Stoch R, Marcus R, Jackson E. lteraton of human pan thresholds by nutrtonal manpulaton and L- tryptophan supplementaton. Pan 1982;13: Chapman CR, Chen C, Bonca JJ. Effects of ntrasegmental electrcal acupuncture on dental pan: evaluaton by threshold estmaton and sensory decson theory. Pan 19^: Chapman CR, Wlson ME, Gehrg JD. Comparatve effects of acupuncture and transcutaneous stmulaton on the percepton of panful dental stmul. Pan 196;2: rteral hypertenson: report of WHO Expert Commttee. WHO Tech Rep Ser 198;no Brown E, Beeler WJ, Kloka C, Felds RW. Spatal summaton of pre-pan and pan n human teeth. Pan 1985; 21: Korner PI. Integratve neural cardovascular control. Physol Rev 191^1:312-36

7 HYPLGESI IN HYPERTENSION/G//one et al Loewy D, McKellar S. The neuroanatomcal bass of central cardovascular control. Fed Proc 1980^39: Felds HL, Basbaum I. Branstem control of spnal pan transmsson neurons. nnu Rev Physol 198;40: Dworkn BR, Flewch RJ, Mller NE, Cragmyle N, Pckerng TG. Baroreceptor actvaton reduces reactvty to noxous stmulaton: mplcatons n hypertenson. Scence 199:205: Morley GK, Mooradan D, Levne S, Morley JE. Mechansm of pan n dabetc perpheral neuropathy: effect of glucose on pan perceptons n humans. m J Med 1984;: 9-82