Physiological Psychology 1983, Vol. 11 (3),214-220 Activation of the sinoaortic baroreceptor reflex arc induces analgesia: Interactions between cardiovascular and endogenous pain inhibition systems
ALAN RANDIeH and eERIe HARTUNIAN University ojIowa, Iowa City, Iowa Two experiments examined the view that activation of the sinoaortic baroreceptor reflex arc induces analgesia. Rats were instrumented with carotid artery and jugular vein cannulae for measurement of arterial blood pressure, central venous blood pressure, and heart rate during assays of pain sensitivity using tail-flick responses to radiant heat. In Experiment 1, increases in arterial blood pressure effected by infusion of phenylephrine resulted in profound analgesia that persisted for a 28-min observation period following termination of the infusion. During the phenylephrine infusion period, the degree of analgesia was significantly correlated to the degree of reflex bradycardia, but was not significantly correlated to changes in either arterial or venous blood pressure. In Experiment 2, increases in arterial blood pressure effected by in fusion of phenylephrine failed to induce analgesia in rats with bilateral sinoaortic deafferenta tions, indicating that activation of the sinoaortic baroreceptor reflex arc is required for this form of analgesia. As in Experiment 1, reflex bradycardia, rather than increases in arterial blood pressure, was correlated with analgesia. These outcomes are consistent with the view that sys tems involved in the regulation of blood pressure are physiologically linked to systems involved in the regulation of pain. The implications of these findings for the etiology of hypertension are discussed.
Administration of sympathomimetic compounds Gebhart, & Long, 1982; Randich, 1982; Randich & induces a reduction in pain sensitivity, or analgesia, Maimer, 1981; Zarnir & Segal, 1979; Zarnir, Simantov, in a variety of species, including humans (Fellows & Segal, 1980). Specifically, it is possible that ac & Ullyot, 1951; Goetzl, Burrill, & Ivy, 1944; Randall tivation of the sinoaortic baroreceptor reflex arc re & Selitto, 1958; Witkin, Heubner, Galdi, O'Keefe, sulting from sympathomimetic-induced increases in Spitalletta, & Plummer, 1961). For instance, subcu arterial blood pressure is capable of engaging en taneous administration of norepinephrine, meth dogenous pain inhibition systems. This view is sup oxamine, methamphetamine, or 2-aminoindane in ported indirectly by a number of experimental find duces analgesia in rats and mice as assayed by the ings. First, peripheral administration of phenyle inflamed foot, writhing, or hot-plate tests of pain phrine in doses capable of increasing arterial blood sensitivity (Colville & Chaplin, 1964; Little & Rees, pressure attenuates wheel-turn escape/avoidance 1978). In general, these studies have favored the view responding produced by aversive trigeminal stimula that central, rather than peripheral, actions of sym tion in rats, but this attenuation effect does not occur pathomimetic compounds are responsible for the following bilateral sinoaortic deafferentation analgesia, an interpretation consistent with known (Dworkin, Filewich, Miller, Craigmyle, & Pickering, central adrenergic mechanisms of pain inhibition 1979). Second, bilateral sinoaortic deafferentation (see Harvey & Simansky, 1981). lowers the threshold for both flinch and jump re However, an alternative mechanism of action of sponses to an electric shock stimulus in spontane some sympathomimetic compounds is suggested by ously hypertensive rats (SHRs) and Wistar-Kyoto recent demonstrations that genetic, renal, and DOCA (WKYs) normotensive rats (Randich, 1982). Third, salt hypertensive rats manifest analgesia in some as treatments that lower arterial blood pressure in hy says of pain sensitivity (Maixner, Touw, Brody, pertensive rats, for example, administration of hex amethonium in SHRs (Maixner et aI., 1982) or re moval of the stenotic kidney in renal hypertensive This research was supported by an N_LH_ grant (NSI834l) to rats (Zamir & Segal, 1979), are associated with a loss A_ Randich. We gratefully acknowledge the technical and secre of analgesia. Finally, Maixner and Randich (Note 1) tarial help provided by P. Nichols and M. Bowersox, respectively. The authors' mailing address is: Department of Psychology, Uni demonstrated that elevations in central venous pres versity of Iowa, Iowa City, Iowa 52242. sure by a volume loading procedure induces a pro-
214 Copyright 1983 Psychonomic Society, Inc. BLOOD-PRESSURE-INDUCED ANALGESIA 215 found, long-lasting analgesia in rats. These authors constant for all subjects, was adjusted to produce a tail-flick re argued that activation of low-pressure cardiopul sponse of approximately 3-4 sec in a normal rat. Arterial blood pressure, heart rate, and central venous blood monary baroreceptors is a sufficient condition for pressure were recorded on a Beckman RIIA rectilinear dynagraph. the production of analgesia. Although this experi The arterial blood pressure signal was transduced by a Century ment does not bear directly upon the role of arterial pressure transducer, and the venous blood pressure signal was blood pressure in modulating pain sensitivity, it is transduced by a Statham pressure transducer. consistent with the more general proposal that sys Suqical teebalques. Each rat was anesthetized with Equithesin (3 rat/kg). An incision was made in the pectoral region 1 cm to tems involved in cardiovascular regulation are physio the right of the midventralline and extending 2 cm craniad from logically linked to systems modulating pain percep the pectoralis. The external jugular vein was exposed at its junc tion. tion with the right subclavian vein, and the connective tissue sur The purpose of the present experiments was to as rounding the area was cleared. A cannula (Silastic) was inserted caudad through the brachiocephalic vein approximately 4 cm. sess directly the view that increases in arterial blood The cannula was anchored to adjacent tissue. pressure and concomitant activation of the sinoaortic A 3-cm midventral incision was then made in the cervical re baroreceptor reflex arc are capable of activating en gion. Dissection continued until the underlying sternocleido dogenous pain inhibition systems. In these experi mastoid group was exposed. The left sternomastoid was displayed ments, increases in arterial blood pressure were pro laterally, and the deeper omohyoid was cut at right angles to its fiber direction. The left common carotid artery was then separated duced by infusions of phenylephrine and pain sensi from the surrounding tissues and nerves. A cannula was advanced tivity was assayed by tail-flick responses to radiant caudad 3-4 cm and anchored to adjacent muscles (Micro-line). heat. Arterial blood pressure, central venous blood The arterial and venous cannulae were then drawn subcutane pressure, and heart rate were recorded during all ously around the neck and exited through a dorsal incision. The phases of the experiment. Experiment 1 examined cannulas were anchored to the neck and flushed with a saline heparin solution. whether increases in arterial blood pressure induced Testing. All rats were allowed a minimum of 1 day of recovery analgesia in normal rats. Experiment 2 examined prior to testing. Each rat was then placed in a Plexiglas restrain whether phenylephrine-induced analgesia was a con ing tube, and the cannulas were connected to the pressure trans sequence of arterial pressure activation of the sino ducers and an infusion pump (Harvard Apparatus 941). Saline was then infused through the venous cannula, and initial base aortic baroreceptor reflex arc by assessing pain sen line tail-flick latencies were obtained every 2 min. sitivity in rats with either sham operations or bilateral Following stabilization of the tail-flick response, phenylephrine sinoaortic deafferentations. (1 mg/ml) was infused through the venous cannula at rates rang ing from 24 to 192 ",g/min. Tail-flick trials were presented every EXPERIMENT 1 2 min, and the infusion procedure continued until the rat exhibited a tail-flick latency of no more than 10 sec. When a 100sec latency was obtained, the infusion procedure was stopped and tail-flick In Experiment I, rats were implanted with a right trials were administered across a 28-min observation period. Trials jugular vein cannula, for administration of phenyle were administered every I min during the first 10 min of the ob phrine and recording of central venous pressure, and servation period and every 3 min during the remaining 18 min of the observation period. Arterial blood pressure, central venous a left carotid cannula, for recording of arterial blood blood pressure, and heart rate were recorded simultaneously dur pressure and heart rate. Phenylephrine was infused ing all tail-flick trials. at various rates to produce graded increases in ar Data aaalysls. Linear regression was used to analyze the data. terial blood pressure as a means of determining Alpha was set at 0.05 in all analyses. whether the degree of analgesia reflected the magni tude of the pressure increment. Measurements of Results pain sensitivity (tail-flick) to a radiant heat stimulus Arterial blood pressure, heart rate, and venous were obtained every 2 min. If increases in arterial blood pressure were recorded during the infusions of blood pressure and concomitant activation of the phenylephrine and tail-flick trials. The changes in sinoaortic baroreceptor reflex arc induce analgesia, each of these measures from the initial baseline values then the rats should show reductions in tail-flick re obtained during the infusions of saline were com sponse latencies in proportion to increases in arterial pared with changes in tail-flick latencies from their pressure. initial baseline values. The results of these correla tional analyses indicated that (1) there was no signif Method cant correlation between increases in tail-flick laten Subjects. Six male Sprague-Dawley rats obtained from Hor cies from baseline and increases in arterial blood mone Assay Laboratories in Chicago served as subjects. The rats were individually housed in wire-mesh cages in a colony room pressure [r= .13; F(l,61)= 1.05], (2) there was a sig under a 12:12 h light-dark cycle. Food and water were available nificant correlation between increases in tail-flick in the home cages on an ad-lib basis. latencies and decreases in heart rate [r = .25; F(I,61) Apparatus. Nociceptive responses were measured with a tail = 3.35], and (3) there was no significant correlation flick apparatus. The radiant heat stimulus was produced by a 35- between increases in tail-flick latencies and increases rom proj~or bulb housed in a metal casing and focused on the rat's tail through a small opening in the metal housing. Onset and in venous pressure [r= .07; F(1,60)=0.34]. A sep termination of each trial were controlled automatically by a digital arate analysis of variance on the integrity of the baro timer. The intensity of the radiant heat stimulus, which was receptor reflex arc indicated a significant correlation 216 RANDICH AND HARTUNIAN between decreases in heart rate and increases in ar cardiovascular responses (changes from baseline) terial blood pressure [r = .77; F(I,61) = 73.79]. during this observation period. The top panel of Infusions of phenylephrine in two of the six rats Figure 1 shows that mean tail-flick latencies remained were terminated in midcourse because of loss of a elevated above baseline values during the entire 28- signal. The remaining four rats all achieved the max min observation period. A randomized block analy imum response of a IO-sec tail-flick latency indicat sis of variance also indicated that there were no sig ing profound analgesia. At this point, the infusion nificant reductions in tail-flick latencies during the procedure was terminated and tail-flick latencies and observation period [F(l ,46) = 1.81], although there cardiovascular variables were recorded during the 28- was a trend towards a decrease in tail-flick latencies min observation period. Figure 1 presents changes in with time. The second panel of Figure 1 shows that mean tail-flick latencies (absolute values) and mean mean arterial blood pressure rapidly returned to baseline or below baseline values following termina tion of phenylephrine infusion before stabilizing. 10 There was a significant decrease in arterial blood 9 pressure during the observation period [F(l ,46) = ¥ 8 6.18J. The third panel of Figure 1 shows that mean .!!!. 7 heart rate did tend to normalize following termina >- c 6 tion of phenylephrine infusion but that, similar to !" to 5 tail-flick responses, there were no significant changes ~ .. 4 in heart rate during the 28-min observation period "~ • u:: 3 [F(l,40)= 1.19]. Thus, both increases in tail-flick "; I- 2 latencies and bradycardia far outlast changes in ar terial pressure. Finally, the bottom panel of Figure 1 indicates that there were only small increases in ve o Baseline 0 2 4 6 8 10 13 16 19 22 25 28 nous pressure produced by phenylephrine, and a ran :z:$ 50 domized block analysis of variance indicated no sig E 40 .§. nificant changes in venous pressure during the ob !,. 30 servation period [F(1 ,46) = 1.72]. .. 20 ! 10 Q. Discussion iii 0 • T --. Experiment 1 demonstrates that administration of ! -10 ~. phenylephrine produces a profound, long-lasting c 10 concomitant activation of the sinoaortic barore 9 ceptor arc, and neither a central effect of phenyle i 8 phrine nor some nonspecific drug effect. .e,.. 7 u As noted in Experiment 1, the degree of analgesia c 6 ! during phenylephrine infusion was significantly cor .. 5 ...J ... 4 related with reflex bradycardia and not with increased .!! • arterial pressure. Indeed, using a low constant rate ...iL 3 .... 2 of infusion made it possible for some sham-operated 1 rats to regulate arterial blood pressure at a near nor 0~B~a~se~lin-e~0--~-2~~3~~4--~5--6~~7~~8--~9~10 mal value through steady decreases in heart rate. 70 Finally, sham-operated rats all manifested pro ~ 60 found analgesia similar to that reported in Experi E 50 ment 1. The analgesia persisted in an undiminished .§. 40 ! form during the to-min observation period, while .,ill 30 arterial blood pressure rapidly returned towards ...! 20 baseline values. Only the bradycardia response was iii 10 sustained during the to-min observation period. The "i 0 • implications of this will be discussed later. ~ -10 10 Baseline 0 2 3 4 5 6 7 8 9 10 a central or a nonspecific effect of phenylephrine was demonstrated by the failure of rats with bilateral la 1 SADs to show any consistent increases in tail-flick ,;:::&:~ 2~ ~ ~ 0 • latencies with increases in arterial blood pressure, when the magnitude of the pressure increases were !--1_ I ~~ : : ;:: Experiment 2 showed elevations in tail-flick latencies since resection of the right vagal nerve trunk not only while maintaining arterial blood pressure at near attenuated the analgesic response, but also eliminated normal values during infusions of phenylephrine. the correlation between increases in venous pressure However, the baroreceptor reflex arc appeared to be and the magnitude of analgesia. Collectively, these engaged, since steady decreases in heart rate were findings suggest that endogenous pain inhibition sys observed. Thus, we would expect arterial blood pres tems receive multiple inputs from cardiovascular reg sure to be related to the degree of analgesia only ulatory mechanisms, although it is unclear whether when these correctional mechanisms are fully en low-pressure vagal afferents and high-pressure sino gaged but failing to adequately lower arterial blood aortic afferents converge on the same neuronal pool pressure. to induce analgesia. There were several instances in which tail-flick la Finally, it is important to consider whether altera tencies were not elevated despite profound hyper tions in pain sensitivity are important for the etiology tension and bradycardia. This indicates that factors of hypertension. Other studies (Maixner et al., 1982; other than simple activation of the sinoaortic baro Randich, 1982) have shown that resection of the right receptor reflex arc contribute to the production of vagal nerve trunk but not bilateral SAD eliminates the analgesia. Factors such as the total peripheral the analgesia manifested by SHRs in the hot-plate resistance, the rate of arterial pressure increase, baro assay of pain sensitivity. Although these outcomes receptor gain, baroreceptor threshold, and the length suggest that changes in central venous pressure rather of time arterial pressure is elevated should be con than arterial blood pressure are critical for the anal sidered. Moreover, the analgesic response was main gesia manifested by SHRs, the bilateral SADs were tained over a 28-min observation period following carried out after the development of hypertension. termination of the infusion of phenylephrine and at Thus, it is possible that initial increases in arterial a time when arterial blood pressure was at normal blood pressure during the development of hyperten or below normal values. Thus, it is plausible to as sion contribute to the production of the analgesia sume that activation of the sinoaortic baroreceptor through the mechanisms elucidated in the present reflex arc may "trigger" the release of some long experiments. lasting peptide or hormone to produce this analgesia. On the other hand, it is useful to consider whether The present experiments did not address the in interactions between systems involved in the regula volvement of opioids, but it is possible that the "read" tion of blood pressure and endogenous pain inhibi for the analgesic response is in some fashion related tion are important for the etiology of hypertension. to structures subserving the opioid-modulated con In this view, increases in either arterial or venous trol of either vagal or sympathetic tone, since brady blood pressure could provide a short-term active cardia is often associated with analgesia. The admin coping response to stress, since reductions in pain istration of morphine-like agents and opioid peptides sensitivity and possible associated motivational ef have been shown to increase vagal tone, reduce sym fects, for example, sedation, would represent some pathetic tone, and induce a long-lasting analgesia. form of psychophysiological reflief from stress. En Possible sites of action of these agents include the gaging these mechanisms might serve to reinforce the nucleus of the solitary tract, nucleus gigantocellularis increase in blood pressure through conditioning and reticularis, and nucleus ambiguus (Chan & Kuo, learning mechanisms, and make them more likely 1980; Chen & Chan, 1980; Feldberg & Wei, 1977; to occur either in advance of or under similar stim Florez & Mediavilla, 1977; Laubie & Schmitt, 1981; ulus situations in the future. Thus, an animal may Laubie, Schmitt, Canellas, Roquebert, & Desmichel, learn to increase blood pressure as a means of coping 1974; Lemaire, Tseng, & Lemaire, 1978). with stress, but this eventuates in sustained hyper There are also interesting parallels between the tension leading to deleterious cardiovascular func outcomes of the present experiments and those of tioning. Maixner and Randich (Note 1). In the latter experi ment, analgesia was induced by a volume-loading REFERENCE NOTE procedure in which Ficoll (a volume expander) was 1. Maixner. W .• & Randich. A. The role of the right vagal nerve infused into the right jugular vein. This volume trunk in antinociception. Manuscript submitted for publication. loading procedure resulted in an increase in central 1983. venous pressure, reflex bradycardia, mild hypoten sion, and analgesia as assayed by the tail-flick re REFERENCES sponse. The magnitude and duration of both the CHAN. S. H. H., & Kuo. J. S. Interaction of gigantocellular analgesia and reflex bradycardia were similar to reticular nucleus with reflex bradycardia and tachycardia in those observed in the present experiments. Maixner the cat. Brain Research. 1980. 111.457-460. CHEN. Y. H .• & CHAN. S. H. H. The involvement of gigantocellu and Randich (Note 1) argued that the effective stim lar reticular nucleus in clonidine-promoted hypotension and ulus for the analgesia obtained with the volume bradycardia in experimentally-induced hypertensive cats. Neuro loading procedure was activation of vagal afferents, pharmacology. 1980.19.939-945. 220 RANDICH AND HARTUNIAN COLVILLE, K. I., & CHAPLIN, E. Sympathomimetics as anal LEMAIRE, I., TSENG, R., & LEMAIRE, S. Systemic administration gesics: Effects of methoxamine, methamphetamine, metaram of B-endorphin: Potent hypotensive effect involving a sero inol, and norepinephrine. Life Sciences, 1964, 3, 315-322. tonergic pathway. Proceedings of the National Academy of DWORKIN, B. R., FILEWICH, R. J., MILLER, N. E., CRAIGMYLE, Science, 1978,75,6240-6242. N., & PICKERING, T. G. Baroreceptor activation reduces re LITTLE, H. J., & REEs, J . M. H. Naloxone antagonism of sym activity to noxious stimulation: Implications for hypertension. pathomimetic analgesia. In J. M. Van Ree & L. Terenius (Eds.), Science, 1979, 2OS, 1299-1301. Characteristics and functions of opioids. Amsterdam: Elsevier FELDBERG, W., & WEI, E. The central origin and mechanism of North Holland Biomedical Press, 1978. cardiovascular effects of morphine as revealed by naloxone in MAIXNER, W., Touw, K. B., BRODY, M. J., GEBHART, G. F., cats. Journal of Physiology (London), 1977,272,99-100. & LONG, J. P. Factors influencing the altered pain perception FELLOWS, E. J., & ULLYOT, G. E. Analgesics: A. Aralkylamines. in the spontaneously hypertensive rat. Brain Research, 1982, In C. M. Suter (Ed.), Medicinal chemistry. New York: Wiley, 237,137-145. 1951. RANDALL, L. 0 ., & SELITTO, J. J. Anti-inflammatory effect of FLOREZ, J ., & MEDIAVILLA, A. Respiratory and cardiovascular Romilar CF. Journal of the American Pharmacological Asso effects of metenkephalin applied to the ventral surface of the ciation, 1958,47,313-314. brainstem. Brain Research, 1977, 131, 585-590. RANDlCH, A. Sinoaortic baroreceptor reflex arc modulation of GOETZL, F. R., BURRILL, D. Y., & Ivy, A. C. The analgesic ef nociception in spontaneously hypertensive and normotensive fect of morphine alone and in combination with dextroamphet rats. Physiological Psychology, 1982, 10, 267-272. amine. Proceedings of the Society of Experimental Biology and RANDlCH, A., & MAdtNER, W. Acquisition of conditioned sup Medicine, 1944,55,248-250. pression and responsivity to thermal stimulation in spontane HARVEY, J. A., & SIMANSKY, K. J. The role of serotonin in ously hypertensive, renal hypertensive and normotensive rats. modulation of nociceptive reflexes. In B. Harber (Ed.), Sero Physiology &: Behavior, 1981,27,585-590. tonin: Current aspects of neurochemistry and function. New WITKIN, L. B., HEUBNER, C. F., GALDI, F., O'KEEFE, E., York: Plenum Press, 1981. SPITALLETTA, P., & PLUMMER, A. J . Pharmacology of 2- KRIEGER, E. M. Neurogenic hypertension in the rat. Circulation amino-indane hydochloride (SU-8629): A potent non-narcotic Research, 1964, 15, 511-521. analgesic. Journal of Pharmacology and Experimental Ther LAUBIE, M., & SCHMITT, H. Sites of the vagally mediated brady apeutics, 1961,133,400-408. cardia induced by morphine-like agents and opioid peptides. ZAMIR, N., & SEGAL, M. Hypertension induced analgesia: In J. P. Buckley, C. M. Ferrario, & M. F. Lokhandwala (Eds.), Changes in pain sensitivity in experimental hypertensive rats. Perspectives in cardiovascular research: Central nervous system Brain Research, 1979,201,170-173. mechanisms in hypertension (Vol. 6). New York: Raven Press, ZAMIR, N., SIMANTOV, R., & SEGAL, M. Pain sensitivity and 1981 . opioid activity in genetically and experimentally hypertensive LAUBIE, M., SCHMITT, H., CANELLAS, J., ROQUEBERT, J., & rats. Brain Research, 1980, 184,299-310. DESMICHEL, P. Centrally mediated bradycardia and hypoten sion induced by narcotic analgesics: Dextromoramide and (Manuscript received April 11, 1983; fentanyl. European Journal of Pharmacology, 1974, 21,66-75. revision accepted for publication July 25, 1983.)