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