Water Pressor Research Articles

A randomised, double-blind study investigating the relationship between early childhood trauma and the rewarding effects of morphine.

Experiences of childhood trauma (abuse and neglect) are disproportionately higher in those with opioid use disorder (OUD). Childhood trauma may affect the reinforcing and rewarding properties of opioid drugs and responses to pain, potentially via developmental changes to the endogenous opioid system. This has been supported by preclinical research, yet this has not been investigated in non-addicted humans. Physically healthy participants with either a history of severe childhood trauma or no previous history of childhood trauma attended two sessions where they received either an intramuscular active dose of morphine (0.15 mg/kg) or a very low dose control (0.01 mg/kg) in a randomised, double-blind crossover design. Sessions were held 1 week apart. Participants' physical pain threshold and tolerance were measured pre- and post-drug administration using the cold water pressor test, alongside acute subjective and behavioural responses over 2.5 h. The trauma group reported liking the effects of morphine, feeling more euphoric and wanting more of the drug over the session, as well as feeling less nauseous, dizzy, and dislike of the effects of morphine compared to the non-trauma comparison group. Morphine increased pain threshold and tolerance, yet this did not differ between the groups. Childhood trauma may therefore sensitise individuals to the pleasurable and motivational effects of opioids and reduce sensitivity to the negative effects, providing compelling evidence for individual differences in opioid reward sensitivity. This may explain the link between childhood trauma and vulnerability to OUD, with consequent implications on interventions for OUD, the prescribing of opioids, and reducing stigmas surrounding OUD.

Simultaneous Non‐invasive Recording of Skin Sympathetic Nerve Activity

Our research laboratory recently invented a new method (neuECG) to simultaneously and non‐invasively record electrocardiogram (ECG) and skin sympathetic nerve activity (SKNA) from humans using standard ECG patch electrodes. These methods are non‐invasive and stable over long periods of time. However, because the neuECG analyses required custom written software, these methods have not been widely used or tested by the scientific community. The purpose of the present study was to develop a method for neuECG recording and analyses using commercially available hardware and software. We used ADInstruments PowerLab to record bipolar electrical signals from the skin of thorax and arms. Wide bandwidth and high sampling rate (10,000/s) were used for recording. The data were then analyzed offline using LabChart Pro 8 software. The digitized neuECG signals are amplified and band‐pass filtered between 0.05 Hz and 150 Hz to display ECG and between 500 Hz and 1,000 Hz to show the SKNA (μV). We full‐wave rectify then integrate all digitized SKNA signals using leaky integrator with 100 ms time constant and display the results over time to simulate the display methods of microneurography (iSKNA, μV.s). For quantitative analyses, we divide the absolute sum of the voltage samples by the number of digitized samples in the chosen window to obtain the aSKNA (μV). We can also examine the distribution of the aSKNA and determine a threshold to separate baseline activity from the burst activity. As compared with the microneurography studies, the neuECG does not require invasive procedures to impale electrodes in nerves and is voltage calibrated. The latter characteristics allow investigators to compare aSKNA, iSKNA and burst duration between subjects or groups. Figure shows the actual neuECG recording. SKNA band‐pass filtered from the digitized signal was converted to iSKNA and aSKNA. Down arrows show premature ventricular contractions. The dotted line indicates the commencement of cold water pressor test that elevated the aSKNA (red double headed arrows) and heart rate. We conclude that neuECG can be recorded and analyzed using commercially‐available hardware and software. These new methods may facilitate the testing and use of this novel technology in experimental biology research.Support or Funding InformationThis study was supported in part by NIH Grants 1OT2OD028190, R01 HL139829, R56 HL71140, TR002208‐01 (Dr. Chen), R42DA043391 (Dr Everett), a Charles Fisch Cardiovascular Research Award endowed by Dr Suzanne B. Knoebel of the Krannert Institute of Cardiology (Drs. Kusayama and Everett), a Medtronic‐Zipes Endowment, and the Indiana University Health‐Indiana University School of Medicine Strategic Research Initiative (Dr. Chen).Example of actual neuECG recordingFigure 1

Cold Water Pressor Test Differentially Modulates Functional Network Connectivity in Fibromyalgia Patients Compared with Healthy Controls.

Fibromyalgia is a multifaceted chronic pain condition of unknown etiology. Conditioned pain modulation (CPM) such as cold water pressor test of the foot, is widely documented as being disrupted in patients with fibromyalgia. To date, the mechanisms underlying such dysregulation of the descending control of pain in fibromyalgia remain poorly understood. In this study, we used ICA-based network analysis to comprehensively compare differences in functional network connectivity among relevant (nonartifactual) intrinsic connectivity brain networks during the resting state before and after cold pressor test in patients with fibromyalgia and healthy controls. The results revealed significant differences in functional connectivity between the two groups that included the networks that integrate cognitive control and attention systems with memory, emotion and brainstem regions. Specifically, functional connectivity involving central executive network was absent in patients with fibromyalgia compared with controls. Patients showed significant functional connectivity changes involving subcortical and brainstem networks with the sensorimotor and dorsal attention networks. Accordingly, aberrant CPM in patients with fibromyalgia may be due to the differences in functional connectivity involving the subcortical/brainstem regions, and is facilitated by the recruitment of the dorsal attention network in lieu of the central executive network. Future research replicating the present findings with larger sample size can shed more light on neurobiology of endogenous pain modulation in fibromyalgia.

Simultaneous noninvasive recording of skin sympathetic nerve activity and electrocardiogram

Sympathetic nerve activity is important to cardiac arrhythmogenesis. The purpose of this study was to develop a method for simultaneous noninvasive recording of skin sympathetic nerve activity (SKNA) and electrocardiogram (ECG) using conventional ECG electrodes. This method (neuECG) can be used to adequately estimate sympathetic tone. We recorded neuECG signals from the skin of 56 human subjects. The signals were low-pass filtered to show the ECG and high-pass filtered to show nerve activity. Protocol 1 included 12 healthy volunteers who underwent cold water pressor test and Valsalva maneuver. Protocol 2 included 19 inpatients with epilepsy but without known heart diseases monitored for 24 hours. Protocol 3 included 22 patients admitted with electrical storm and monitored for 39.0 ± 28.2 hours. Protocol 4 included 3 patients who underwent bilateral stellate ganglion blockade with lidocaine injection. In patients without heart diseases, spontaneous nerve discharges were frequently observed at baseline and were associated with heart rate acceleration. SKNA recorded from chest leads (V1-V6) during cold water pressor test and Valsalva maneuver (protocol 1) was invariably higher than during baseline and recovery periods (P < .001). In protocol 2, the average SKNA correlated with heart rate acceleration (r = 0.73 ± 0.14, P < .05) and shortening of QT interval (P < .001). Among 146 spontaneous ventricular tachycardia episodes recorded in 9 patients of protocol 3, 106 episodes (73%) were preceded by SKNA within 30 seconds of onset. Protocol 4 showed that bilateral stellate ganglia blockade by lidocaine inhibited SKNA. SKNA is detectable using conventional ECG electrodes in humans and may be useful in estimating sympathetic tone.

The influence of water ingestion on postexercise hypotension and standing haemodynamics

In young healthy adults, postexercise hypotension (PEH) occurs after a single bout of dynamic exercise due to peripheral vasodilation. Gravitational stress may further aggravate the magnitude of PEH, thus predisposing to orthostatic intolerance. As water drinking activates sympathetic vasoconstriction, it might offset PEH via enhanced α-adrenergic vascular responsiveness. We hypothesized that water ingestion before exercise would decrease the magnitude of PEH and improve the haemodynamic reaction to active standing postmaximal exercise. In a randomized fashion, 17 healthy adults (nine men; eight women, 21·2±1·6years) ingested 50 and 500ml of water before completing resting, cycle ergometer and recovery protocols on two separate days. After exercise, measurements [arterial blood pressure (BP), heart rate and spectral heart rate variability (HRV)] were taken in the seated position followed by 5min of active standing. Compared to that seen post-50ml of water, the 500ml volume elicited an overall increase in BP (P<0·05). Nevertheless, the magnitude of PEH was not different after either volume of water. There was an overall bradycardic effect of water, and this was accompanied by increased high-frequency power (P<0·05). Finally, no BP, heart rate or HRV differences were found between conditions in response to active standing. These data suggest that, despite being well preserved after maximal exercise, the water pressor response does not affect the magnitude of PEH. They also indicate that drinking 500ml of water does not impact the BP, heart rate or HRV response to 5min of active standing during recovery postmaximal exercise.

Cardiovascular responses to water ingestion at rest and during isometric handgrip exercise

Water drinking activates sympathetic vasoconstriction in healthy young adults; however, this is not accompanied by a concomitant increase in resting blood pressure. It is not known whether the water pressor effect is unmasked by a physiological condition such as exercise. Therefore, we examined the effect of water ingestion (50 vs. 500 mL) on the cardiovascular and autonomic responses to isometric handgrip in 17 healthy participants (9 men, 8 women, aged 28.4 ± 9.7 years). Beat-to-beat blood pressure and R-R intervals were recorded in both conditions at rest (pre- and post-ingestion) and during handgrip at 30% of maximal voluntary contraction. R-R series were spectrally decomposed using an autoregressive approach. Water ingestion did not interact with the increase in mean arterial pressure (MAP) from rest to exercise, which was similar between conditions. In contrast, there was an overall bradycardic effect of water and this was accompanied by increased high frequency power (condition main effect, p < 0.05). When the differences in high frequency power between conditions were controlled for, MAP was significantly higher after drinking 500 mL of water (condition main effect, p < 0.05). In addition, water ingestion attenuated the increase in the low to high frequency power ratio from rest to handgrip (interaction effect, p < 0.05). In conclusion, the rise in blood pressure post-water ingestion is prevented both at rest and during isometric handgrip. Interestingly, this is not sustained after controlling for the enhanced vagal drive caused by water ingestion. Therefore, the mechanisms underlying this response most likely depend on reflex bradycardia of vagal origin.

Extraversion and Accuracy of Aspects of Memory for Pain in the Cold Water Pressor Test

The role of Erlebnistypus personality features were investigated in 40 healthy subjects, as defined by the Rorschach Comprehensive System by Exner, in determining accuracy in recollecting acute tonic experimental pain, induced by the Cold Water Pressor Test. Multiple-regression analysis revealed that the difference between the number of movement answers and the number of chromatic answers in the Rorschach test, an index of general Extroversion, predicted accuracy in recollecting the qualitative features of pain, defined as affective and evaluative pain scores on the McGill Pain Questionnaire. Also, Extratensive subjects were less accurate than Introversive and Ambitent participants at recollecting sensory scores. The data suggest that general extroversion may have a role in individual differences in the higher cognitive processing of pain comprising pain memory.

The pressor effect of water: mechanism and location of action

Water ingestion induces a robust, sustained pressor response in patients with baroreflex impairment and in mice with sinoaortic deafferentation (SAD). The mechanism of water's effect on blood pressure remains unknown. In order to isolate the location at which water acts, SAD mice were given water via intragastric or intraduodenal routes. In both cases a similar pressor response appeared. The presence of a pressor response following intraduodenal infusion indicates that the pharynx, esophagus, and stomach are not critical sites for water's pressor action. Administering an identical volume of physiological saline did not induce a significant pressor response. Osmolality of portal and systemic circulations was measured 15 minutes post intraduodenal water infusion and found to be 292.7 and 304.4 mOsm/kg, respectively. TRPV4 is an osmo‐sensitive cation channel found throughout the body, and has been reported to be activated under hypotonic conditions. To investigate the potential role of TRPV4 in water's pressor response, animals lacking TRPV4 were given water intraduodenally. Compared to wild type, TRPV4 ‐/‐ animals had a greatly diminished pressor response to water. We conclude that the pressor effect of water is not dependent on pharyngeal, esophageal, nor gastric mechanisms; portal osmolality is reduced following water administration; and that the TRPV4 channel is essential for water's effect.

Relationships among Eysenck's Extraversion, Rorschach's Erlebnistypus, and Tolerance of Experimental Tonic Pain (Cold Water Pressor Test)

In a group of 42 healthy volunteers the correlations between the concept of Extraversion-Introversion as defined by Eysenck and Erlebnistypus as defined by Rorschach were analysed to relate these with the tolerance of an experimentally induced tonic pain. We conducted an experimental procedure comprising a test and retest. At test the subjects were administered the Rorschach, the Eysenck Personality Inventory, the Cold Water Pressor Test, a nongraduated Visual Analogue Scale, and the Italian version of the McGill Pain Questionnaire. At retest the experimental induction of pain was measured again. At test subjects who scored higher on the EPI Extraversion scale tolerated pain longer and did not modify their performance at retest. Also, the concepts of Extroversion defined by the Rorschach test and by the Extraversion scale of the Eysenck Personality Inventory shared some psychophysiological features of higher tolerance to pain. These personality features did not influence how subjects qualitatively describe the immediate painful experience.

Effect of water drinking on sympathetic nervous activity and blood pressure

Recent studies suggest that water drinking elicits acute changes in human physiology. Water drinking profoundly increases blood pressure in patients with autonomic failure. Water drinking also increases blood pressure in quadriplegic patients, cardiac transplant recipients, and older healthy subjects, but to a lesser extent. Blood pressure does not change in healthy young subjects. More recently, water drinking was shown to increase energy expenditure. The acute changes in cardiovascular regulation and in energy expenditure with water drinking appear to be mediated through activation of the sympathetic nervous system. The sympathetic activation may involve a spinal reflex-like mechanism. The stimulus that causes the sympathetic activation is not known. The acute water pressor response can be exploited in the treatment of patients with impaired orthostatic tolerance caused by autonomic failure, postural tachycardia syndrome, or, perhaps, neurocardiogenic (vasovagal) syncope. The increase in energy expenditure with water drinking should be recognized as an important confounding variable in metabolic studies and may hold some promise as an adjunctive measure in the prevention or treatment of obesity.

Water drinking in the management of orthostatic intolerance due to orthostatic hypotension, vasovagal syncope and the postural tachycardia syndrome.

Water drinking recently has been shown to raise blood pressure in normal subjects and in patients with autonomic failure who have orthostatic hypotension. However, in normal young subjects, ingestion of approximately 500 ml has no pressor effect; but in older subjects there is an increase in blood pressure. An even greater rise in blood pressure occurs in cases with autonomic failure. The possible mechanisms responsible for the pressor response to water include neural and humoral factors; fluid redistribution also needs to be considered. This review will concentrate on the water pressor response in normal subjects and different groups of patients with autonomic diseases who have orthostatic intolerance, on the mechanisms that could be involved, and on whether this pressor response may be used in the management of orthostatic hypotension, vasovagal syncope and the postural tachycardia syndrome.

Pressor effect of water instilled via a gastrostomy tube in pure autonomic failure

Background: The oral ingestion of water increases seated blood pressure in chronic autonomic failure although the mechanisms of this effect remain unclear. Recent studies in normal subjects suggest that oropharyngeal stimulation during swallowing may be of greater importance in causing a rise in blood pressure (BP) than the gastric effects of water. We therefore assessed the haemodynamic effects of water instilled directly into the stomach via a gastrostomy tube in pure autonomic failure (PAF). Methods: The subject had longstanding (>20 years) PAF. A gastrostomy tube had been previously placed because of dysphagia. Distilled water (480 ml) was instilled in the seated position with BP and heart rate (HR) measured over the following 40 min while the subject remained seated. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were recorded intermittently every 3 min with a Dinamap automated syphgmomanometer and continuously using a Portapres device. Subsequent model flow analysis of the Portapres data provided beat-to-beat estimates of cardiac output, stroke volume, and total peripheral resistance (TPR). Subjective orthostatic symptoms were recorded before and after water. Results: Seated SBP and DBP increased after water instillation with increases first noted between 5 and 8 min after the water had been instilled. The BP remained elevated until 35 min post water increase over baseline being +36.5 mm Hg SBP and +24.3 mm Hg DBP. HR, cardiac output, and stroke volume remained unchanged during the study. Total peripheral resistance (TPR) increased post water. These results are similar to those reported in a recent study involving oral ingestion of 480 ml of water in PAF subjects. Conclusions: Instilling water directly into the stomach in a patient with PAF resulted in similar haemodynamic responses to those seen when water is taken orally. Thus, oropharyngeal factors and swallowing do not appear to be essential in the generation of the water pressor effect in autonomic failure.

Diagnosis of vasospastic angina by hyperventilation and cold-pressor stress echocardiography: Comparison to 123I-MIBG myocardial scintigraphy

Objectives: We assessed the usefulness of hyperventilation and cold-pressor stress echocardiography in the diagnosis of vasospastic angina compared with that of iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy. Background: Various noninvasive methods have been used to detect vasospastic angina, but they are not very sensitive in the diagnosis of vasospastic angina.123I-MIBG images and stress echocardiography have recently been proposed as a useful tool for detecting vasospastic angina. Method: Thirty patients (21 males and 9 females, mean age: 52 ± 14 years) who complained of rest angina were enrolled for this study. The hyperventilation and cold-pressor stress echocardiography test consisted of hyperventilation for 6 minutes, followed by cold water pressor for 2 minutes under continuous electrocardiographic and echocardiographic monitoring. Left ventricular regional wall motion by echocardiogram was analyzed by using the 16-segment model, and wall motion ranging from normokinesis to dyskinesis was evaluated visually in each segment. Single-photon emission computed tomography images of 123I-MIBG myocardial scintigraphy were divided into 26 segments. Defect scores were established using the 4 grades. The echocardiographic criteria for coronary spasm was worsening wall motion and the scintigraphic criteria was defect score more than moderately reduced. Acetylcholine was selectively injected into the right coronary artery (20 μg and 50 μg) and left coronary artery (20 μg, 50 μg, and 100 μg). Results: Of 30 patients, 20 patients had coronary spasm on coronary angiography with an intracoronary injection of acetylcholine, whereas 10 patients showed no spasm. Multivessel spasms were observed in 15 patients. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of hyperventilation and cold-pressor stress echocardiography for diagnosing in patients with vasospastic angina were 90%, 90%, 95%, 82%, and 90%, respectively. However, those of 123I-MIBG myocardial scintigraphy for diagnosing in patients with vasospastic angina were 90%, 40%, 75%, 67%, and 73%, respectively. The specificity of hyperventilation and cold-pressor stress echocardiography was significantly higher than that of 123I-MIBG myocardial scintigraphy (P <.05). Conclusion: The specificity of hyperventilation and cold-pressor stress echocardiography in diagnosing coronary spasm were higher than that shown by 201I-MIBG myocardial scintigraphy. (J Am Soc Echocardiogr 2002;15:617-23.)

Hyperventilation and cold-pressor stress echocardiography for noninvasive diagnosis of coronary artery spasm

We report the usefulness of 2-dimensional echocardiography during the cold-pressor test immediately after hyperventilation for noninvasive diagnosis of coronary vasospasm in 43 patients with suspected vasospastic angina. The stress test consisted of hyperventilation for 6 minutes, followed by cold water pressor stress for 2 minutes under continuous electrocardiographic and echocardiographic monitoring. Coronary angiography with an intracoronary injection of acetylcholine was performed within 2 weeks after the stress test. Coronary spasm was observed in 33 patients by angiography. Multivessel spasm was diagnosed in 26 patients by stress echocardiography and in 23 patients by angiography. The stress-induced wall motion abnormalities occurred earlier than the ST-segment changes and chest pain. The wall motion abnormalities shown on the echocardiogram correlated well with the vascular territories of the coronary artery that had the spasm. The sensitivity, specificity, and diagnostic accuracy of hyperventilation and cold-pressor stress echocardiography for detecting vasospastic angina against coronary angiography with an intracoronary injection of acetylcholine were 91%, 90%, and 91%, respectively. However, the sensitivity, specificity, and diagnostic accuracy of hyperventilation and cold-pressor stress electrocardiography for detecting vasospastic angina were 48%, 100%, and 60%, respectively. No major side effects were observed during or after the stress test. Echocardiographic monitoring during the stress test detected spasm unaccompanied by either ST- segment changes or chest pain and revealed the location of multivessel coronary spasm. Hyperventilation and cold-pressor stress echocardiography is thus a noninvasive and useful tool for the diagnosis of vasospastic angina. (J Am Soc Echocardiogr 2001;14:626-33.)

Tonic pain: a SPET study in normal subjects and cluster headache patients

Whether the pathogenesis of cluster headache (CH) is peripheral or central is still matter of debate. An involvement of central structures related to pain perception and modulation, which also causes an alteration of the physiological pattern of pain perception in CH, has been hypothesized. We investigated the pattern of brain response to pain in normal subjects and CH patients by evaluating the cerebral blood flow (CBF) changes using an experimental model of tonic aching pain stimulation, the cold water pressor test (CWPT). CBF was assessed quantitatively by the Xe-133 inhalation method and single photon emission tomography (SPET), at rest and during CWPT, as previously described ( Di Piero et al., 1994). CWPT was performed in 12 volunteers and in seven patients with CH. All the CH patients had a left-sided headache and were studied in a headache-free phase out of the cluster period. During CWPT, volunteers showed a significant CBF increase in the contralateral primary sensorimotor ( P<0.001), frontal ( P<0.01) and temporal ( P<0.002) regions and thalamus ( P<0.01) and in the ipsilateral temporal ( P<0.005) and anterior cingulate ( P<0.01) regions. During left-hand stimulation (ipsilateral to the headache side) by CWPT in CH patients, CBF changes were significantly lower than those observed in volunteers in the contralateral primary sensorimotor region ( P<0.0005) and thalamus region ( P<0.01). There were no significant differences in the brain response observed during the stimulation of the hand contralateral to the headache side. In conclusion, in a headache-free phase out of the cluster period, the pattern of cerebral activation during tonic pain stimulation of the hand ipsilateral to the headache side is critically modified in CH patients in areas which are probably involved in the detection of the stimulus intensity. This modification may reflect a marker of a biological modification of the pain conveyance system. The fact that it is also present out of the active period of the disease, suggests a possible involvement of central tonic pain mechanisms in the pathogenesis of CH.

Quantitative EEG modifications during the cold water pressor test: hemispheric and hand differences

In a study designed to investigate the neurophysiological correlates of the Cold Water Pressor Test, a standardized experimental model of tonic pain, spectral EEGs were examined during the test in 15 young right-handed adults. Each subject performed a “cold water” and a “warm water” session. The subject immersed in cold water (0°C) either the right or the left hand alone, in a randomized way. EEG activity was recorded for an initial 3 min baseline and for the first and second minute epochs after immersion. A further EEG recording was obtained after a 30-min rest. Pain intensity was measured with a visual analogue scale. The EEG recordings showed several patterns of cortical activation during the test. Alpha 2 desynchronization was more evident on the contralateral parietal electrodes of the stimulated hand and lasted longer over all the right hemisphere. Delta activity increased bilaterally, predominantly in the frontal leads. Stimulation of the left hand resulted in a higher delta increase during the second minute after immersion.