Comparable Conditioned Pain Modulation and Painful-Exercise-Induced Hypoalgesia in Healthy Young Adults: A Randomized Crossover Trial.

Conditioned pain modulation and exercise-induced hypoalgesia reflect inhibitory pain controls emanating from the brain. The aim of this study was to compare the extent of pain inhibition from exercise-induced hypoalgesia (isometric wall squat), conditioned pain modulation (cold-water immersion), and their combination (wall squat followed by cold water in fixed order) in healthy pain-free adults. Sixty-one participants (median age 21 years) completed 3 sessions (wall-squat, cold-water, and combined) in random order. Sessions were separated by at least a week. In each session, pressure-pain thresholds, single-pinprick-pain ratings, and pinprick-temporal summation of pain (the fifth minus the first) were obtained at quadriceps, forearms, and forehead, before and after wall squat and/or cold water. Each intervention inhibited pain to pressure (partial η2 = .26) and single pinprick (partial η2 = .16) to a similar extent; however, pressure-pain inhibition was negligible in the forehead. After adjusting for age and sex, single-pinprick-pain inhibition in the forehead induced by wall squat was associated with that induced by cold water (adjusted R2 = .15; P = .007), and stronger pain inhibition was predicted by a higher thigh-pain rating to wall squat (adjusted R2 = .10; P = .027). Neither intervention affected pinprick-temporal summation of pain. Together, the findings suggest that pain-inhibitory effects of exercise-induced hypoalgesia and conditioned pain modulation may overlap when exercise is at least moderately painful (6/10 intensity). Pressure pain in body regions remote from the exercised or conditioned sites may be weakly modulated. PERSPECTIVE: The current findings suggest that pain-inhibitory effects induced by painful wall squat and by cold-water immersion may overlap. The magnitude of pain inhibition in the forehead remote from the exercised thigh or the conditioned foot appears smaller, which could be examined further in future research.

The impact of different music genres on pain tolerance: emphasizing the significance of individual music genre preferences.

Music is a promising (adjunctive) treatment for both acute and chronic pain, reducing the need for pharmacological analgesics and their side effects. Yet, little is known about the effect of different types of music. Hence, we investigated the efficacy of five music genres (Urban, Electronic, Classical, Rock and Pop) on pain tolerance. In this parallel randomized experimental study, we conducted a cold pressor test in healthy volunteers (n = 548). The primary outcome was pain tolerance, measured in seconds. No objective (tolerance time) or subjective (pain intensity and unpleasantness) differences were found among the five genres. Multinomial logistic regression showed that overall genre preference positively influenced pain tolerance. In contrast, the music genres that participants thought would help for pain relief did not. Our study was the first to investigate pain tolerance at genre level and in the context of genre preference without self-selecting music. In conclusion, this study provides evidence that listening to a favored music genre has a significant positive influence on pain tolerance, irrespective of the kind of genre. Our results emphasize the importance of individual music (genre) preference when looking at the analgesic benefits of music. This should be considered when implementing music in the clinical setting.

Effects of single- and bilateral limb immersion on systemic and cerebral hemodynamic responses to the cold pressor test.

The cold pressor test (CPT) involves cold water immersion of either the upper or lower limb(s) and elicits increases in sympathetic nervous activity (SNA), heart rate (HR), and mean arterial pressure (MAP) via stimulation of pain and cutaneous thermoreceptors. Greater pain perception during the CPT is associated with greater increases in SNA and more robust physiological responses. Due to potential differential sensitivity to both painful and thermal stimuli between upper and lower limbs, as well as potential effects of total exposure area, it is unclear whether the choice of limb(s) in CPT protocol design differentially affects systemic and cerebral hemodynamic responses. Our objective was to assess systemic and cerebral hemodynamic and ventilatory responses to different CPT protocols of the hand (CPTH), foot (CPTF), or bilateral feet (CPTBF). We hypothesized CPTBF would elicit greatest physiological responses due to increased exposure area to the cold stimulus. Twenty-eight (14 M, 14 F) healthy young adults [23.4 (SD: 2.4) yr] participated in three 3-min CPT protocols during a single visit. Blood pressure, HR, middle cerebral artery blood velocity (MCAv) and cerebrovascular conductance index, and end-tidal carbon dioxide ([Formula: see text]) were averaged over the final 30 s of each minute of the CPT for each protocol, and perceived pain was recorded at the end of each minute of the CPT. We found significant effects of the time-CPT protocol interaction on systolic blood pressure (P = 0.02), diastolic blood pressure (P < 0.01), MAP (P < 0.01), and HR (P < 0.001). There were no differences between CPT protocols on either MCAv (P = 0.4) or cerebrovascular conductance index (P = 0.1). HR responses peaked in the first minute of the CPT, and changes from baseline were greater in CPTBF [Δ14(16) beats/min] compared with CPTH [Δ5(13) beats/min; P = 0.01] and CPTF [Δ4.04(13.3) beats/min; P = 0.02]. MAP responses peaked in minute 2 of the CPT, and changes from baseline were greater in CPTH [Δ12(8) mmHg) and CPTBF (Δ13(9) mmHg] compared with CPTF [Δ8(7) mmHg; P < 0.01]. Perceived pain was significantly greater in the CPTBF [CPT1 7(2.3), CPT2 6.5(2.3), CPT3 6(3)] condition compared with CPTH [CPT1 6(1.3), CPT2 6(2.3), CPT3 6(2.3)] and CPTF [CPT1 6(3.0), CPT2 6(2.0), CPT3 5.5(3.0)] protocols at all three stages of the CPT (P ≤ 0.01). Our findings suggest choice of limb(s) in CPT protocols may lead to differences in systemic hemodynamic responses, with pain perception potentially influencing these responses. Based on our results, we suggest that choice of limb should be considered in future design of CPT studies, with hand CPT providing the best balance between participant tolerability and robust physiological responses.NEW & NOTEWORTHY Choice of limb(s) in cold pressor test (CPT) studies appears to influence systemic hemodynamics. Hand and bilateral feet induce more robust responses than single-foot CPT, potentially due to increased exposure area and pain perception. Despite no significant cerebrovascular effects, a sustained hyperventilatory response was noted in bilateral feet CPT. Hand CPTs may provide a balance between robust physiological responses and tolerability. These findings underscore the need for careful limb selection in future CPT studies.

Low-dose sufentanil does not affect tolerance to LBNP-induced central hypovolemia or blood pressure responses during the cold pressor test.

Hemorrhage is a leading cause of death in the pre-hospital setting. Since pain often accompanies a hemorrhagic insult, the administered pain medication must not interfere with critical autonomic regulation of arterial blood pressure and vital organ perfusion. The purpose of this study was to test two unique hypotheses: a) sublingual sufentanil (Dsuvia) impairs tolerance to progressive central hypovolemia, and b) sublingual sufentanil attenuates pain sensation and the accompanying cardiovascular responses to a noxious stimulus. Twenty-nine adults participated in this double-blinded, randomized, crossover, placebo-controlled trial. Following sublingual administration of sufentanil (30 µg) or placebo, participants completed a progressive lower-body negative pressure (LBNP) challenge to tolerance, followed by a cold pressor test (CPT) after LBNP recovery. Addressing the first aim, tolerance to LBNP was not different between trials (p = 0.495). Decreases in systolic blood pressure from baseline to the end of LBNP also did not differ between trials (time: p<0.001, trial p=0.477, interaction p=0.587). Finally, increases in heart rate from baseline to the end of LBNP did not differ between trials (time: p < 0.001, trial p= p=0.626, interaction p = 0.424). Addressing the second aim, sufentanil attenuated perceived pain (p < 0.001) in response to the CPT, though the magnitude of the change in mean blood pressure during the CPT (p = 0.078) was not different between trials. These data demonstrate that sublingual sufentanil does not impair tolerance to progressive central hypovolemia. Additionally, sublingual sufentanil attenuates perceived pain, but not the accompanying mean blood pressure responses to the CPT.

Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects.

AIMS: Dopamine beta-hydroxylase (DßH) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS). METHODS: A single-centre, prospective, double-blind, randomized, placebo-controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days -1 and 10. Plasma and 24 h-urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma DßH activity, were measured. RESULTS: Compared to placebo, zamicastat showed a - 4.62 mmHg decrease in systolic blood pressure during the cold stimulus vs. rest phases on Day 10 of CPT (P = .020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (-2.62 mmHg; P = .025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63 ng/L; P = .040) and after CPT (19.22 ng/L; P = .001) as well as the estimated plasma EPI change from baseline after CPT (P = .040). Inhibition of plasma DßH activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24-h urinary excretion of EPI (P = .002) and NE (P = .001) were observed. Zamicastat Cτ geometric mean ± GSD ranged from 45.86 ± 1.46 ng/mL on Day 3 to 58.64 ± 1.52 ng/mL on Day 10, with moderate inter-individual variability (CV: 32.6%-36.6%). Steady state was already achieved on Day 6. CONCLUSIONS: Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.

Pain-induced effects on the pupillary light response under high and low illumination conditions.

Objective: The present study investigated the impact of two different light intensities on the pain-modulated pupillary light response (PLR). Additionally, it aimed to demonstrate parasympathetic and sympathetic influences on PLR parameters in response to pain, as predicted by functional models. Method: A total of 24 participants were included in a randomized, repeated-measures design. The PLR was measured in response to both dark and bright light stimuli within two test cycles. Pain was induced using the cold pressor test (CPT), which involved immersing participants' feet in ice water. PLR measurements were taken during baseline and ice-water immersion within each test cycle. The assessed PLR parameters included initial diameter (INIT), latency (LAT), amplitude (AMP), and re-dilation time (ReDIL25). Along with these parameters, heart rate (HR) and pain ratings were also computed and analyzed. Main results: The CPT caused moderate pain in participants, and the resulting PLR parameters were found to be congruent with the expected parasympathetic and sympathetic nervous system activities. Although the luminance of the stimulus did influence PLR parameters, no interaction with pain exposure was found. Significance: The results showed that different aspects of pain experienced by an individual, as modulated through the sympathetic and parasympathetic nervous systems, are visible in their pupillary reactions to light. Notably, within the range used in the current study, light intensity did not significantly affect the pain-related PLR effects.

Measuring pain intensity through physical interaction in an experimental model of cold-induced pain: A method comparison study.

OBJECTIVES: Assessment of pain is challenging given its subjective nature. Standard pain assessment tools have limitations. We aimed to compare the verbal numeric rating scale (NRS) and Grasp, a novel handheld electronic device that reports pain by squeezing. METHODS: To compare Grasp and NRS, healthy adult volunteers were invited to undergo two subsequent standardised tests of cold-triggered pain using a cold pressor test (CPT) at a temperature of 3°C. Pain intensity was in a randomised manner reported by NRS (scale 0-10) or by squeezing Grasp (0-3 V) during the two CPTs. A third CPT was performed 1 to 14 days later where subjects reported pain by Grasp a second time in order to study the association of repeated Grasp measurements. Acceptable association was a priori considered as mean Kendall's τ-b coefficient (τ-b) ≥ 0.7. The subjects reported their experience of using Grasp in a purpose-made questionnaire. RESULTS: In total, 102 subjects were included, and 96 subjects (56 females) completed all three tests. The association of pain intensity reported by Grasp and NRS was moderate with a mean τ-b of 0.53 (95% confidence interval [CI] 0.47-0.58). The association between the repeated Grasp measurements was weak with a mean τ-b of 0.43 (95% CI 0.37-0.48). Most subjects reported that Grasp was intuitive and easy to use. CONCLUSIONS: Pain intensity reported by squeezing Grasp did not show acceptable association with pain intensity reported by NRS during CPTs. The association between pain intensity reported by Grasp during two CPTs on separate days was weak. Further improvements of the Grasp ball are needed before use in clinical settings.

Sympathetic and blood pressure reactivity in young adults with major depressive disorder.

BACKGROUND: Sympathetic and blood pressure (BP) hyper-reactivity to stress may contribute to increased cardiovascular disease (CVD) risk in adults with major depressive disorder (MDD); however, whether this is evident in young adults with MDD without comorbid disease remains unclear. We hypothesized that acute stress-induced increases in muscle sympathetic nerve activity (MSNA) and BP would be exaggerated in young adults with MDD compared to healthy non-depressed young adults (HA) and that, in adults with MDD, greater symptom severity would be positively related to MSNA and BP reactivity. METHODS: In 28 HA (17 female) and 39 young adults with MDD of mild-to-moderate severity (unmedicated; 31 female), MSNA (microneurography) and beat-to-beat BP (finger photoplethysmography) were measured at rest and during the cold pressor test (CPT) and Stroop color word test (SCWT). RESULTS: There were no group differences in resting MSNA (p = 0.24). Neither MSNA nor BP reactivity to either the CPT [MSNA: ∆24 ± 10 HA vs. ∆21 ± 11 bursts/min MDD, p = 0.67; mean arterial pressure (MAP): ∆22 ± 7 HA vs. ∆21 ± 10 mmHg MDD, p = 0.46)] or the SCWT (MSNA: ∆-4 ± 6 HA vs. ∆-5 ± 8 bursts/min MDD, p = 0.99; MAP: ∆7 ± 8 HA vs ∆9 ± 5 mmHg MDD; p = 0.82) were different between groups. In adults with MDD, symptom severity predicted MAP reactivity to the CPT (ß = 0.78, SE = 0.26, p = 0.006), but not MSNA (p = 0.42). LIMITATIONS: The mild-to-moderate symptom severity reflects only part of the MDD spectrum. CONCLUSIONS: Neither sympathetic nor BP stress reactivity are exaggerated in young adults with MDD; however, greater symptom severity may amplify BP reactivity to stress, thereby increasing CVD risk.

Cold pressor stress effects on cardiac repolarization.

The cold pressor test (CPT) elicits strong cardiovascular reactions via activation of the sympathetic nervous system (SNS), yielding subsequent increases in heart rate (HR) and blood pressure (BP). However, little is known on how exposure to the CPT affects cardiac ventricular repolarization. Twenty-eight healthy males underwent both a bilateral feet CPT and a warm water (WW) control condition on two separate days, one week apart. During pre-stress baseline and stress induction cardiovascular signals (ECG lead II, Finometer BP) were monitored continuously. Salivary cortisol and subjective stress ratings were assessed intermittently. Corrected QT (QTc) interval length and T-wave amplitude (TWA) were assessed for each heartbeat and subsequently aggregated individually over baseline and stress phases, respectively. CPT increases QTc interval length and elevates the TWA. Stress-induced changes in cardiac repolarization are only in part and weakly correlated with cardiovascular and cortisol stress-reactivity. Besides its already well-established effects on cardiovascular, endocrine, and subjective responses, CPT also impacts on cardiac repolarization by elongation of QTc interval length and elevation of TWA. CPT effects on cardiac repolarization share little variance with the other indices of stress reactivity, suggesting a potentially incremental value of this parameter for understanding psychobiological adaptation to acute CPT stress.

Periodontitis is associated with decreased experimental pressure pain tolerance: The Tromsø Study 2015-2016.

AIM: To assess the relationship between periodontitis and experimental pain tolerance. MATERIALS AND METHODS: Participants from the population-based seventh survey of the Tromsø Study with data on periodontitis were included (n = 3666, 40-84 years old, 51.6% women). Pain tolerance was assessed through (i) pressure pain tolerance (PPT) test with a computerized cuff pressure algometry on the leg, and (ii) cold-pressor tolerance (CPT) test where one hand was placed in circulating 3°C water. Cox proportional hazard regression was used to assess the association between periodontitis and pain tolerance adjusted for age, sex, education, smoking and obesity. RESULTS: In the fully adjusted model using the 2012 Centers for Disease Control/American Academy of Periodntology case definitions for surveillance of periodontitis, moderate (hazard ratio [HR] = 1.09; 95% confidence interval [CI]: 1.01, 1.18) and severe (HR = 1.25, 95% CI: 1.11, 1.42) periodontitis were associated with decreased PPT. Using the 2018 classification of periodontitis, having Stage II/III/IV periodontitis was significantly associated with decreased PPT (HR = 1.09; 95% CI: 1.01, 1.18) compared with having no or stage I periodontitis. There were no significant associations between periodontitis and CPT in fully adjusted models. CONCLUSIONS: Moderate and severe periodontitis was associated with experimental PPT.

Associations between cognitive test scores and pain tolerance: The Tromsø study.

OBJECTIVES: Previous studies have suggested that experimental pain sensitivity is associated with cognitive function. The aim of this study is to assess this relationship in a large population-based sample. METHODS: We included 5,753 participants (aged 40-84 years) from the seventh wave of the population-based Tromsø Study who had been examined with cognitive tests and experimental pain assessments, and for whom information on covariates were available. Cox regression models were fitted using standardized scores on cognitive tests (12-word immediate recall test, digit symbol coding test, and Mini-Mental State Examination [MMS-E]) as the independent variable and cold pressor or cuff pressure pain tolerance as the dependent variables. Statistical adjustment was made for putative confounders, namely, age, sex, education, smoking, exercise, systolic blood pressure, body mass index, symptoms indicating anxiety or depression, analgesic use, and chronic pain. RESULTS: In multivariate analysis, cold pressor tolerance time was significantly associated with test scores on the 12-word immediate recall test (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.90-0.97, p < 0.001), the digit symbol coding test (HR 0.94, 95% CI 0.89-0.98, p = 0.004), and the MMS-E (HR 0.93, 95% CI 0.90-0.96 p < 0.001). Tolerance to cuff pressure algometry was significantly associated with 12-word immediate recall (HR 0.94-0.97, p < 0.001) and Digit Symbol Coding test scores (HR 0.93, 95% CI 0.89-0.96, p < 0.001) while there was no significant association with Mini Mental State Examination test score (HR 0.98, 95% CI 0.95-1.00, p = 0.082). CONCLUSION: Lower pain tolerance was associated with poorer performance on cognitive tests.

Changes in Retinal Hemodynamics in the Optic Nerve Head of Healthy Participants Measured Using Laser Speckle Flowgraphy after a Cold Pressor Test.

PURPOSE: Autoregulation of retinal vessels is stronger than that of choroidal vessels. This study aimed to use laser speckle flowgraphy to determine the time course of changes in retinal hemodynamics of healthy eyes after a cold pressor test. METHODS: This prospective study included 44 right eyes of 44 healthy volunteers (age, 21.7 ± 5.0 years). The mean blur rate, which is a quantitative index of the relative blood flow velocity in the retina, was measured using laser speckle flowgraphy. The vessel average of mean blur rate at the optic nerve head, intraocular pressure, systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate, and ocular perfusion pressure were evaluated at baseline, immediately after the cold pressor test, and 10, 20, and 30 minutes after the test. RESULTS: Immediately after the test (0 minutes), systolic blood pressure, diastolic blood pressure, mean blood pressure, and ocular perfusion pressure were significantly increased compared with those at baseline; however, no changes were observed at 10, 20, and 30 minutes after the test. In contrast, intraocular pressure, heart rate, and the vascular mean blur rate values at the optic nerve head did not change throughout the course of the study. CONCLUSIONS: Sympathetic hyperactivity induced by the cold pressor test increased systemic circulatory dynamics, but not retinal circulatory hemodynamics, suggesting the involvement of vascular autoregulation.

Limb-specific muscle sympathetic nerve activity responses to the cold pressor test.

Recent studies have demonstrated that muscle sympathetic nerve activity (MSNA) responses to isometric exercise differs between active and inactive limbs. Whether limb-dependent responses are characteristic of responses to the cold pressor test (CPT) remains to be established. Therefore, we tested the hypothesis that CPT-induced MSNA responses differ between affected and unaffected limbs such that MSNA in the affected lower limb is greater than MSNA responses in the contralateral lower limb and the upper limb. Integrated peroneal MSNA (microneurography) was measured in young healthy individuals (n = 10) at rest and during three separate 3-min CPTs: the microneurography foot, opposite foot, and opposite hand. Peak MSNA responses were extracted for further analysis, as well as corresponding hemodynamic outcomes including mean arterial pressure (MAP; Finometer). MSNA responses were greater when the microneurography foot was immersed in ice water than when the opposite foot was immersed (38 ± 18 vs 28 ± 16 bursts/100hb: P < 0.01). MSNA responses when the opposite hand was immersed were greater than both the microneurography foot (46 ± 22 vs 38 ± 18 bursts/100hb: P < 0.01) and opposite foot (46 ± 22 vs 28 ± 16 bursts/100hb: P ≤0.01). Likewise, MAP responses were greater during the hand CPT than the microneurography foot (99 ± 9 vs 96 ± 8 mmHg: P < 0.01) and opposite foot CPT (99 ± 9 vs 96 ± 9 mmHg: P < 0.01). These data indicate that (a) upper limbs and (b) immersed limbs elicit greater MSNA responses to the CPT than lower and/or non-immersed limbs.

Contrast-enhanced ultrasonography reveals a lower cortical perfusion and a decreased renal flow reserve in hypertensive patients.

BACKGROUND: Microvascular structural alteration and dysfunction is a hallmark of arterial hypertension. So far, the visualization and the quantification of renal microcirculation in humans has been hampered by the lack of non-nephrotoxic and non-invasive radiologic techniques. Contrast-enhanced ultrasonography (CEUS) is an appealing method to investigate renal microcirculation and has not been investigated in this setting. We aimed to compare renal microcirculation in normotensive (NT) and hypertensive (HT) participants using CEUS at rest and during a sympathetic stress test. METHODS: We measured the renal perfusion index (PI, primary outcome), the renal resistive index (RRI), beat-to-beat systemic hemodynamics and plasma catecholamines before and during a 2-min cold pressor test (CPT) in NT and HT participants. Linear mixed model analysis was used to compare the effect of the CPT on the variables of interest. RESULTS: Seventy-three participants (32 HT) with normal kidney function were included. HT participants had a lower baseline PI compared with NT participants [median (interquartile range) 1476 (959-2155) arbitrary units (a.u.) vs 2062 (1438-3318) a.u., P < .001]. The CPT increased blood pressure, heart rate and catecholamines in all participants. The increase in PI observed in NT during the CPT was blunted in HT [+504 (117-920) a.u. vs +1159 (678-2352) a.u in NT, interaction P = .013]. Age, sex and body mass index did not modify these results. CONCLUSIONS: HT patients had a lower basal renal cortical perfusion. During the cold pressor test, HT participants had a smaller increase in the PI, suggesting that renal cortical flow reserve is impaired.

Repetitive high-sustained gravitoinertial stress does not modulate pressure responsiveness to peripheral sympathetic stimulation.

PURPOSE: We evaluated the hypothesis that repetitive gravitoinertial stress would augment the arterial-pressure response to peripheral sympathetic stimulation. METHODS: Before and after a 5-weeks G-training regimen conducted in a human-use centrifuge, twenty healthy men performed a hand cold-pressor test, and nine of them also a foot cold-pressor test (4 min; 4 °C water). Arterial pressures and total peripheral resistance were monitored. RESULTS: The cold-induced elevation (P ≤ 0.002) in arterial pressures and total peripheral resistance did not vary between testing periods, either in the hand [mean arterial pressure: Before = + 16% vs. After = + 17% and total peripheral resistance: Before = + 13% vs. After = + 15%], or in the foot [mean arterial pressure: Before = + 19% vs. After = + 21% and total peripheral resistance: Before = + 16% vs. After = + 16%] cold-pressor tests (P > 0.05). CONCLUSION: Present results demonstrate that 5 weeks of prolonged iterative exposure to hypergravity does not alter the responsiveness of sympathetically mediated circulatory reflexes.

Acute self-myofascial release modulates cardiac autonomic function and hemodynamic parameters at rest and reduces cardiovascular stress reaction.

PURPOSE: Self-myofascial release (SMR) is a form of self-massage aiming to release tension, improve blood flow, and alleviate muscle soreness. This study aimed to determine whether a single session of SMR could impact cardiovascular parameters at rest and during a cold pressor test (CPT). METHODS: Twenty male participants (aged 26 ± 2 years) underwent a 20-min SMR and a 20-min seated control condition (CON) on two separate test days in a randomized order. Peripheral and central blood pressure (BP), total peripheral resistance (TPR), pulse wave velocity (PWV), heart rate (HR), root mean square of successive RR interval differences (RMSSD), and the quotient of low-frequency power and high-frequency power (LF/HF) were measured both at rest and during a CPT before (t0), 2 min (t1), and 20 min (t2) after the SMR and CON. RESULTS: Time × condition interactions could be detected for peripheral and central diastolic BP, TPR, HR, and RMSSD. Following the SMR, peripheral diastolic BP, central diastolic BP, TPR, and RMSSD were reduced, while HR was increased compared to the CON. Regarding the CPT time × condition interactions could be detected for peripheral, and central diastolic BP, with lower values after SMR. CONCLUSION: The results of the present study suggest that a single bout of SMR confers favorable cardiovascular benefits in healthy normotensive individuals. Furthermore, SMR can attenuate the hemodynamic reactivity to a stress test. Future research should address whether regular SMR leads to chronic adaptations similar to regular, moderate aerobic exercise, massage therapy, and static stretching.

Remote ischaemic preconditioning increase tolerance to experimentally induced cold pain.

Ischaemic preconditioning (IPC) applied locally and remotely has been shown to reduce pain which may underpin its ergogenic effect on exercise performance, however, it is unclear how many IPC cycles are needed to induce hypoalgesia. Therefore the purpose of this study was to examine the number of cycles of IPC on experimental pain perception. Sixteen healthy participants underwent four, randomised, experimental sessions where they either underwent a sham protocol (1 × 5 min at 20 mmHg), and 1, 2 or 3 cycles × 5 min of remote IPC at 105% of limb occlusion pressure. Ten minutes post-intervention, participants underwent a cold-pressor test where pain threshold, pain tolerance and pain intensity were examined and compared between conditions with a one-way repeated measure analysis of variance. Pain threshold was not different between conditions (P = 0.065); but pain tolerance was increased by ∼30% in the 1 × 5 condition, 2 × 5 condition, and 3 × 5 condition compared to the sham condition. No differences in pain tolerance were seen between the different numbers of cycles (all P > 0.05). There was also no difference in the perception of pain 30 s into the cold pressor test (P = 0.279). Remote IPC appears to significantly improve tolerance to pain which may have significant implications for endurance performance and exercise rehabilitation, but this warrants further investigation.

We found that one, two or three cycles of ischaemic preconditioning improved cold pain tolerance by 30% compared to a sham protocol, but there was no clear effect of IPC on pain threshold or pain intensity.The pain reported during IPC decreased from cycle one to cycle three in the three cycle condition, suggesting a potential conditioned pain modulation effect.An increase in pain tolerance may explain why IPC can improve exercise performance and IPC itself could be used as a tool to improve tolerance to pain.

Transcutaneous Auricular Vagus Nerve Stimulation Attenuates Early Increases in Heart Rate Associated With the Cold Pressor Test.

INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) may be useful in treating disorders characterized by chronic parasympathetic disinhibition. Acute taVNS decreases resting heart rate in healthy individuals, but little is known regarding the effects of taVNS on the cardiac response to an acute stressor. To investigate effects on the acute stress response, we investigated how taVNS affected heart rate changes during a cold pressor test (CPT), a validated stress induction technique that reliably elicits a sympathetic stress response with marked increases in heart rate, anxiety, stress, and pain. MATERIALS AND METHODS: We recruited 24 healthy adults (ten women, mean age = 29 years) to participate in this randomized, crossover, exploratory trial. Each subject completed two taVNS treatments (one active, one sham) paired with CPTs in the same session. Order of active versus sham stimulation was randomized. Heart rate, along with ratings of anxiety, stress, and pain, was collected before, during, and after each round of taVNS/sham + CPT. RESULTS: In both stimulation conditions, heart rate was elevated from baseline in response to the CPT. Analyses also revealed a difference between active and sham taVNS during the first 40 seconds of the CPT (Δ heart rate [HR] = 12.75 ± 7.85 in the active condition; Δ HR = 16.09 ± 11.43 in the sham condition, p = 0.044). There were no significant differences in subjective ratings between active and sham taVNS. CONCLUSIONS: In this randomized, sham-controlled study, taVNS attenuated initial increases in HR in response to the CPT. Future studies are needed to investigate the effects of various taVNS doses and parameters on the CPT, in addition to other forms of stress induction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00113453.

The forearm vascular response to sympathetic activation is attenuated in female, but not male, participants following acute intermittent hypoxia.

Acute exposure to hypoxia promotes both an increase in sympathetic nervous system activity (SNA) and local vasodilation. In rodents, intermittent hypoxia (IH)-mediated increases in SNA are associated with an increase in blood pressure in males but not females; notably, the protective effect of female sex is lost following ovariectomy. These data suggest the vascular response to hypoxia and/or SNA following IH may be sex- and/or hormone specific-although mechanisms are unclear. We hypothesized that hypoxia-mediated vasodilation and SNA-mediated vasoconstriction would be unchanged following acute IH in male adults. We further hypothesized that hypoxic vasodilation would be augmented and SNA-mediated vasoconstriction would be attenuated in female adults following acute IH, with the greatest effect when endogenous estradiol was high. Twelve male (25 ± 1 yr) and 10 female (25 ± 1 yr) participants underwent 30 min of IH. Females were studied in a low (early follicular) and high (late follicular) estradiol state. Preceding and following IH, participants completed two trials [steady-state hypoxia and cold pressor test (CPT)], where forearm blood flow and blood pressure were measured and used to determine forearm vascular conductance (FVC). The FVC response to hypoxia (P = 0.67) and sympathetic activation (P = 0.73) were unchanged following IH in males. There was no effect of IH on hypoxic vasodilation in females, regardless of estradiol state (P = 0.75). In contrast, the vascular response to sympathetic activation was attenuated in females following IH (P = 0.02), independent of estradiol state (P = 0.65). Present data highlight sex-related differences in neurovascular responsiveness following acute IH.NEW & NOTEWORTHY We examined the effects of acute intermittent hypoxia (AIH) on the vascular response to sympathetic activation and acute hypoxia. Present findings show, despite no effect of AIH on the vascular response to hypoxia, the forearm vasoconstrictor response to acute sympathetic activation is attenuated in females following AIH, independent of estradiol state. These data provide mechanistic understanding of potential benefits of AIH, as well as the impact of biological sex.

Optimal timing of oral metyrapone intake for the suppression of cold-pressor stress-induced cortisol release.

BACKGROUND: Pharmacological manipulation of cortisol levels is instrumental in elucidating mechanisms underlying acute stress effects and for distinguishing the physiological and behavioral effects of cortisol from those of the adrenergic system. Administration (oral or IV) of hydrocortisone is a direct and efficient method to elevate cortisol, and thus, frequently used in psychobiological stress research. However, lowering of cortisol (i.e. blockade of stress cortisol) requires a more sophisticated approach, such as the administration of the corticostatic compound metyrapone (MET). However, there is insufficient knowledge about the temporal dynamics of MET for the blocking of stress-induced cortisol reactivity. Thus, the present study aimed to build up an experimental protocol suitable to suppress acute behavioral stress-induced cortisol secretion by MET. METHODS: 50 healthy young men were randomly assigned to one of five treatment groups. They received 750 mg oral MET either 30 (n = 9), 45 (n = 11), or 60 (n = 10) minutes before exposure to a combined cold pressor and mental arithmetic test (stress induction), or were subjected to two different control treatments (placebo 60 min before stress (n = 10) or MET 30 min before non-stressful warm-water condition (n = 10)). Salivary cortisol concentration, hemodynamics, and subjective ratings were assessed. RESULTS: Suppression of cold stress-induced cortisol release was strongest when MET intake was scheduled 30 min prior to stress onset. Cardiovascular stress-responses and subjective ratings remained unaffected by MET. CONCLUSION: In healthy young males, 750 mg of MET efficiently block cold stress-induced cortisol release when oral administration is scheduled 30 min prior to stress onset. This finding may guide future research in improving timing of suppression of stress-induced cortisol secretion.