Aerobic Fitness and Opioidergic Inhibition of Cardiovascular Stress Reactivity

The role of endogenous opioids in aerobic fitness-induced decrements in cardiovascular stress reactivity was examined by comparing the effects of opioid antagonism with naltrexone on responses to stress in young adults with high versus low levels of aerobic fitness. Two hundred forty subjects were given an activity questionnaire and males with the highest (Fit) and lowest (Nonfit) aerobic activity profiles were recruited for maximal oxygen consumption (VO2max) treadmill testing and psychological stress testing (final sample N = 28). Heart rate and blood pressures were measured during performance on a computer-controlled arithmetic task after pretreatment with either naltrexone (Trexan, DuPont) or a placebo. During placebo challenges, Fit subjects, compared with Nonfit, showed lower heart rate reactivity during stress and lower mean arterial blood pressures immediately before and during recovery from stress. Naltrexone eliminated these reactivity differences by increasing heart rate reactivity and raising mean arterial blood pressure in Fit subjects. These data suggest that aerobic fitness is associated with enhanced opioidergic inhibition of circulatory stress reactivity. Opioidergic modulatory effects on stress reactivity may comprise an important mechanism in fitness-associated risk reduction for cardiovascular disease.     

Hypoalgesia associated with elevated resting blood pressure: evidence for endogenous opioid involvement

This study used a placebo-controlled, between-subjects opioid blockade design to evaluate endogenous opioid involvement in the hypoalgesia associated with elevated resting blood pressure (BP) in 163 healthy individuals. Participants were randomly assigned to Drug condition (placebo, naltrexone) and Task Order (computerized maze task with harassment followed by an ischemic pain task or vice versa). Resting BP was assessed, followed by drug administration, and then the pain and maze tasks. A significant Drug × Systolic BP (SBP) interaction was observed on McGill Pain Questionnaire-Affective pain ratings (P < .01), indicating that BP-related hypoalgesia observed under placebo was absent under opioid blockade. A significant Gender × Drug × SBP × Task Order interaction was observed for VAS pain intensity (P < .02). Examination of simple effects comprising this interaction suggested that BP-related hypoalgesia occurred only in male participants who experienced the pain task in the absence of emotional arousal, and indicated that this hypoalgesia occurred under placebo but not under opioid-blockade. Results suggest that under some circumstance, BP-related hypoalgesia may have an endogenous opioid-mediated component in healthy individuals, particularly men.     

The psychobiology of hostility: Possible endogenous opioid mechanisms

This study examined the role of endogenous opioids in the relation between hostility and cardiovascular stress responsiveness. Forty-six men completed the Cook-Medley Hostility Scale and experienced a laboratory pain stressor once under opioid blockade and once under placebo. Hostility scores were significantly related to the magnitude of change in cardiovascular reactivity/recovery resulting from opioid blockade. Low scorers on the Cynicism subscale displayed increases in heart rate (HR) reactivity under blockade relative to placebo, with reactivity decreases noted in high scorers. Low Hostile Affect scores were similarly associated with impaired diastolic blood pressure recovery under opioid blockade. HR recovery results were somewhat different, with high scorers on Aggressive Responding and the total Cook-Medley displaying improved HR recovery under opioid blockade, with no change noted in low scorers. These data provide preliminary support for the hypothesis that low hostile individuals rely on endogenous opioids for buffering cardiovascular stress responsiveness, but high hostiles do not.     

Effects of opioid blockade on nociceptive flexion reflex thresholds and nociceptive responding in hypertensive and normotensive individuals

Hypertension and risk for hypertension have been associated with reduced pain sensitivity. It has been hypothesised that endogenous opioids contribute to this hypertensive hypoalgesia. The nociceptive flexion reflex can be used as a tool to investigate modulation of nociceptive transmission at spinal level. The current study employed a double-blind placebo-controlled design to compare the effects of naltrexone, an opioid antagonist, and placebo on nociceptive flexion reflex thresholds and nociceptive responding in unmedicated patients with essential hypertension and normotensive individuals. Neither nociceptive flexion reflex thresholds nor nociceptive responding differed between hypertensives and normotensives during placebo or naltrexone. These data provide no support for the hypothesis that essential hypertension is characterised by higher levels of endogenous opioids in the central nervous system and reveal no association between blood pressure status and nociceptive flexion reflex responses.     

Psychological coping with acute pain: An examination of the role of endogenous opioid mechanisms

This study examined the relationship among endogenous opioids, Monitoring and Blunting coping styles, and acute pain responses. Fifty-eight male subjects underwent a 1-min pressure pain stimulus during two laboratory sessions. Subjects experienced this pain stimulus once under endogenous opioid blockade with naltrexone and once in a placebo condition. Blunting was found to be negatively correlated with pain ratings, but this relationship was significantly more prominent under opioid blockade. Results for coping behaviors subjects used to manage the experimental pain were generally consistent with the Blunting results, indicating that cognitive coping was related more strongly to decreased pain ratings and cardiovascular stress responsiveness under opioid blockade. Overall, the beneficial effects of Blunting and cognitive coping on pain responses did not depend upon endogenous opioids and, in fact, became stronger when opioid receptors were blocked. The relationship between endogenous opioids and coping appears to be dependent upon situational and stimulus characteristics.     

Effects of Opioid Blockade with Naltrexone and Distraction on Cold and Ischemic Pain in Hypertension

Essential hypertension is characterised by reduced pain sensitivity. Hypertensive hypoalgesia has been attributed to elevated endogenous opioids and/or increased activation of descending pain modulation systems. A double-blind placebo-controlled design compared the effects of naltrexone and placebo on cold and ischemic pain in unmedicated newly-diagnosed patients with essential hypertension. Patients performed a cold pressor task while resting and while performing a distracting secondary task. They also performed a forearm ischemia task while resting. Although the cold pressor and ischemia tasks elicited significant increases in pain and blood pressure, pain ratings and pressor responses did not differ between naltrexone and placebo. Cold pain was reduced by distraction compared to rest. The finding that opioid blockade with naltrexone did not moderate the pain and pressor responses to cold and ischemia suggests that pain and associated blood pressure responses are not modulated by opioids in hypertension. The finding that the distracting secondary task successfully reduced pain ratings suggests normal supraspinal pain modulation in essential hypertension.     

Four-Year Stability of Cardiovascular Reactivity to Psychological Stress

The 4-year stability of cardiovascular responses to laboratory psychological stress (mental arithmetic) was examined in 75 adults. The stability coefficients were .76 for heart rate (HR) change and .81 for absolute HR, .66 for systolic blood pressure (SBP) change and .52 for absolute SBP, .16 for diastolic blood pressure (DBP) change and .27 for absolute DBP. Males had greater SBP and DBP reactivity than females in the first session, but this reactivity decreased by the 4-year follow-up session (which was not the case for women).     

Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing

The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter-balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain.     

Anger regulation style,anger arousal and acute pain sensitivity: evidence for an endogenous opioid “triggering” model

Findings suggest that greater tendency to express anger is associated with greater sensitivity to acute pain via endogenous opioid system dysfunction, but past studies have not addressed the role of anger arousal. We used a 2 × 2 factorial design with Drug Condition (placebo or opioid blockade with naltrexone) crossed with Task Order (anger-induction/pain-induction or pain-induction/anger-induction), and with continuous Anger-out Subscale scores. Drug × Task Order × Anger-out Subscale interactions were tested for pain intensity during a 4-min ischemic pain task performed by 146 healthy people. A significant Drug × Task Order × Anger-out Subscale interaction was dissected to reveal different patterns of pain intensity changes during the pain task for high anger-out participants who underwent pain-induction prior to anger-induction compared to those high in anger-out in the opposite order. Namely, when angered prior to pain, high anger-out participants appeared to exhibit low pain intensity under placebo that was not shown by high anger-out participants who received naltrexone. Results hint that people with a pronounced tendency to express anger may suffer from inadequate opioid function under simple pain-induction, but may experience analgesic benefit to some extent from the opioid triggering properties of strong anger arousal.     

Stress-induced suppression of natural killer cell cytotoxicity in the rat: a naltrexone-insensitive paradigm

The suppression of natural killer (NK) cell cytotoxicity by footshock stress can be attenuated by opioid antagonists, implicating endogenous opioids in its mediation. A stress paradigm that induces NK suppression that is not blocked by the opioid antagonist naltrexone is reported. This stress paradigm is also shown to cause analgesia and elevated plasma corticosterone levels that are not attenuated by naltrexone. In the first experiment, a significant suppression of NK cell cytotoxicity after forced swimming was demonstrated in Fischer 344 rats treated with either saline or naltrexone, compared with nonstressed controls. Significantly higher corticosterone levels were evident in both stressed groups. In the second experiment, the same stress paradigm was shown to cause significant analgesia in the tail-flick test, whereas no differences were seen between groups pretreated with saline and naltrexone. It is concluded that opioids need not always be involved in the suppression of NK cell cytotoxicity by stress.     

Sex Differences in Salivary Cortisol Levels Following Naltrexone Administration1

Effects of endogenous opioid peptide blockade by naltrexone on salivary Cortisol levels were examined in healthy men (n= 8) and women (n= 6). Participants received naltrexone (100 mg) during one laboratory session and a placebo pill during another session. Drug order was counterbalanced across participants. Saliva samples were collected 24 hr after each pill was administered. Among women, salivary Cortisol levels significantly increased following naltrexone administration compared with a placebo pill. Naltrexone administration did not alter salivary Cortisol levels in men. Results suggest sex differences in neuroendocrine sensitivity to opioid blockade, a finding that may hold significance with regard to the treatment of alcohol addiction with naltrexone.     

Chronic pain and cardiovascular stress responses in a general population: the Tromsø Study

We tested whether cardiovascular stress responsiveness is elevated in individuals experiencing chronic pain in a large general population sample. Blood pressure (BP) and heart rate (HR) were assessed at rest, during the cold pressor test, and during subsequent recovery in 554 individuals reporting daily chronic pain and 3,082 individuals free of chronic pain. After correcting for potential confounds, differences as a function of chronic pain status were noted for only 5 of 23 cardiovascular outcomes despite very high statistical power. Compared to the pain-free group, the chronic pain group displayed higher baseline HR/mean arterial pressure (MAP) ratio (p = .03), greater systolic BP (SBP) reactivity during the cold pressor test (p = .04), and higher HR/MAP ratio (p = .047) and significantly less SBP (p = .017) and MAP (p = .041) return to baseline during recovery. Findings suggest that changes in cardiovascular stress responsiveness associated with chronic pain are of limited clinical significance and unlikely to contribute to increased cardiovascular risk in the chronic pain population.     

Change in urinary cortisol excretion mediates the effect of angry/hostile mood on 9 month diastolic blood pressure in HIV+ adults

Cardiovascular disease is a growing concern in HIV disease management and nearly 1 out of 3 persons living with the virus is hypertensive. Biobehavioral factors such as anger, hostility, and HPA axis reactivity are emperically linked to blood pressure regulation. Whether HPA axis or mood disturbance increases risk for hypertension remains unclear in HIV disease. The aim of this study was to determine whether 9-month change in angry/hostile mood predicts alterations in systolic (SBP) or diastolic blood pressure (DBP), and whether this change is mediated by 24-h urinary cortisol (CORT) output. Sixty-one HIV positive adults, aged 41.1 ± 8.6 years, assigned to the control condition of a stress management intervention provided blood samples, 24-h urine specimens, blood pressure in-office, and self-reported mood at baseline and a 9-month follow-up. CORT was tested as a mediator in two separate models controlling for baseline BP, CD4 count, HIV-1 viral load, protease inhibitor use, body mass index, smoking status, and family history of cardiometabolic disease. Increase in angry/hostile mood was associated with greater SBP (β = 0.33, CI 0.09, 0.56, p = 0.01) and DBP (β = 0.39, CI 0.16, 0.62, p < 0.001) at follow-up. CORT partially mediated the effect of angry/hostile mood on DBP (β = 0.28, CI 0.03, 0.54, p = 0.03). Change in CORT was not related to SBP (β = 0.12, CI ?0.20, 0.44, p = 0.46). The final mediation model accounted for 41.2% of the variance in 9-month DBP. Angry or hostile mood may contribute to increased risk for hypertension in persons treated for HIV via disturbance of the HPA-axis.     

Osteopenia is associated with glycemic levels and blood pressure in Chinese postmenopausal women: a cross-sectional study

The aim of present study was to explore the relationships between osteopenia and dyslipidemia, glycemic levels or blood pressure in postmenopausal Chinese women. A total of 4080 women aged 42–85 years were enrolled in this cross-sectional study, which was nested in an ongoing longitudinal (REACTION) study. Calcaneus quantitative ultrasound (QUS) was performed and QUS T score was calculated to assess bone mineral density. Osteopenia was defined as a T score ≤?1.0. The relationship between osteopenia and dyslipidemia, glycemic levels or blood pressure was investigated. The prevalence of osteopenia was significantly lower in subjects with systolic blood pressure (SBP) ≥140 mmHg, fasting blood glucose (FBG) ≥8.0 mmol/L, postprandial blood glucose (PBG) ≥15.0 mmol/L, hemoglobin A1c (HbA1C) 6.5–7.5 %, HbA1C ≥7.5 %. These relationships remained significant after controlling for multiple factors. Moreover, significant trend between osteopenia and SBP, FBG, PBG and HbA1C was observed in women. In contrast, no significant associations between osteopenia and diastolic blood pressure (DBP), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) were found, and no significant trend relationship between osteopenia and DBP, TC, TG, HDL-C, LDL-C was found in postmenopausal Chinese women. The present study showed a relationship between SBP, FBG, PBG, HbA1C and osteopenia in postmenopausal Chinese women, while no significant relationship was observed between dyslipidemia, DBP and osteopenia, even after controlling for multiple confounding factors.     

Psychosocial Correlates of Cardiovascular Reactivity to Anticipation of an Exercise Stress Test Prior to Attending Cardiac Rehabilitation: A Preliminary Test1

We examined social and psychological correlates of cardiovascular reactivity (CVR), or exaggerated heart rate (HR) and blood pressure (BP) responses to mental stress, in 45 men (mean age = 60.1, SD = 9.9) and 17 women (mean age = 9.9, SD = 11.8) prior to cardiac rehabilitation. HR and BP increased from rest to anticipation, and women had higher resting and preexercise BP. Anxiety was positively related to HR reactivity. HR reactivity was negatively related to self‐efficacy in women and positively related to self‐efficacy in men. Men and women with more self‐efficacy had lower systolic blood pressure (SBP) reactivity, and anxiety was positively related to SBP reactivity in women. Results suggest that the relationship among psychosocial factors and CVR might differ among men and women.     

The Availability of Social Support Reduces Cardiovascular Reactivity to Acute Psychological Stress

The influence of the availability of social support on cardiovascular reactivity to acute psychological stress was examined. Twenty-eight men and twenty-one women performed a speech task either in a support availability or no support availability condition while measures of systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were assessed. Consistent with past research, the speech stressor was associated with significant increases in SBP, DBP, and HR. More important, the availability of social support moderated cardiovascular reactivity to the acute stressor: individuals in the support availability condition were characterized by lower SBP and DBP reactivity to the acute stressor compared to individuals in the no support availability condition. These data suggest that simply having potential access to support is sufficient to foster adaptation to stress in the absence of enacted support.     

Matching intra-procedural information with coping style reduces psychophysiological arousal in women undergoing colposcopy

This study assessed the combined effects of coping style and intra-procedural information on indices of distress (physiological measures, observed distress, self-report measures of anxiety and affect) among a group of patients undergoing colposcopy. High and low monitors were exposed to one of three interventions: high information (live video feed of colposcopy); low information (complete audiovisual distraction); and control. Results revealed a 2 (monitoring style) × 3 (information level) × 2 (time) interaction for systolic blood pressure (SBP), F(2, 111) = 3.55, p = .032. Among low monitors, patients in the low-information group exhibited significant SBP reductions during colposcopy, while those in the high-information group exhibited SBP increases. Among high monitors, patients in the high-information and control groups exhibited SBP reductions. Further, significant differences in observed signs of distress were found between groups with high monitors in the low-information group faring best overall, F(2, 111) = 4.41, p = .014. These findings indicate that tailoring information to suit individual coping style may maximize the apparent efficacy of interventions aimed at reducing stress during medical examinations.     

Opioid mediation of odor preferences induced by sugar and fat in 6-day-old rats.

Intraoral infusions of sucrose, fat or polycose reduce ultrasonic vocalizations during isolation, and increase pain threshold in infant rats. These effects are naltrexone reversible. The present study determined whether these substances, when paired with an odor, caused a change in preference for that odor. In 6-day-old rats, pairing orange odor with intraoral infusions of sucrose or corn oil, but not polycose, water, mineral oil or 0.01% quinine hydrochloride, caused a substantial increase in preference for orange. Preference formation was blocked by systemic injection of naltrexone (0.25 mg/kg) prior to pairing orange with either sucrose or corn oil. Moreover, preference expression was prevented by naltrexone injection prior to testing. Thus certain substances thought to reduce stress in infant rats via endogenous opioid release can also cause preference for substances that predict their occurrence. Preference formation depends upon the availability of endogenous opioids. Preference expression reflects the conditioned stimulus causing opioid release.     

Beta-endorphin and dynorphin mimic the circadian immunoenhancing and anti-stress effects of melatonin

We have recently demonstrated that the pineal neurohormone melatonin can enhance immune reactivity in normal mice and counteract the effects of acute stress or corticosterone treatment on antibody production, thymus weight and anti-viral resistance. These remarkable immunopharmacologic effects of melatonin were abolished by naltrexone, suggesting an involvement of the endogenous opioid system. Here we compared the immunopharmacologic action of beta-endorphin, dynorphin 1-13, leu-enkephalin and metenkephalin with that of melatonin in restraint-stressed or prednisolone-treated mice and in normal nonstressed animals. We found that beta-endorphin and dynorphin 1-13 can mimic the immunoenhancing and antistress effect of melatonin. However, at variance with the pineal neurohormone, these opioids were effective in umprimed mcie, too. We found also that restraint stress or prednisolone treatment decreases the immunopharmacologic potency of beta-endorphin and augments that of dynorphin 1-13. In fact, at the doses used, beta-endorphin enhanced the antibody response in normal but not in stressed or prednisolone-treated mice, while dynorphin 1-13 was effective only in counteracting the effect of stress or prednisolone treatment. Most interestingly, all these effects proved to be dependent on the time of administration, i.e. showed a circadian rhythm in analogy with the effects of melatonin. Again, naltrexone abolished all the opioid effects, indicating that their action was exerted via opioid receptors. These findings have important scientific and practical implications.