G-CSF Receptor Blockade Ameliorates Arthritic Pain and Disease.

G-CSF or CSF-3, originally defined as a regulator of granulocyte lineage development via its cell surface receptor (G-CSFR), can play a role in inflammation, and hence in many pathologies, due to its effects on mature lineage populations. Given this, and because pain is an extremely important arthritis symptom, the efficacy of an anti-G-CSFR mAb for arthritic pain and disease was compared with that of a neutrophil-depleting mAb, anti-Ly6G, in both adaptive and innate immune-mediated murine models. Pain and disease were ameliorated in Ag-induced arthritis, zymosan-induced arthritis, and methylated BSA/IL-1 arthritis by both prophylactic and therapeutic anti-G-CSFR mAb treatment, whereas only prophylactic anti-Ly6G mAb treatment was effective. Efficacy for pain and disease correlated with reduced joint neutrophil numbers and, importantly, benefits were noted without necessarily the concomitant reduction in circulating neutrophils. Anti-G-CSFR mAb also suppressed zymosan-induced inflammatory pain. A new G-CSF-driven (methylated BSA/G-CSF) arthritis model was established enabling us to demonstrate that pain was blocked by a cyclooxygenase-2 inhibitor, suggesting an indirect effect on neurons. Correspondingly, dorsal root ganglion neurons cultured in G-CSF failed to respond to G-CSF in vitro, and Csf3r gene expression could not be detected in dorsal root ganglion neurons by single-cell RT-PCR. These data suggest that G-CSFR/G-CSF targeting may be a safe therapeutic strategy for arthritis and other inflammatory conditions, particularly those in which pain is important, as well as for inflammatory pain per se.

Blood Pressure, Emotional Dampening, and Risk Behavior: Implications for Hypertension Development.

OBJECTIVE: Elevated resting blood pressure (BP) is associated with risk for hypertension and emotional dampening, including reduced responses to emotionally meaningful stimuli. Perception of threat is a critical motivator in avoidance of risky health-damaging behavior. We hypothesize that BP-associated dampening of threat appraisal may increase risk-taking behavior. METHODS: We measured resting BP, perception of affect, and risk behavior in 92 healthy women (n = 49) and men (n = 43) recruited from university students and staff as well as members of the surrounding community. Mean (SE) age for the sample was 21.5 (4.3) year. BP was measured using an automated BP monitor, and risk behavior was assessed with a modified National College Health Risk Behavior Survey. We also measured recognition of affect using the Perception of Affect Task (PAT). RESULTS: Risk-taking behavior was positively correlated with both systolic (r(89) = .278, p = .008) and diastolic BP (r(89) = .309, p < .003). Regression analyses indicated that the association between risk-taking behavior and BP was not mediated by PAT scores. CONCLUSIONS: Results show that persons with higher resting BP levels report increased risk-taking behavior. PAT scores, while correlated with systolic BP, did not mediate the relationship between BP and risk. The relationship between BP and risk behavior reflects the potential involvement of central nervous system regulation of both BP and emotional responsivity, and its relationship to health-damaging behavior and risk for hypertension.

Auditory Attention and Comprehension During a Simulated Night Shift: Effects of Task Characteristics.

OBJECTIVE: The current study investigated performance on a dual auditory task during a simulated night shift. BACKGROUND: Night shifts and sleep deprivation negatively affect performance on vigilance-based tasks, but less is known about the effects on complex tasks. Because language processing is necessary for successful work performance, it is important to understand how it is affected by night work and sleep deprivation. METHOD: Sixty-two participants completed a simulated night shift resulting in 28 hr of total sleep deprivation. Performance on a vigilance task and a dual auditory language task was examined across four testing sessions. RESULTS: The results indicate that working at night negatively impacts vigilance, auditory attention, and comprehension. The effects on the auditory task varied based on the content of the auditory material. When the material was interesting and easy, the participants performed better. Night work had a greater negative effect when the auditory material was less interesting and more difficult. CONCLUSION: These findings support research that vigilance decreases during the night. The results suggest that auditory comprehension suffers when individuals are required to work at night. Maintaining attention and controlling effort especially on passages that are less interesting or more difficult could improve performance during night shifts. APPLICATION: The results from the current study apply to many work environments where decision making is necessary in response to complex auditory information. Better predicting the effects of night work on language processing is important for developing improved means of coping with shiftwork.

Emotional dampening in persons with elevated blood pressure: affect dysregulation and risk for hypertension.

BACKGROUND: Persons with higher blood pressure have emotional dampening in some contexts. This may reflect interactive changes in central nervous system control of affect and autonomic function in the early stages of hypertension development. PURPOSE: The purpose of this study is to determine the independence of cardiovascular emotional dampening from alexithymia to better understand the role of affect dysregulation in blood pressure elevations. METHODS: Ninety-six normotensives were assessed for resting systolic and diastolic (DBP) blood pressure, recognition of emotions in faces and sentences using the Perception of Affect Task (PAT), alexithymia, anxiety, and defensiveness. RESULTS: Resting DBP significantly predicted PAT emotion recognition accuracy in men after adjustment for age, self-reported affect, and alexithymia. CONCLUSIONS: Cardiovascular emotional dampening is independent of alexithymia and affect in men. Dampened emotion recognition could potentially influence interpersonal communication and psychosocial distress, thereby further contributing to BP dysregulation and increased cardiovascular risk.

Effects of estrogen and opioid blockade on blood pressure reactivity to stress in postmenopausal women.

Estrogen may influence coronary heart disease risk in women through the effects of endogenous opioids on autonomic control of blood pressure. In a randomized, placebo-controlled trial, we examined the combined effects of estrogen and the opioid antagonist, naltrexone, on blood pressure responses to psychological stress in 42 postmenopausal women. After 3 months of estrogen or estrogen plus progestin (hormone replacement therapy; n = 27) or placebo replacement, participants completed a mental arithmetic task after administration of .7 mg/kg oral naltrexone or placebo. Systolic blood pressure (SBP), diastolic blood pressure, mean arterial pressure and heart rate (HR) were measured at rest and during the arithmetic stressor. Stress produced significant increases in circulatory measures regardless of estrogen condition or opioid blockade (p's < .001). Interestingly, there was an estrogen by naltrexone interaction on SBP reactivity scores [F(1,38) = 4.36, p < .05], where women on estrogen with intact opioid receptors showed the largest SBP responses to stress, compared with all other conditions. This is consistent with some studies of premenopausal women, suggesting that estrogens may alter opioid function during stress. The interaction between estrogen and endogenous opioids may explain sex differences in opioid effects on stress reactivity in younger premenopausal women.

Cardiovascular-emotional dampening: the relationship between blood pressure and recognition of emotion.

OBJECTIVE: Persons with elevated blood pressure (BP) show dampened emotional responses to affect-laden stimuli. We sought to further examine cardiovascular-emotional dampening by examination of the relationship between resting hemodynamic measures and recognition of emotion in an African American community-based sample. METHODS: Participants were 106 African American men and women (55 women; mean age = 52.8 years), mainly low in socioeconomic status, and part of the Healthy Aging in Nationally Diverse Longitudinal Samples pilot study. Participants evaluated emotional expressions in faces and sentences using the Perception of Affect Test (PAT). Resting BP, total peripheral resistance (TPR), cardiac output, and heart rate were obtained continuously using a Portapres BP monitor. RESULTS: Total PAT scores were inversely related to systolic (r = -0.30) and diastolic (r = -0.24) BPs, TPR (r = -0.36), and age (r = -0.31; p values < .01) and were positively related to cardiac output (r = 0.27) and education (r = 0.38; p values < .01), as well as with mental state (r = 0.25) and body mass index (r = -0.20; p values < .05). Accuracy of emotion recognition on the PAT tasks remained inversely related to TPR and BP after adjustment for demographic variables, medication, mental state, and body mass index. CONCLUSIONS: Elevated BP and TPR were associated with reduced perception of affect. TPR was the most consistent independent hemodynamic correlate of emotional dampening for the PAT scores. These results suggest potentially important links among central nervous system regulation of emotions, hemodynamic processes, and hypertension development.

Blood pressure increases during a simulated night shift in persons at risk for hypertension.

BACKGROUND: Shift work with sleep disruption is a systemic stressor that may possibly be associated with blood pressure dysregulation and hypertension. PURPOSE: We hypothesize that rotation to a simulated night shift with sleep deprivation will produce blood pressure elevations in persons at risk for development of hypertension. METHOD: We examined the effects of a simulated night shift on resting blood pressure in 51 diurnal young adults without current hypertension. Resting blood pressure was monitored throughout a 24-h period of total sleep deprivation with sustained cognitive work. Twelve participants (23.5%) reported one or more parents with a diagnosis of hypertension. Ten participants were classified as prehypertensive by JNC-7 criteria. Only two prehypertensive subjects reported parental hypertension. RESULTS: Results indicate that, as the night shift progressed, participants with a positive family history of hypertension showed significantly higher resting diastolic blood pressure than those with a negative family history of hypertension (p = 0.007). Prehypertensive participants showed elevated blood pressure throughout the study. CONCLUSION: These data suggest that rotation to a simulated night shift with sleep deprivation may contribute to blood pressure dysregulation in persons with a positive family history of hypertension.

Blood pressure-associated emotional dampening and risky behavior: Elevated resting blood pressure predicts risky simulated driving in women.

Elevated resting blood pressure (BP) is associated with dampened responses to emotionally meaningful stimuli. This BP-associated emotional dampening may also influence threat appraisal and, hence, motivation to avoid risk. The present study was designed to determine if resting BP is associated with risky driving behavior assessed in a high fidelity driving simulator. Fifty-one healthy women (n = 20) and men (n = 31) rested for BP determinations both before and after a simulated driving scenario in a DriveSafety automotive simulator with six visual channels, single-axis motion, and functioning controls and instrumentation. Resting systolic (SBP) and diastolic (DBP) BPs were obtained systematically with a calibrated GE Dinamap Pro V100. Risky driving was assessed by speed relative to the posted speed limit, and a speed-adjusted time to collision index of tailgating. Regression analyses indicated that sex interacted with resting BP, with significant associations between BP and risk in women, but not men. For example, risky driving in women was associated with higher resting DBP (p = .006), with similar but less reliable effects for resting SBP (p = .058). These results provide some partial, preliminary support for the notion that BP-associated emotional dampening may reduce threat appraisal and thereby decrease motivation for risk avoidance, but these effects are confined to women in this simulated driving scenario. Interacting central nervous system (CNS) mechanisms controlling BP and emotional responsivity may mediate the relationship between BP and risk-taking behavior. Relative expression of this relationship in women and men may depend on multiple psychosocial and physiological mechanisms. The association of higher BP with increased risk-taking behaviors may have relevance to the early pathogenesis of essential hypertension.

Exploring the relationship between frontal asymmetry and emotional dampening.

Cardiovascular emotional dampening is the term used to describe the inverse relationship between resting blood pressure and emotional responsivity which extends from normotensive to hypertensive ranges. Little is known about its underlying physiological mechanisms, but it is thought to involve some disruption in emotion processing. One area that has yet to be explored in the literature is the relationship between emotional dampening and frontal asymmetry, a psychophysiological indicator for motivational direction and emotional valence bias. The present study explored that relationship using data from a sample of 48 healthy college students. Measures of baseline resting blood pressure and frontal cortical activity were recorded, after which participants completed a series of emotion-related tasks. Results revealed a significant relationship between resting systolic blood pressure and left frontal activity. Likewise, left frontal activity was associated with neutral appraisal of emotionally valenced stimuli within the tasks. The findings from the present study yield support for a link between emotional dampening and left frontal activity. Implications are discussed.

Language performance under sustained work and sleep deprivation conditions.

INTRODUCTION: Although substantial research has been completed on the effects of sleep deprivation on performance, very little research has focused on language-based tasks. The purpose of the current study was two-fold: 1) to determine the extent to which short-term sleep deprivation affects language performance; and 2) to examine whether relatively short and easy-to-administer "probe" tasks could signal decrements in language performance under sleep deprivation conditions. METHODS: There were 38 non-native English-speaking students who were paid to complete a 28-h sleep deprivation study. The participants completed several potential cognitive and vigilance probe tasks and a variety of language-based tasks. Each task was administered four times, once in each testing session during the night (18:30-22:30, 23:00-03:00, 03: 30-07:30, and 08:00-12:00). All tasks were counterbalanced across the testing sessions. RESULTS: Repeated-measures ANOVAs indicated that language tasks that required sustained attention and higher level processing (e.g., reading comprehension) were negatively affected by sleep deprivation, whereas other tasks that relied primarily on more basic language processing (e.g., antonym identification) were not affected. Hierarchical linear modeling analyses assessed how well the probe tasks predicted language performance. These results indicated that performance accuracy and/or speed on many of the probe tasks predicted decrements in language performance. CONCLUSIONS: These findings suggest that sustained work conditions and sleep deprivation negatively affect some types of language performance. Moreover, the use of probe tasks indicates that easy-to-administer tasks may be useful to identify when detriments are likely to occur in language-based performance under sleep deprivation conditions.

Opioid analgesia in persons at risk for hypertension.

OBJECTIVE: Acute pain sensitivity is reduced in clinical hypertension, but the precise relationship between pain perception and altered blood pressure control is not well-characterized. A negative correlation between resting blood pressure and pain sensitivity is observed throughout the normotensive range, suggesting links between basic mechanisms of blood pressure control and pain regulation. The opioid peptides are important endogenous analgesic mechanisms, but their role in the hypoalgesia of blood pressure elevations has not been well-established. The current study sought to examine the effects of endogenous opioids on blood pressure-associated hypoalgesia in young adults at risk for hypertension development. METHODS: The effects of the opioid receptor antagonist, naltrexone, on cold pressor pain sensitivity were assessed in young adult men (n = 49) and women (n = 76) with mildly elevated casual blood pressure. RESULTS: Results indicate interactions between hypertension risk and the effects of opioid blockade on pain sensitivity. CONCLUSIONS: These findings suggest exaggerated opioid analgesia in persons at enhanced risk for hypertension and point to important links between altered neuropeptide regulation of pain and altered blood pressure control mechanisms in the early stages of hypertension.

Resting blood pressure differentially predicts time course in a tonic pain experiment.

Resting blood pressure (BP) shows a negative relationship with pain sensitivity (BP-related hypoalgesia). In chronic pain conditions, this relationship is inverted. The precise mechanisms responsible for the inversion are unknown. Using a tonic pain protocol, we report findings closely resembling this inversion in healthy participants. Resting BP and state measures of anxiety and mood were assessed from 33 participants (21 female). Participants then immersed their dominant hand in painfully hot water (47 °C) for five trials of 1-min duration, with 30-s intertrial intervals. Throughout the trials, participants continually registered their pain. After a 35-min intermission, the trial sequence was repeated. A disassociation of the negative relationship of resting systolic BP (as per Trial 1) was found using hierarchical linear modeling (p < .001, R(2) = .07). The disassociation unfolds over each consecutive trial, with an increasingly positive relationship. In Sequence 2, the initially negative relationship is almost completely absent. Furthermore, the association of BP and pain was found to be moderated by anxiety, such that only persons with low anxiety exhibited BP hypoalgesia. Our findings expand the existing literature by incorporating anxiety as a moderator of BP hypoalgesia. Furthermore, the protocol emulates the changing relationship between BP and pain observed in chronic pain patients. The protocol has potential as a model for chronic pain; however, future research should determine if similar physiological systems are involved. The finding holds potential diagnostic or prognostic relevance for certain clinical pain conditions, especially those involving dysfunction of the descending modulation of pain.

Subclinical Posttraumatic Stress Disorder Symptoms: Relationships with Blood Pressure, Hostility, and Sleep.

The purpose of this study was to examine the relationships among subclinical PTSD symptoms, blood pressure, and several variables linked to both frank PTSD and the basic psychobiological adaptation to stress. The authors recruited a sample of 91 healthy, young men and women between 18 and 35 years. We examined links among subclinical posttraumatic stress disorder symptoms, blood pressure, sleep quality, and hostility. Posttraumatic stress disorder symptoms were associated with poorer sleep quality and higher hostility scores in both women and men. In men, PTSD symptoms were also associated with elevated resting diastolic blood pressure, and sex was an important moderator of that relationship. Moreover, sleep quality and hostility are substantive mediators of the relationship between diastolic blood pressure and PTSD. Behavioral interventions designed to increase sleep quality and restructure hostile attitudes could potentially serve as preventive interventions for PTSD and the underlying cardiovascular comorbidities in young adults.

Post-traumatic stress disorder among patients with orofacial pain.

AIMS: To examine the presence and impact of post-traumatic stress disorder (PTSD) in a sample of patients seeking treatment for orofacial pain. METHODS: One hundred forty-one consecutive patients with an array of orofacial pain conditions were screened using a structured clinical interview for PTSD and the PTSD Symptom Checklist--Civilian Version (PCL), a brief PTSD self-report inventory. Additionally, participants received a clinical examination and self-report questionnaires to assess pain, coping styles, and presence of post-traumatic symptoms. RESULTS: Thirty-three (23%) patients received a full lifetime or current PTSD diagnosis, with an additional 11 patients receiving a partial PTSD diagnosis. Only 5 of these 44 patients had ever been previously diagnosed with PTSD. PTSD symptoms were associated with higher pain scores (P < .05) and affective distress (P < .01). Furthermore, discriminant function analyses suggested that the PCL accurately classified 89% of these cases (sensitivity = .85, specificity = .90, positive predictive power = 74%, negative predictive power = 95%). CONCLUSION: These results suggest that PTSD is prevalent in the orofacial pain setting and that PTSD symptomatology is associated with increased pain and affective distress that may complicate clinical presentation. Furthermore, PTSD can be accurately and efficiently assessed using a brief, self-report inventory.

Do endogenous opioids mediate the relationship between blood pressure and pain sensitivity in normotensives?

Elevated resting blood pressure is associated with decreased pain sensitivity in both animals and humans. Recent evidence suggests that this relationship may be mediated by endogenous opioid peptides in hypertensives, but the precise mechanism has not been investigated in normotensives. We examined the effect of opioid receptor blockade with naloxone on the relationship between resting blood pressure and pain sensitivity in normotensive humans. Sixteen young adults were given cold pressor and handgrip challenges after treatment with either naloxone or saline in a placebo-controlled, within-subject design. Multiple regression procedures indicated that resting systolic blood pressure was a significant predictor of cold pain ratings even after the effects of naloxone were statistically controlled. The interaction between systolic blood pressure and opioid blockade was non-significant. These data suggest that the relationship between resting blood pressure and pain sensitivity in normotensive humans is mediated, at least in part, by non-opioid mechanisms.

Two brief interventions for acute pain.

This study evaluated two brief (3-5 min) interventions for controlling responses to acute pain. Eighty male subjects were randomly assigned to 1 of 2 intervention groups (Positive Emotion Induction (PEI) or Brief Relaxation (BR)) or to 1 of 2 control groups (No-instruction or Social Demand). The PEI focused on re-creating a pleasant memory, while the BR procedure involved decreasing respiration rate and positioning the body in a relaxed posture. All subjects underwent a 60-sec finger pressure pain trial. Analyses indicated that the PEI subjects reported lower ratings of pain, fear, and anxiety, and experienced greater finger temperature recovery than controls. The BR procedure resulted in greater blood pressure recovery, but did not alter ratings of pain or emotion relative to controls. Further research is needed to explore the clinical use of the PEI for acute pain management.

The relationship between pain sensitivity and blood pressure in normotensives.

Hypertension has been found to be related to decreased sensitivity to painful stimuli. The current study explored whether this relationship extends into the normotensive range of blood pressures. Resting blood pressures were assessed in 60 male normotensives. Subjects then underwent a 1 min finger pressure pain stimulation trial. Pain ratings were inversely related to resting systolic blood pressure. This relationship was unrelated to emotional state or coping styles. Multiple regression analyses indicated that over one-third of the variance in pain ratings can be accounted for by resting blood pressure, coping style, and emotional state.

The relationship between resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain sufferers: the effects of opioid blockade.

Resting blood pressure is inversely correlated with acute pain sensitivity in healthy normotensives. This study tested: (1) whether endogenous opioid activity is necessary for this adaptive relationship to occur, (2) whether this relationship is altered in chronic low back pain (LBP), and (3) whether endogenous opioid dysfunction underlies any such alterations. Fifty-one pain-free normotensives and 44 normotensive chronic LBP sufferers received opioid blockade (8 mg naloxone i.v.) or placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each session, subjects participated in a 1-min finger pressure (FP) pain task followed by an ischemic (ISC) forearm pain task. Among pain-free normotensives, elevated resting systolic (SBP) and diastolic (DBP) blood pressure were associated with significantly higher ISC pain thresholds (P values <0.05). Elevated SBP was also associated with significantly lower FP pain ratings (P<0.05). Opioid blockade had no significant effect on the BP-pain relationships detected (P values >0.10). In combined groups analyses, a significant subject typexSBP interaction (P<0.005) was found on ISC pain threshold: elevated SBP was associated with higher pain threshold in pain-free controls, but with lower pain threshold in LBP subjects. Although subject typexBP interactions on FP and ISC pain ratings were not significant, inclusion of LBP subjects in these analyses resulted in the overall relationship between BP and pain sensitivity becoming positive (P values <0.05). Opioid blockade exerted no significant main or interaction effects in these combined groups analyses (p values >0.10). Higher DBP was associated with greater clinical pain intensity among the LBP subjects (P<0.001). Overall, these results suggest: (1) endogenous opioids do not mediate the inverse relationship between resting blood pressure and acute pain sensitivity in pain-free normotensives; (2) the BP-pain sensitivity relationship is altered in chronic pain, suggesting dysfunction in pain regulatory systems, and (3) these alterations are not related to opioid dysfunction.

Blood pressure control and hormone replacement therapy in postmenopausal women at risk for coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) in women is strongly associated with estrogen deprivation. For example, risk for CHD increases dramatically after menopause. However, the role of hormone replacement therapy (HRT) in CHD prevention currently is unresolved. To better understand CHD in women, the precise mechanisms by which estrogen affects circulatory function require clarification. Evidence suggests that exogenous estrogen may affect blood pressure (BP) control, but its interaction with other CHD risk factors has not been systematically characterized. The present study examines the role of mildly elevated resting BP, family history of CHD, and HRT on BP responses to stress in postmenopausal women. METHODS: Postmenopausal women on long-term HRT were recruited along with a control group of postmenopausal women not on HRT. These women were divided into higher versus lower risk for CHD on the basis of resting BP and family history of CHD. BP control mechanisms were assessed before, during, and after a computer-controlled laboratory stressor. RESULTS: Results indicate that women with elevated resting BP and positive family history of CHD have exaggerated BP reactivity to stress and that HRT inhibits this effect. CONCLUSIONS: This study suggests that unmedicated postmenopausal women with mildly elevated resting BP and positive family history of CHD have altered BP control as indicated by exaggerated BP responses to stress. HRT eliminates the cumulative effect of resting BP and family history on BP reactivity, suggesting that the circulatory effects of estrogen replacement may operate, at least in part, through normalization of BP reactivity in higher-risk postmenopausal women.

Elevated resting blood pressure and dampened emotional response.

OBJECTIVE: Increased blood pressure is associated with decreased reports of aversiveness for both physical pain and psychosocial stressors. Based on these findings, higher blood pressure could be associated with altered emotional responses to a broader range of stimuli. There are at least 3 ways this could happen: a) less dire response to negative stimuli with no change in response to positive stimuli; b) more positive responses to both negative and positive stimuli; or c) dampened emotional responses to both positive and negative stimuli. METHODS: Sixty-five normotensive volunteers had their resting blood pressure measured, then rated their emotional responses to a series of positive and negative photographs. RESULTS: Resting systolic blood pressure was significantly and negatively correlated with subjective emotional ratings of both positive (r = -.26) and negative (r = -.35) photographs. CONCLUSION: Results were consistent with emotion dampening for elevated resting blood pressure and may reflect homeostatic integration of neurocirculatory control and affect regulation.