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Native Americans (NAs) are at increased risk for chronic pain. One mechanism contributing to this pain disparity could be personal pain beliefs, which may influence actual pain sensitivity. Thus, we examined whether self-evaluated pain sensitivity (SEPS) mediates the relationship between ethnicity [NAs vs. non-Hispanic Whites (NHWs)] and objectively-measured pain tolerance, and whether catastrophic thinking and pain-related anxiety influence these pain beliefs. 232 healthy, pain-free NAs and NHWs completed questionnaires measuring SEPS, catastrophizing, and anxiety. Objective pain tolerance was also assessed. Results suggested: (1) NAs reported higher levels of SEPS, catastrophizing, and anxiety, (2) catastrophizing may have enhanced anxiety and both catastrophizing and anxiety were associated with higher SEPS, and (3) anxiety and SEPS were associated with lower pain tolerance. A significant bootstrapped mediation analysis suggested NAs experienced higher pain-related anxiety, which may have promoted higher SEPS, that in turn reduced pain tolerance. Longitudinal research is needed to confirm this.

The nociceptive flexion reflex (NFR) is a spinally mediated withdrawal response and is used as an electrophysiological marker of descending modulation of spinal nociception. Chemical and pharmacological modulation of nociceptive neurotransmission at the spinal level has been evidenced by direct effects of neurotransmitters and pharmacological agents on the NFR. Largely unexplored are, however, the effects of nonpharmacological noninvasive conservative interventions on the NFR. Therefore, a systematic review and meta-analysis was performed and reported following the PRISMA guidelines to determine whether and to what extent spinal nociception measured through the assessment of the NFR is modulated by conservative therapy in patients and healthy individuals. Five electronic databases were searched to identify relevant articles. Retrieved articles were screened on eligibility using the predefined inclusion criteria. Risk of bias was investigated according to Version 2 of the Cochrane risk-of-bias assessment tool for randomized trials. The evidence synthesis for this review was conducted in accordance with the Grading of Recommendations Assessment, Development and Evaluation. Thirty-six articles were included. Meta-analyses provided low-quality evidence showing that conservative therapy decreases NFR area and NFR magnitude and moderate-quality evidence for increases in NFR latency. This suggests that conservative interventions can exert immediate central effects by activating descending inhibitory pathways to reduce spinal nociception. Such interventions may help prevent and treat chronic pain characterized by enhanced spinal nociception. Furthermore, given the responsiveness of the NFR to conservative interventions, the NFR assessment seems to be an appropriate tool in empirical evaluations of treatment strategies.PROSPERO registration number: CRD42020164495.

Chronic pain results in considerable suffering, as well as significant economic and societal costs. Previous evidence suggests that Native Americans (NAs) have higher rates of chronic pain than other U.S. racial or ethnic groups, but the mechanisms contributing to this pain disparity are poorly understood. The Oklahoma Study of Native American Pain Risk was developed to address this issue and recruited healthy, pain-free NAs and non-Hispanic Whites. Cross-sectional analyses identified several measures of adversity (eg, trauma and discrimination), cognitive-affective factors (perceived stress and pain-related anxiety/catastrophizing), and cardiometabolic factors (eg, body mass index, blood pressure, and heart rate variability) that were associated with pronociceptive processes (eg, central sensitization, descending inhibition, and hyperalgesia). Every 6-months after enrollment, eligible participants (N = 277) were recontacted and assessed for the onset of chronic pain. This study examines predictors of chronic pain onset in the 222 participants (80%) who responded over the first 2 years. The results show that NAs developed chronic pain at a higher rate than non-Hispanic Whites (OR = 2.902, P0.05), even after controlling for age, sex, income, and education. Moreover, serial mediation models identified several potential pathways to chronic pain onset within the NA group. These paths included perceived discrimination, psychological stress, pain-related anxiety, a composite measure of cardiometabolic risk, and impaired descending inhibition of spinal nociception (assessed from conditioned pain modulation of the nociceptive flexion reflex). These results provide the first prospective evidence for a pain disparity in NAs that seems to be promoted by psychosocial, cardiometabolic, and pronociceptive mechanisms.

Compared to other racial/ethnic groups, Native Americans (NAs) are more likely to develop health conditions associated with allostatic load (stress-related wear-and-tear). Psychosocial factors (i.e., adverse life events, discrimination, psychological distress) often promote stress and may help explain greater allostatic load in NAs. Moreover, previous research suggests sleep may either mediate or moderate the effects of some psychosocial stressors, like discrimination, on allostatic load. The current study investigated the relationship between adverse life events, discrimination, psychological stress, sleep, and cardiometabolic load. Using a sample of 302 healthy, chronic pain-free NAs and non-Hispanic White (NHW) participants, bootstrapped mediation analyses were conducted to determine whether the relationship between NA race/ethnicity and cardiometabolic allostatic load (composite score of body mass index, mean arterial pressure, and heart rate variability) was mediated by psychosocial stressors. Models also assessed whether sleep disturbance served as an additional mediator or a moderator to the effects. Consistent with prior research, we found that NAs experienced greater discrimination, adverse life events (potentially traumatic events), and cardiometabolic allostatic load than NHWs. Further, discrimination was associated with increased psychological stress for NAs, but this did not explain why NAs experience higher cardiometabolic allostatic load. A moderating effect of sleep on discrimination was found, such that discrimination partially contributed to the relationship between NA race/ethnicity and cardiometabolic allostatic load, but only for participants reporting greater sleep disturbance. Implications These findings highlight that good sleep can buffer the effect of psychosocial stress on cardiometabolic allostatic load in Native Americans.

Jamie L Rhudy,1 Randolph C Arnau,2 Felicitas A Huber,1 Edward W Lannon,1 Bethany L Kuhn,1 Shreela Palit,1 Michael F Payne,1,3 Cassandra A Sturycz,1 Natalie Hellman,1 Yvette M Guereca,1 Tyler A Toledo,1 Joanna O Shadlow1 1The University of Tulsa, Department of Psychology, Tulsa, OK, USA; 2University of Southern Mississippi, Department of Psychology, Hattiesburg, MS, USA; 3Department of Pediatrics, Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USACorrespondence: Jamie L RhudyThe University of Tulsa, Department of Psychology, Tulsa, OK, USATel +1918 631-2839Fax +1918 631-2833Email jamie-rhudy@utulsa.eduIntroduction: Native Americans (NAs) have a higher prevalence of chronic pain than other US racial/ethnic groups, but the mechanisms contributing to this pain disparity are under-researched. Pain catastrophizing is oneof the most important psychosocial predictors of negative pain outcomes, and the Pain Catastrophizing Scale (PCS) has been established as a reliable and valid measure of the pain catastrophizing construct. However, before the PCS can be used to study pain risk in NAs, it is prudent to first determine whether the established 3-factor structure of the PCS also holds true for NAs.Methods: The current study examined the measurement (configural, metric, and scalar) invariance of the PCS in a healthy, pain-free sample of 138 NA and 144 non-Hispanic white (NHW) participants.Results: Results suggest that the previously established 3-factor solution fits for both groups (configural invariance) and that the factor loadings were equivalent across groups (metric invariance). Scalar invariance was also established, except for 1 minor scalar difference in a single threshold for item 3 (suggesting NHWs were more likely to respond with a 4 on that item than NAs).Discussion: Results provide additional evidence for the psychometric properties of the PCS and suggest it can be used to study pain catastrophizing in healthy, pain-free NA samples.Keywords: confirmatory factor analysis, pain catastrophizing, Native Americans, pain, ethnic differences, pain coping

Adverse life events (ALEs) are major life stressors that can occur throughout the lifespan and pose a significant physical or psychological threat to safety and/or security. Research suggests there is a link between ALE exposure and the development of chronic pain. Mechanistic animal and human studies indicate that stressors can have a long-lasting sensitization on nociceptive systems. This chapter reviews studies on ALE exposure and nociceptive processing in pain-free individuals to identify changes in nociceptive pathways that might confer chronic pain risk. Together, these studies indicate that ALE exposure accumulates, in a dose-dependent manner, to promote spinal sensitization. This spinal sensitization is not consistently accompanied by hyperalgesia, implying that compensatory pain inhibitory mechanisms are concurrently activated to keep amplified spinal nociception from resulting in amplified pain perception (i.e., latent spinal sensitization). Thus, chronic pain may be initiated by ALE-evoked latent spinal sensitization, followed by events that impair compensatory pain inhibition processes (e.g., additional adversity/stress, advanced age). Suggestions are made for future research.

Native Americans (NAs) have a higher prevalence of chronic pain than other U.S. racial/ethnic groups, but there have been few attempts to understand the mechanisms of this pain disparity. This study used a comprehensive battery of laboratory tasks to assess peripheral fiber function (cool/warm detection thresholds), pain sensitivity (eg, thresholds/tolerances), central sensitization (eg, temporal summation), and pain inhibition (conditioned pain modulation) in healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Multiple pain stimulus modalities were used (eg, cold, heat, pressure, ischemic, and electric), and subjective (eg, pain ratings and pain tolerance) and physiological (eg, nociceptive flexion reflex) outcomes were measured. There were no group differences on any measure, except that NAs had lower cold-pressor pain thresholds and tolerances, indicating greater pain sensitivity than NHWs. These findings suggest that there are no group differences between healthy NAs and NHWs on peripheral fiber function, central sensitization, or central pain inhibition, but NAs may have greater sensitivity to cold pain. Future studies are needed to examine potential within-group factors that might contribute to NA pain risk.

Sexual assault (SA) is associated with an increased risk of chronic pain, but the mechanisms for this relationship are poorly understood. To explore whether disrupted descending inhibition is involved, this study used a conditioned pain modulation task to study the inhibition of pain and the nociceptive flexion reflex (NFR; a correlate of spinal nociception) in 32 pain-free SA survivors. This group was compared with 32 pain-free, trauma-exposed persons without SA and a group of 40 pain-free persons who reported no trauma exposure. Conditioned pain modulation was assessed from painful electric stimulations (test stimulus) delivered to the ankle before, during, and after participants submerged their hand in painful 10°C water (conditioning stimulus). Pain ratings and NFR were assessed in response to test stimuli. All groups demonstrated significant inhibition of pain during conditioned pain modulation. However, only the no trauma exposure group demonstrated significant inhibition of NFR. The persons without SA group showed no inhibition of NFR, whereas the SA group showed significant facilitation of the NFR. These findings suggest that trauma exposure may impair inhibitory cerebrospinal circuits, but that SA may specifically promote facilitation of spinal nociception. Perspective: This study suggests that trauma exposure disrupts the cerebrospinal inhibition of spinal nociception, but that exposure to SA further promotes chronic pain risk by facilitating spinal nociception. This finding help may help to elucidate the pain risk mechanisms in trauma survivors.

Native Americans (NAs) have a higher prevalence of chronic pain than any other U.S. racial/ethnic group; however, little is known about the mechanisms for this pain disparity. This study used quantitative sensory testing to assess pain experience in healthy, pain-free adults (n = 137 NAs (87 female), n = 145 non-Hispanic whites (NHW; 68 female)) after painful electric, heat, cold, ischemic, and pressure stimuli. After each stimulus, ratings of pain intensity, sensory pain, affective pain, pain-related anxiety, and situation-specific pain catastrophizing were assessed. The results suggested that NAs reported greater sensory pain in response to suprathreshold electric and heat stimuli, greater pain-related anxiety to heat and ischemic stimuli, and more catastrophic thoughts in response to electric and heat stimuli. Sex differences were also noted; however, with the exception of catastrophic thoughts to cold, these finding were not moderated by race/ethnicity. Together, findings suggest NAs experience heightened sensory, anxiety, and catastrophizing reactions to painful stimuli. This could place NAs at risk for future chronic pain and could ultimately lead to a vicious cycle that maintains pain (eg, pain → anxiety/catastrophizing → pain). Perspective NAs experienced heightened sensory, anxiety, and catastrophizing reactions in response to multiple pain stimuli. Given the potential for anxiety and catastrophic thoughts to amplify pain, this characteristic may place them at risk for pain disorders and could lead to a vicious cycle that maintains pain.

Background The tendency to inhibit anger (anger-in) is associated with increased pain. This relationship may be explained by the negative affectivity hypothesis (anger-in increases negative affect that increases pain). Alternatively, it may be explained by the cognitive resource hypothesis (inhibiting anger limits attentional resources for pain modulation). Methods A well-validated picture-viewing paradigm was used in 98 healthy, pain-free individuals who were low or high on anger-in to study the effects of anger-in on emotional modulation of pain and attentional modulation of pain. Painful electrocutaneous stimulations were delivered during and in between pictures to evoke pain and the nociceptive flexion reflex (NFR; a physiological correlate of spinal nociception). Subjective and physiological measures of valence (ratings, facial/corrugator electromyogram) and arousal (ratings, skin conductance) were used to assess reactivity to pictures and emotional inhibition in the high anger-in group. Results The high anger-in group reported less unpleasantness, showed less facial displays of negative affect in response to unpleasant pictures, and reported greater arousal to the pleasant pictures. Despite this, both groups experienced similar emotional modulation of pain/NFR. By contrast, the high anger-in group did not show attentional modulation of pain. Conclusions These findings support the cognitive resource hypothesis and suggest that overuse of emotional inhibition in high anger-in individuals could contribute to cognitive resource deficits that in turn contribute to pain risk. Moreover, anger-in likely influenced pain processing predominantly via supraspinal (e.g., cortico-cortical) mechanisms because only pain, but not NFR, was associated with anger-in.

Native Americans (NAs) experience higher rates of chronic pain than the general U.S. population, but the risk factors for this pain disparity are unknown. NAs also experience high rates of stressors and cardiovascular and metabolic health disparities (eg, diabetes, cardiovascular disease) consistent with allostatic load (stress-related wear-and-tear on homeostatic systems). Given that allostatic load is associated with chronic pain, then allostatic load may contribute to their pain disparity. Data from 302 healthy, pain-free men and women (153 NAs, 149 non-Hispanic Whites [NHW]) were analyzed using structural equation modeling to determine whether cardiometabolic allostatic load (body mass index, blood pressure, heart rate variability) mediated the relationship between NA ethnicity and experimental measures of pronociceptive processes: temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR), conditioned pain modulation of pain (CPM-pain) and NFR (CPM-NFR), and pain tolerance. Results indicated that NAs experienced greater cardiometabolic allostatic load that was related to enhanced TS-NFR and impaired CPM-NFR. Cardiometabolic allostatic load was unrelated to measures of pain perception (CPM-pain, TS-pain, pain sensitivity). This suggests cardiometabolic allostatic load may promote spinal sensitization in healthy NAs, that is not concomitant with pain sensitization, perhaps representing a unique pain risk phenotype in NAs. Perspective: Healthy, pain-free Native Americans experienced greater cardiometabolic allostatic load that was associated with a pronociceptive pain phenotype indicative of latent spinal sensitization (ie, spinal sensitization not associated with hyperalgesia). This latent spinal sensitization could represent a pain risk phenotype for this population.

Threat-induced pain modulation can increase survival by amplifying physiological and behavioral reactions toward danger. Threat can also modulate spinal nociception, suggesting engagement of endogenous top-down circuitry. A unique method to assess spinal nociception is via reflex receptive fields (RRF) associated with the nociceptive withdrawal reflex (NWR, a protective spinally-mediated reflex). The size of nociceptive RRFs can be modulated by top-down circuitry with the enlargement of RRFs related to increased spinal nociception. Threat has been previously shown to enhance pain and spinal nociception, but the relationship between threat and RRFs has not been investigated. The present study investigated this issue in 25 healthy individuals. RRFs were determined from NWRs measured by electromyography of the tibialis anterior following electrocutaneous stimulations. RRFs and pain were assessed during periods in which participants were under threat of unpredictable painful abdominal stimulations and when they were not under threat. Results indicated that threat periods led to significantly higher pain, larger nociceptive RRFs and NWR magnitudes. These findings imply that threat produces changes in protective reflexes related to spinal nociceptive sensitivity and increased pain perception. This is likely mediated by top-down circuitry that enhances dorsal horn nociceptive neurons by enlarging RRFs and amplifying ascending pain signals. PERSPECTIVE: This article presents the enlargement of RRF during periods of threat. The results from this study may help clarify the mechanism underlining emotional modulation of spinal nociception.

Adverse life events (ALEs) are a risk factor for chronic pain; however, mechanisms underlying this association are not understood. This study examined whether cumulative ALE exposure impairs endogenous inhibition of pain (assessed from pain report) and spinal nociception (assessed from nociceptive flexion reflex; NFR) in healthy, pain-free Native Americans (n = 124) and non-Hispanic Whites (n = 129) during a conditioned pain modulation (CPM) task. Cumulative ALE exposure was assessed prior to testing by summing the number of potentially traumatic events experienced by each participant across their lifespan. Multilevel modeling found that ALEs were associated with NFR modulation during the CPM task even after controlling for general health, body mass index, sex, age, blood pressure, sleep quality, stimulation intensity, stimulus number, perceived stress, and psychological distress. Low exposure to ALEs was associated with NFR inhibition, whereas high exposure to ALEs was associated with NFR facilitation. By contrast, pain perception was inhibited during the CPM task regardless of the level of ALE exposure. Race/ethnicity did not moderate these results. Thus, ALEs may be pronociceptive for both Native Americans and non-Hispanic Whites by impairing descending inhibition of spinal nociception. This could contribute to a chronic pain risk phenotype involving latent spinal sensitization. Perspective This study found that adverse life events were associated with impaired descending inhibition of spinal nociception in a sample of Native Americans and non-Hispanic Whites. These findings expand on previous research linking adversity to chronic pain risk by identifying a proximate physiological mechanism for this association.

Native Americans (NAs) experience higher rates of chronic pain. To examine the mechanisms for this pain inequity, we have previously shown that NAs report higher levels of pain-related anxiety and pain catastrophizing, which are in turn related to pronociceptive (pain-promoting) processes. But, it is currently unclear why NAs would report greater pain-related anxiety and catastrophizing. Given that NAs are also more likely to experience adverse life events (ALEs) and associated psychological distress, it was hypothesized that higher anxiety/catastrophizing in NAs would be partially explained by higher rates of ALEs and psychological distress. Structural equation modeling was used to analyze these pathways (NA ethnicity ➔ ALEs ➔ psychological distress ➔ pain anxiety/catastrophizing) in 305 healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Pain-related anxiety and situational pain catastrophizing were assessed in response to a variety of painful tasks. The Life Events Checklist was used to assess cumulative exposure to ALEs that directly happened to each participant. A latent psychological distress variable was modeled from self-reported perceived stress and psychological symptoms. Results found that NAs experienced more ALEs and greater psychological distress which was associated with higher rates of pain-related anxiety and pain catastrophizing. Notably, NAs did not report greater psychological distress when controlling for ALE exposure. This suggests that a higher risk of chronic pain in NAs may be due, in part, to psychological distress, pain-related anxiety, and pain catastrophizing that are promoted by exposure to ALEs. These results highlight several targets for intervention to decrease NA pain risk.

Emotion has a strong modulatory effect on pain perception and spinal nociception. Pleasure inhibits pain and nociception, whereas displeasure facilitates pain and nociception. Dysregulation of this system has been implicated in development and maintenance of chronic pain. The current study sought to examine whether emotional modulation of pain could be altered through the use of transcranial direct current stimulation (tDCS) to enhance (via anodal stimulation) or depress (via cathodal stimulation) cortical excitability in the dorsolateral prefrontal cortex. Thirty-two participants (15 female, 17 male) received anodal, cathodal, and sham tDCS on three separate occasions, followed immediately by testing to examine the impact of pleasant and unpleasant images on pain and nociceptive flexion reflex (NFR) responses to electrocutaneous stimulation. Results indicated that tDCS modulated the effect of image content on NFR, F(2, 2175.06) = 3.20, P= .04, with the expected linear slope following anodal stimulation (ie, pleasantneutralunpleasant) but not cathodal stimulation. These findings provide novel evidence that the dorsolateral prefrontal cortex is critical to emotional modulation of spinal nociception. Moreover, the results suggest a physiological basis for a previously identified phenotype associated with risk for chronic pain and thus a potentially new target for chronic pain prevention efforts. PERSPECTIVE: This study demonstrated that reduction of dorsolateral prefrontal cortical excitability by transcranial direct current stimulation attenuates the impact of emotional image viewing on nociceptive reflex activity during painful electrocutaneous stimulation. This result confirms there is cortical involvement in emotional modulation of spinal nociception and opens avenues for future clinical research.

BackgroundConditioned pain modulation (CPM) is a task that involves measuring pain in response to a test stimulus before and during a painful conditioning stimulus (CS). The CS pain typically inhibits pain elicited by the test stimulus; thus, this task is used to assess endogenous pain inhibition. Moreover, less efficient CPM-related inhibition is associated with chronic pain risk. Pain catastrophizing is a cognitive-emotional process associated with negative pain sequelae, and some studies have found that catastrophizing reduces CPM efficiency.PurposeThe current study examined the relationship between catastrophizing (dispositional and situation specific) and CPM-related inhibition of pain and the nociceptive flexion reflex (NFR; a marker of spinal nociception) to determine whether the catastrophizing–CPM relationship might contribute to the higher risk of chronic pain in Native Americans (NAs).MethodsCPM of pain and NFR was assessed in 124 NAs and 129 non-Hispanic Whites. Dispositional catastrophizing was assessed at the beginning of the test day, whereas situation-specific catastrophizing was assessed in response to the CS, as well as painful electric stimuli.ResultsSituation-specific, but not dispositional, catastrophizing led to less NFR inhibition but more pain inhibition. These effects were not moderated by race, but mediation analyses found that: (a) the NA race was associated with greater situation-specific catastrophizing, which led to less NFR inhibition and more pain inhibition, and (b) situation-specific catastrophizing was associated with greater CS pain, which led to more pain inhibition.ConclusionsCatastrophizing may contribute to NA pain risk by disrupting descending inhibition.

Several studies have recently suggested that an abnormal processing of respiratory interoceptive and nociceptive (painful) stimuli may contribute to eating disorder (ED) pathophysiology. Mood and anxiety disorders (MA) are also characterized by abnormal respiratory symptoms, and show substantial comorbidity with ED. However, no studies have examined both respiratory and pain processing simultaneously within ED and MA. The present study systematically evaluated responses to perturbations of respiratory and nociceptive signals across the levels of physiology, behavior, and symptom report in a transdiagnostic ED sample (n = 51) that was individually matched to MA individuals (n = 51) and healthy comparisons (HC; n = 51). Participants underwent an inspiratory breath-holding challenge as a probe of respiratory interoception and a cold pressor challenge as a probe of pain processing. We expected both clinical groups to report greater stress and fear in response to respiratory and nociceptive perturbation than HCs, in the absence of differential physiological and behavioral responses. During breath-holding, both the ED and MA groups reported significantly more stress, feelings of suffocation, and suffocation fear than HC, with the ED group reporting the most severe symptoms. Moreover, anxiety sensitivity was related to suffocation fear only in the ED group. The heightened affective responses in the current study occurred in the absence of group differences in behavioral (breath hold duration, cold pressor duration) and physiological (end-tidal carbon dioxide, end-tidal oxygen, heart rate, skin conductance) responses. Against our expectations, there were no group differences in the response to cold pain stimulation. A matched-subgroup analysis focusing on individuals with anorexia nervosa (n = 30) produced similar results. These findings underscore the presence of abnormal respiratory interoception in MA and suggest that hyperreactivity to respiratory signals may be a potentially overlooked clinical feature of ED.

OBJECTIVE Sexual assault (SA) is associated with an increased risk for chronic pain and affective distress. Given that emotional processes modulate pain (e.g., negative emotions enhance pain, positive emotions inhibit pain), increased pain risk in SA survivors could stem from a disruption of emotional modulation processes. METHODS A well-validated affective picture-viewing paradigm was used to study emotional modulation of pain in 33 healthy, pain-free SA survivors and a control group of 33 healthy, pain-free individuals with no reported history of SA (matched on age, sex, race, and number of non-SA traumas). Unpleasant (mutilation), neutral, and pleasant (erotic) pictures were presented, while painful electrocutaneous stimulations were delivered at the ankle. Pain intensity ratings and nociceptive flexion reflex (NFR) magnitudes (a physiologic measure of spinal nociception) were recorded in response to electric stimuli. Multilevel models were used to analyze the data with group (SA versus non-SA) and content (mutilation, neutral, erotic) as independent variables. RESULTS Both groups demonstrated similar emotional modulation of pain (FGroupbyContent(2,646.52) = 0.44, p = .65), but a main effect of group (FGroup(1,65.42) = 4.24, p = .043) indicated the SA group experienced more overall pain from electric stimuli (hyperalgesia). A significant group by content interaction for NFR (p = .035) indicated that emotional modulation of NFR was present for the non-SA group (FContentSimpleEffect(2,684.55) = 12.43, p < .001), but not the SA group (FContentSimpleEffect(2,683.38) = 1.71, p = .18). CONCLUSIONS These findings suggest that SA survivors have difficulty emotionally engaging brain-to-spinal cord mechanisms to modulate spinal nociception. A disruption of descending inhibition plus hyperalgesia could contribute to comorbidity between sexual trauma and chronic pain.

Negative affect is considered an important factor in the etiology of depression and anxiety, and is highly related to pain. However, negative affect is not a unitary construct. To identify specific targets for treatment development, we aimed to derive latent variables of negative affect and test their unique contributions to affective processing during anticipation of unpredictable, painful shock. Eighty-three subjects (43 with depression and anxiety spectrum disorders and 40 healthy controls) completed self-report measures of negative valence and underwent neuroimaging while exploring computer-simulated contexts with and without the threat of a painful, but tolerable, shock. Principal component analysis (PCA) extracted distinct components of general negative affect (GNA) and pain-related negative affect (PNA). While elevated GNA and PNA were both indicative of depression and anxiety disorders, greater PNA was more strongly related to task-specific anxious reactivity during shock anticipation. GNA was associated with increased precuneus and middle frontal gyrus activity, whereas PNA was related to increased bilateral anterior insula activity. Anterior insula activity mediated the relationship between PNA and task-specific anxious reactivity. In conclusion, GNA and PNA have distinct neural signatures and uniquely contribute to anxious anticipation. PNA, via insula activity, may relate to arousal in ways that could contribute to affective dysregulation, and thus may be an important treatment target.

Habituation (ie, decreases in responding) and sensitization (ie, increases in responding) after prolonged or repeated exposures to a fixed stimulus have been identified as important in adaptation to repeated or prolonged noxious stimulation. Determinants of habituation or sensitization are poorly understood, and experimental investigation of habituation of pain ratings have generally relied on pain reports and statistical techniques that average responses across a group of participants. Using a cross-sectional design, the current study used multilevel growth curve analyses to examine changes in the nociceptive flexion reflex (NFR), a spinal nociceptive withdrawal reflex, and pain ratings in response to 12 repeated, constant intensity, noxious electrocutaneous stimuli. Unconditional growth curve models indicated that, on average, participants evidenced habituation of the NFR and sensitization of pain ratings. However, a substantial subgroup of participants exhibited the opposite pattern of change. In conditional models, behavioral inhibition, b = .10, P = .003, and behavioral activation, b = −.07, P = .07, independently interacted with the growth curve to predict changes in NFR, but not pain ratings, across the 12 stimuli. These findings provide preliminary experimental support for Jensen and colleagues' 2-factor model of pain experience and implicate a role for approach and avoidance motivations in descending modulation of NFR. Perspective Using repeated NFR stimulation, this study showed that most participants exhibited NFR habituation and pain sensitization; however, a substantial subgroup showed an opposite pattern of pain habituation (25.0%) and NFR sensitization (31.4%). Further, NFR habituation was moderated by individual differences in behavioral activation and behavioral inhibition.

Introduction: Evidence suggests Native Americans (NAs) experience higher rates of chronic pain than the general US population, but the mechanisms contributing to this disparity are poorly understood. Recently, we conducted a study of healthy, pain-free NAs (n = 155), and non-Hispanic whites (NHWs, n = 150) to address this issue and found little evidence that NAs and NHWs differ in pain processing (assessed from multiple quantitative sensory tests). However, NAs reported higher levels of pain-related anxiety during many of the tasks. Objective: The current study is a secondary analysis of those data to examine whether pain-related anxiety could promote pronociceptive processes in NAs to put them at chronic pain risk. Methods: Bootstrapped indirect effect tests were conducted to examine whether pain-related anxiety mediated the relationships between race (NHW vs NA) and measures of pain tolerance (electric, heat, ischemia, and cold pressor), temporal summation of pain and the nociceptive flexion reflex (NFR), and conditioned pain modulation of pain/NFR. Results: Pain-related anxiety mediated the relationships between NA race and pain tolerance and conditioned pain modulation of NFR. Exploratory analyses failed to show that race moderated relationships between pain-related anxiety and pain outcomes. Conclusion: These findings imply that pain-related anxiety is not a unique mechanism of pain risk for NAs, but that the greater tendency to experience pain-related anxiety by NAs impairs their ability to engage descending inhibition of spinal nociception and decreases their pain tolerance (more so than NHWs). Thus, pain-related anxiety may promote pronociceptive processes in NAs to place them at risk for future chronic pain.

Objective To assess conditioned pain modulation efficiency in persons with and without migraine headaches. Design Cross-sectional assessment of experimental pain. Setting University campus and surrounding community in a large Midwestern US city. Subjects Twenty-three adults with and 32 without a history of migraine headaches participated in the study. Participants were mostly female (N = 40) with an average age of 23 years. Methods Four electrocutaneous stimulations of the supraorbital branch of the left trigeminal nerve were delivered at 150% of an individually determined pain threshold. Conditioned pain modulation was assessed by applying a noxious counterstimulus (forearm ischemia) and delivering four more electrocutaneous stimulations. After each stimulation, pain and the nociceptive blink reflex were assessed. Depression and pain catastrophizing were assessed to control for the potential influence of these variables on pain modulation. Results Participants with and without migraine headaches had similar baseline pain responsivity, without significant differences in pain report or nociceptive blink reflexes. Pain report was inhibited by conditioned pain modulation in both the migraine and control groups. However, unlike nonmigraine controls, participants with migraines did not exhibit an inhibition of nociceptive blink reflexes during the ischemia task. This pattern persisted after controlling for level of pain catastrophizing and depression. Conclusions Migraine sufferers exhibited impaired conditioned pain modulation of the nociceptive blink reflex, suggesting a deficiency in inhibition of trigeminal nociception, which may contribute to the development of migraine headaches.

Objectives: We aimed to investigate the possibility of sample size as a possible source of heterogeneity in trials comparing the nociceptive flexion reflex threshold (NFRthr) in fibromyalgia (FM) patients and healthy controls. Methods: A systematic search strategy was designed and conducted in electronic databases such as Ovid MEDLINE, Cochrane Libraries, Embase, and PsycINFO. In total, nine scholarly records were filtered by the inclusion and exclusion criteria, passed for data extraction (e.g. study designs and settings; methodology; total, male, and female sample sizes in FM and healthy control groups, and effect sizes), and statistical analyses (e.g. metaanalysis and meta-regression). Using random-effects model, the effect size (i.e. mean difference between the NFRthr in FM patients and healthy controls) was meta-analyzed. Investigating the sample size as a possible source of heterogeneity and utilizing a restricted maximum likelihood (REML) technique, the trials’ effect sizes were meta-regressed in multiple meta-regression against the total, male, and female sample sizes. Prior to any investigations, the aims of this research were registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42019140354). Results: Results indicated the deficit in NFRthr (overall mean difference = −3.16; 95% 𝐶𝐼: −6.82 𝑡𝑜 0.50) was heterogenous (𝐼 2 = 0.91, 𝜏 2 = 25.04, 𝜒2= 91.22, df & < 0.00001) and the overall effect was not statistically significant (Z = 1.69; 𝑃 = 0.09). The multiple meta-regression analyses indicated that one of the main sources of bias to the effect size in the trials was found to be the total (𝑆𝑆𝑡𝑜𝑡𝑎𝑙 = −0.0570; 𝑃 = 0.040) and female (𝑆𝑆𝑓𝑒𝑚𝑎𝑙𝑒 = −0.0569; 𝑃 = 0.047) sample sizes that participated in the studies. Conclusion: The findings suggest that the total and female sample sizes might be possible sources of bias to effect sizes determined in NFRthr in FM patient and healthy controls. A possible solution might be to conduct sex-specific trials to determine the NFRthr among FM patients in future research. Funding Statement: Authors received no source of funding for this research. Declaration of Interests: Authors declare no conflict of interest. Ethics Approval Statement: PROSPERO; registration number: CRD42019140354

Adverse life experiences (ALEs) are associated with hyperalgesia and chronic pain, but the underlying mechanisms are poorly understood. One potential mechanism is hyperexcitability of spinal neurons (i.e., central sensitization). Given that Native Americans (NA) are more likely to have ALEs, and have a higher prevalence of chronic pain, the relationship between ALEs and spinal hyperexcitability might contribute to their pain risk. The present study assessed temporal summation of the nociceptive flexion reflex (TS-NFR; correlate of spinal hyperexcitability) and pain (TS-Pain) in 246 healthy, pain-free non-Hispanic whites (NHW) and Native Americans (NA). The Life Events Checklist (LEC-4) assessed the number of ALEs. Multilevel growth models were used to predict TS-NFR and TS-Pain, after controlling for age, perceived stress, psychological problems, negative and positive affect, and painful stimulus intensity. ALEs and negative affect were significantly associated with higher pain, but not enhanced TS-Pain. By contrast, ALEs were associated with enhanced TS-NFR. Race did not moderate these relationships. This implies that ALEs promote hyperalgesia as a result of increased spinal neuron excitability. Although relationships between ALEs and NFR/pain were not stronger in NAs, given prior evidence that NAs experience more ALEs, this might contribute to the higher prevalence of chronic pain in NAs. PERSPECTIVE: This study found a dose-dependent relationship between adverse life experiences (ALE) and spinal neuron excitability. Although the relationship was not stronger in Native Americans (NA) than non-Hispanic whites, given prior evidence that NAs experience more ALEs, this could contribute to the higher prevalence of chronic pain in NAs.

Compared to other racial/ethnic minority groups, Native Americans (NAs) are more likely to report experiences of discrimination and also have the highest prevalence of pain conditions. Thus, there is a need to understand how and why these disproportionately high rates occur. Discrimination has been conceptualized within the biopsychosocial model as a chronic psychosocial stressor that can lead to dysfunction of regulatory processes, such as pain. A recent study found that perceived discrimination increased psychological distress that, in turn, led to increased chronic pain. To date, these relationships have not yet been evaluated in NAs. The present study examined perceived discrimination, stress, and pain tolerance in healthy, pain-free NAs (N=112) and NHWs (N=128). Discrimination was measured with the Everyday Discrimination Scale (EDS), stress was measured with the Perceived Stress Scale (PSS), and pain tolerance was measured in reaction to cold, heat, electrocutaneous, and ischemia pain stimuli. Results indicated NAs experienced more discrimination than NHWs (p

Identification of those at risk for chronic pain development may help prevent its onset. The relationship between blood pressure (BP) and pain processing has been studied extensively, but it is unknown whether BP is related to future pain onset. The current study examined whether resting BP predicts the development of chronic pain in participants from the OK-SNAP study who were healthy and pain-free at the time of enrollment. BP was recorded 3 times and averaged at the time of enrollment. Following the OK-SNAP main study, participants were contacted every 6 months to assess for chronic pain. Of the 139 Native American (NA) and 147 non-Hispanic white (NHW) participants enrolled, 208 (73%) responded to at least 1 follow-up. Participants were deemed to have chronic pain if they experienced pain for >3 months that did not remit at subsequent follow-ups (N=35; 17%). These persons were compared to those that reported no persistent pain at any follow-up (N=133; 64%). First, zero-order correlations were conducted between chronic pain onset, BP, and control variables. Systolic BP, diastolic BP, race, general health perception, and age were significantly related to chronic pain onset (ps

The tendency to inhibit anger (anger-in) is associated with increased pain. This relationship may be explained by the negative affectivity hypothesis such that those with high anger-in experience increased negative affectivity and thus increased pain (because negative affect enhances pain). Alternatively, this relationship may be explained by the cognitive resource hypothesis such that anger-in limits attentional resources normally available for pain modulation. The present study examined these competing hypotheses in healthy, pain-free participants using a well-validated picture viewing paradigm (ie, Emotional Controls of Nociception, ECON). ECON is a paradigm in which painful, electrocutaneous stimulations are delivered during and in between pictures of emotional content (mutilation, neutral, and erotica). Pain ratings were assessed in response to electric stimuli. This allows for the assessment of emotional modulation of pain by comparing pain evoked during mutilation and erotic pictures to pain evoked during neutral pictures. Additionally, ECON allows for the assessment of attentional modulation of pain by comparing pain evoked during neutral pictures (distraction) to pain evoked in the absence of pictures (control). Prior to ECON, participants filled out the Anger Expression Inventory to assess their tendency to inhibit anger and 2 groups were formed (high anger-in, N = 71 and low anger-in, N = 27) from their responses (ie, +/- 1SD from the normative mean of anger-in). Results found that both groups demonstrated similar emotional modulation of pain. By contrast, persons in the low anger-in group displayed attentional modulation of pain, whereas persons in the high anger-in group failed to attentionally modulate pain. These findings suggest that cognitive resource deficits in high anger-in individuals may contribute to increased pain risk.

Pain catastrophizing is associated with enhanced pain; however, the mechanisms by which it modulates pain are poorly understood. Evidence suggests that catastrophizing modulates supraspinal processing of pain but does not modulate spinal nociception (as assessed by nociceptive flexion reflex [NFR]). Unfortunately, most NFR studies have been correlational. To address this, this study experimentally reduced catastrophizing to determine whether it modulates spinal nociception (NFR). Healthy pain-free participants (N = 113) were randomly assigned to a brief 30-minute catastrophizing reduction manipulation or a control group that received pain education. Before and after manipulations, 2 types of painful stimuli were delivered to elicit (1) NFR (single trains of stimuli) and (2) temporal summation of NFR (3 stimulations at 2 Hz). After each set of stimuli, participants were asked to report their pain intensity and unpleasantness, as well as their situation-specific catastrophizing. Manipulation checks verified that catastrophizing was effectively reduced. Furthermore, pain intensity and unpleasantness to both stimulation types were reduced by the catastrophizing manipulation, effects that were mediated by catastrophizing. Although NFRs were not affected by the catastrophizing manipulation, temporal summation of NFR was reduced. However, this effect was not mediated by catastrophizing. These results indicate that reductions in catastrophizing lead to reductions in pain perception but do not modulate spinal nociception and provides further evidence that catastrophizing modulates pain at the supraspinal, not the spinal, level.

OBJECTIVE Premenstrual dysphoric disorder (PMDD) is associated with increased pain, but there has been a lack of well-controlled research assessing pain responsivity, sex hormones, and their relationships in this group. This study was designed to address this gap in the literature. MATERIALS AND METHODS Healthy, regularly cycling participants (14 PMDD, 14 non-PMDD) attended pain testing sessions during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (order counterbalanced) and salivary estradiol, progesterone, and testosterone were assessed at each testing session. Pain sensitivity was measured from electrocutaneous threshold/tolerance, ischemic threshold/tolerance, sensory and affective ratings of electrocutaneous and ischemic stimuli, and the nociceptive flexion reflex threshold (NFR, a measure of spinal nociception). RESULTS Women with PMDD had higher sensory pain ratings of electrocutaneous stimuli and trends for lower ischemic thresholds and higher affective pain ratings of electrocutaneous stimuli. However, there were no group differences observed in NFR threshold. Testosterone levels were also lower during the mid-follicular and ovulatory phases in PMDD. Correlations between pain outcomes and estradiol and testosterone indicated that these hormones are hypoalgesic, with estradiol having a greater hypoalgesic effect within the PMDD group. DISCUSSION Overall, women with PMDD may have a phase-independent hyperalgesia, with pain amplification likely occurring at the supraspinal level rather than the spinal level, given the lack of group differences in NFR threshold. Because testosterone was hypoalgesic and lower in women with PMDD, and there were strong associations between pain and estradiol in PMDD, sex hormones may play a role in PMDD-related hyperalgesia.

Trauma exposure, especially sexual assault (SA), is highly correlated with pain conditions, in that many chronic pain samples report trauma histories. However, our understanding of the mechanisms behind this relationship is limited. Previous findings from our lab suggest that SA disrupts descending pain modulation. However, to date, no study has used quantitative sensory testing (QST) to comprehensively assess the pain system in SA survivors. 41 healthy, pain-free SA survivors were matched to a group of 41 healthy, pain-free trauma exposed persons without SA (TE). These groups were compared to a group of healthy, pain-free persons with no trauma history (no-TE; N=62). QST included warm, cool, heat, cold, ischemia, and electric thresholds, and heat, cold, ischemia, and electric tolerances. The nociceptive flexion reflex (NFR) threshold was used to assess spinal nociception. Results suggested SA survivors had higher cool thresholds than the TE and no-TE groups. Moreover, SA survivors had lower cold thresholds, cold tolerances, and heat tolerances than no-TE. Surprisingly, SA survivors had higher ischemia tolerances than no-TE and TE groups. The TE group had lower heat and cold tolerances than the no-TE group. None of the other group differences were significant for any pain outcome. These findings suggest that SA is associated with greater sensitivity in A-delta fibers (cool thresholds) and hyperalgesia in response to thermal stimuli (heat, cold). However, hypoalgesia was noted in response to deep tissue pain (ischemia). By contrast, TE is primarily associated with reduced tolerance to heat and cold. These group differences are not likely due to spinal sensitization due to the lack of group differences in NFR. Future studies are needed to replicate these findings and determine whether QST responses can predict negative sequela of SA and non-SA trauma exposure.

Previous research has explored cultural differences concerning the prevalence, response, and treatment preferences of individuals experiencing pain. However, the meaning of these painful experiences has not been comprehensively examined. Research tends to generalize findings from predominantly European American samples and assume universality of their findings across cultures. Numerous studies have demonstrated a significantly higher prevalence of physical pain in Native Americans (NA) compared to non-Hispanic Whites (NHW). Because of this, it is important to consider whether our current understanding of painful experiences is indeed universal. To accomplish this, a semi-structured interview was administered to 156 NAs and 151 NHWs that asked open-ended questions related to: words used to describe physically injurious experiences, the purpose of pain, individual and culture-specific pain meaning, and words for the opposite of pain. Next, themes were generated from transcripts and two raters blind to participants’ racial/ethnic group coded transcripts for the themes. Strong agreement between raters was obtained (Kappa= .75-1.00). Chi-square analyses assessed whether the frequency of responses for themes were different between NHWs and NAs. In general, frequency of themes were similar between groups; nonetheless, a few small group differences were noted. NHWs used the word pain more often to describe physically hurtful experiences (45.3% vs. 42.1%; χ 2 [1, N=309]=4.675, p 2 [1, N=309]=7.320, p 2 [1, N=309]=13.310, p

Chronic pain results in tremendous economic and psychological burden. Thus, an ability to identify individuals at risk for chronic pain onset could be an important first step in reducing this burden. One mechanism that may contribute to pain onset is impaired descending pain inhibition. The present study examined whether the efficiency of descending inhibition (as measured by conditioned pain modulation, CPM) predicted future chronic pain onset in a sample of participants who were healthy and pain-free at the time of enrollment in OK-SNAP. Chronic pain onset was determined prospectively from follow-up surveys administered every 6-months following enrollment. Of the 139 Native American (NA) and 147 non-Hispanic white (NHW) participants enrolled, 208 (73%) responded to ≥1 follow-up. Participants were said to have developed chronic pain if they experienced persistent pain for >3 months and the pain did not remit at subsequent follow-ups (N=34, 16%). 174 persons did not develop chronic pain. CPM was assessed from painful electric stimulations delivered before and during hand/forearm submersion in 10˚C water. Pain ratings and nociceptive flexion reflexes (NFR; correlate of spinal nociception) were assessed in response to electric stimuli. CPM efficiency = change in pain/NFR. CPM of pain and NFR were entered as predictors in a logistic regression that controlled for race (NA vs. NHW), age, BMI, sex, general health, depression, anxiety, and somatization. Interactions between race and CPM efficiency were examined as well. Results found less efficient CPM of NFR (OR=6.53, 95%CI: 1.04, 40.95) and more depressive symptoms (OR=10.22, 95%CI: 1.28, 81.36) at enrollment predicted chronic pain onset. The model explained 34.5% of the variance (Nagelkerke R2=.345). Interactions of CPM variables with race were not significant. These findings imply that impaired descending inhibition of spinal nociception (NFR) may play a role in the development of chronic pain.

Objective The aim of this study was to conduct a preliminary dismantling study of exposure, relaxation, and rescripting therapy (ERRT) for nightmares. Method Participants (N = 70) were randomized to 1 of 2 conditions: ERRT with nightmare exposure and rescripting (full protocol; EX) or ERRT without nightmare exposure and rescripting (NEX). Participants completed follow-ups at 1 week, 3 months, and 6 months posttreatment. Results Both conditions yielded statistically significant improvements with medium to large effect sizes on primary outcomes related to nightmares (i.e., nights with nightmares, nightmares per week, and nightmare severity). Both conditions also yielded statistically significant improvements on secondary outcomes with medium to large effect sizes on fear of sleep, sleep quality, insomnia severity, daytime sleepiness, posttraumatic stress disorder symptom severity, and depression severity. The conditions did not differ at any time point. Conclusions Findings indicate that ERRT with and without nightmare exposure and rescripting can significantly alleviate nightmares and related distress. The addition of nightmare exposure and rescription did not contribute incrementally to outcomes in this sample. It is possible that the dose of exposure was not sufficient to result in group differences or that the treatment components included in both conditions (i.e., psychoeducation about trauma, nightmares, and sleep; sleep habit modification; and relaxation training) may adequately treat factors that maintain nightmares for some individuals. Theoretical implications of findings are discussed. The reduction of symptoms of other conditions following this brief intervention provides further evidence for the primary role of nightmares and sleep disturbances posttrauma. (PsycINFO Database Record

Ellen L Terry, Yvette M Güereca, Satin L Martin, Jamie L RhudyDepartment of Psychology, The University of Tulsa, Tulsa, OK, USA Objectives: Prior research has shown a relationship between blood glucose levels and some forms of self-regulation (eg, executive function), with low blood glucose levels associated with impaired self-regulation. Further, engagement in self-regulation tasks depletes blood glucose. Given these relationships, the present study examined whether blood glucose is associated with another form of self-regulation, ie, descending pain modulatory processes. Methods: Forty-seven (32 female) pain-free participants were recruited and completed testing. Blood glucose was measured from finger sticks and a digital meter before and after experimental pain tests. Pain tests included the nociceptive flexion reflex (NFR) threshold to assess descending modulation of spinal nociception, but also electric pain threshold to assess perceptual pain detection. The Stroop color word naming test was also assessed before and after pain testing to examine changes in executive function. Results: Results indicated that mean blood glucose levels decreased after pain testing, but Stroop performance did not significantly change. Importantly, changes in blood glucose were correlated with NFR threshold, such that decreases in blood glucose were associated with lower NFR thresholds (reduced descending inhibition). Changes in blood glucose were unrelated to pain threshold or executive function. Conclusion: This study suggests that glucose depletion may impair performance of descending inhibitory processes, without impacting the perceptual detection of pain (pain threshold). Although findings need to be replicated, maintaining adequate glucose levels may be necessary to support inhibition of spinal nociception. Keywords: pain, nociception, glucose, descending modulation, executive function&nbsp

Shreela Palit,1 Emily J Bartley,2 Bethany L Kuhn,1 Kara L Kerr,1 Jennifer L DelVentura,1 Ellen L Terry,1 Jamie L Rhudy1 1Department of Psychology, University of Tulsa, Tulsa, OK, USA; 2Department of Community Dentistry and Behavioral Science, Pain Research and Intervention Center of Excellence, University of Florida, Gainesville, FL, USA Purpose: Premenstrual dysphoric disorder (PMDD) is characterized by severe affective and physical symptoms, such as increased pain, during the late-luteal phase of the menstrual cycle. The mechanisms underlying hyperalgesia in women with PMDD have yet to be identified, and supraspinal pain modulation has yet to be examined in this population. The present study assessed endogenous pain inhibitory processing by examining conditioned pain modulation (CPM, a painful conditioning stimulus inhibiting pain evoked by a test stimulus at a distal body site) of pain and the nociceptive flexion reflex (NFR, a spinally-mediated withdrawal reflex) during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle. Methods: Participants were regularly-cycling women (14 without PMDD; 14 with PMDD). CPM was assessed by delivering electrocutaneous test stimuli to the sural nerve before, during, and after a painful conditioning ischemia task. Participants rated their pain to electrocutaneous stimuli, and NFR magnitudes were measured. A linear mixed model analysis was used to assess the influence of group and menstrual phase on CPM. Results: Compared with controls, women with PMDD experienced greater pain during the late-luteal phase and enhanced spinal nociception during the ovulation phase, both of which were independent of CPM. Both groups showed CPM inhibition of pain that did not differ by menstrual phase. Only women with PMDD evidenced CPM inhibition of NFR. Conclusion: Endogenous modulation of pain and spinal nociception is not disrupted in women with PMDD. Additionally, greater NFR magnitudes during ovulation in PMDD may be due to tonically-engaged descending mechanisms that facilitate spinal nociception, leading to enhanced pain during the premenstrual phase. Keywords: premenstrual dysphoric disorder, menstrual cycle, pain, conditioned pain modulation, nociception

Slow breathing is used as a means to reduce pain, yet the mechanisms responsible for respiration-induced hypoalgesia are poorly understood. The present study asked 30 healthy partici- pants (Mage = 21 years, Meducation = 15 years, 80% white non-Hispanic) to breathe at normal, slow (50% normal), and fast (125% normal) rates while constant-intensity, suprathreshold electric stimu- lations were delivered to the sural nerve to elicit pain and the nociceptive flexion reflex (NFR, a mea- sure of spinal nociception). Stimulations were equally balanced across inhalations and exhalations to determine whether parasympathetic activation during exhalations contributes to hypoalgesia. Respi- ration rate, heart rate variability (HRV, a measure of parasympathetic activity), heart rate, and subjec- tive arousal were assessed as manipulation checks. Slow breathing reduced pain relative to normal breathing and fast breathing, but NFR was not influenced by breathing. Further, pain and NFR did not differ between exhalations and inhalations, and changes in HRV did not correlate with changes in pain or NFR. Together, these findings suggest that respiration-induced hypoalgesia does not re- quire gating of spinal nociception or changes in parasympathetic activity. Perspective: Slow breathing reduced pain relative to normal and fast breathing. This respiration- induced hypoalgesia does not appear to be due to gating of spinal nociception or changes in para- sympathetic activity.

The nociceptive flexion reflex (NFR) is a polysynaptic withdrawal reflex typically assessed from biceps femoris electromyogram (EMG) following noxious stimulation of the ipsilateral sural nerve. Electrophysiological evidence suggests the reflex is elicited following the activation of small diameter A-delta afferents. As a result, the NFR is assumed to be a categorically distinct construct that emerges from EMG activity only following nociceptor activation. Despite the widespread use of the NFR in pain research, there has been little attempt to verify the latent structure of the NFR. The present study used "coherent cut kinetics" taxometric analyses to examine whether the latent structure of biceps femoris EMG reflects the taxonic structure that would be predicted from electrophysiological evidence. To achieve this end, preliminary analyses first compared different methods of scoring NFR magnitude. Results suggested the presence of a taxon in the covariance of biceps femoris EMG and stimulus intensity that is likely to be the NFR. Furthermore, preliminary analyses suggested the best method of scoring NFR magnitude was using Cohen's d. Implications of these results are discussed.

Prior research has found that pain catastrophizing measured before pain testing is not correlated with the nociceptive flexion reflex (NFR) threshold (a measure of spinal nociception), suggesting that catastrophizing does not alter pain through descending modulatory mechanisms. However, recent evidence suggests that in vivo catastrophizing (measured during or after pain testing) is a better predictor of pain outcomes. In the present study, NFR threshold and pain sensation ratings were assessed in 78 healthy participants by delivering electric stimulations to the sural nerve. After pain testing, participants were asked to rate their affective reaction (displeasure, arousal) to electric stimuli and to report on their pain catastrophizing. Hierarchical regression analyses controlling for participant sex, pre-experiment affect, depressive symptoms, and self-efficacy were used to predict pain-related outcomes (NFR threshold, pain sensation, displeasure ratings, arousal ratings) from in vivo catastrophizing scores. Results indicated that in vivo catastrophizing was related to pain sensation but not to NFR thresholds or arousal reactions. The relation between in vivo catastrophizing and displeasure ratings was not significant after other variables were controlled. These data support prior research suggesting that catastrophizing does not alter pain by engaging descending modulatory mechanisms. Perspective Pain catastrophizing is an important psychological predictor of pain and pain-related functioning. The present study confirms prior reports suggesting that catastrophizing does not work by engaging mechanisms that alter pain transmission in the spinal cord before the signal travels to the brain.

Prior research indicates that exposure to fear-inducing stimuli inhibits finger withdrawal to sudden onset and high intensity radiant heat in humans. Although withdrawal latencies to intense heat are thought to reflect changes in spinal nociceptive processing, supraspinal measures are needed to determine whether pain perception is altered. The present study used gradual onset and low intensity radiant heat to induce a finger withdrawal response that depends on supraspinal processes. After baseline pain threshold tests, 57 healthy human participants were randomly assigned to 1 of 2 groups. In the fear group, participants received 3 brief shocks. In the neutral group, participants did not receive shock. Results suggest that finger withdrawal latencies to low intensity heat were increased after shock presentation, providing additional evidence that fear reduces pain on a measure that is influenced by supraspinal processes. Both self-report and physiological (skin conductance level, heart rate, and blood pressure) measures of emotion confirmed that the intended affective states were induced. Finger temperature was unaffected by emotion manipulations; thus, skin cooling does not appear to mediate increased withdrawal latencies. These findings provide additional evidence that fear not only inhibits spinal nociceptive reflexes, it also inhibits supraspinal measures of pain. Perspective From a clinical perspective, these data suggest that patients who experience intense fear in response to unpredictable threatening events will show a reduction in pain perception.

Objectives. Our laboratory has shown that electrical shocks induce fear in human participants and subsequently inhibit pain on the hand receiving shocks. The present study examined whether pain modulation is bilateral, by testing pain on the hand contralateral to the one receiving shocks. We also evaluated whether individual differences in emotional response to the shocks influenced pain modulation. Design. Following baseline tests, 61 participants were randomly assigned to one of two groups. In the shock group, participants received three surprising electrical shocks. In the control group, stimulating electrodes were removed from participants' fingers, and no shocks were presented. Both groups received two more pain threshold tests 2 and 8 minutes later. Outcome Measures. Similarly to the tail-flick test used in rodents, pain threshold was tested by measuring the latency of finger withdrawal to radiant heat. The following manipulation checks assessed the emotional state induced by shocks and the control procedure: Self-reported affect, skin conductance level (SCL), heart rate (HR), and blood pressure (BP). Results. Surprisingly, self-reported affect data indicate that some participants reacted to the shocks with humor and fear, while others reacted primarily with fear. Therefore, these groups were analyzed separately. Participants reacting with fear only exhibited hypoalgesia; however, participants reacting with mixed fear and humor showed no change in pain. This divergent effect was not mediated by arousal, because SCL, HR, and BP were similar in both shocked groups (fear only, fear + humor). Conclusions. These data suggest that fear-induced hypoalgesia occurs bilaterally. However, humor experienced concurrent with fear appears to inhibit hypoalgesia. These findings may help explain individual differences in pain following traumatic events.

Objective Sex differences in pain are well established, with women reporting greater incidence of clinical pain and heightened responsivity to experimental pain stimuli relative to men. Sex hormones (ie, estrogens, progestins, androgens) could contribute to extant differences in pain sensitivity between men and women. Despite this, there has been limited experimental research assessing the relationship between pain and sex hormones. The purpose of this study was to extend previous research and examine the association between sex hormones and nociceptive processing in healthy women. Materials and methods A total of 40 healthy women were tested during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (testing order counterbalanced). Salivary estradiol, progesterone, and testosterone were collected at each testing session and pain was examined from electrocutaneous threshold/tolerance, ischemia threshold/tolerance, and McGill Pain Questionnaire-Short Form ratings of noxious stimuli. Nociceptive flexion reflex threshold was assessed as a measure of spinal nociception. Results Overall, there were no significant menstrual phase-related differences in pain outcomes. Nonetheless, variability in testosterone (and to a lesser degree estradiol) was associated with pain; testosterone was antinociceptive, whereas estradiol was pronociceptive. No hormone was associated with nociceptive flexion reflex threshold. Discussion Although future research is needed to replicate and extend these findings to clinical populations (ie, chronic pain, premenstrual dysphoric disorder), results from the present study indicate that menstrual phase-related changes in sex hormones have minimal influence on experimental pain. However, individual differences in testosterone may play a protective role against pain in healthy women.

Considerable animal research suggests that exposure to noxious and nonnoxious fear-inducing stimuli can produce hypoalgesia. Although this effect is thought to generalize across species, only a few studies have examined the pain modulatory effects of nonnoxious fear-eliciting stimuli in humans. The present study examined whether exposure to a series of loud noise bursts would produce a fear-related hypoalgesia in male and female human subjects. Both subjective and physiologic measures (skin conductance level, heart rate) indicated that noise exposure resulted in fear, sympathetic arousal, and decreased pain reactivity in women (n = 20). In contrast, men (n = 20) did not experience fear or physiologic arousal, but reacted with surprise and increased pain reactivity. These findings provide additional evidence that hypoalgesia is mediated by fear and physiologic arousal. Although future studies should directly manipulate surprise, it appears that surprise without fear and physiologic arousal might enhance pain processing.