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Native Americans (NAs) have higher pain rates than the general U.S. population. It has been found that increased central sensitization and reduced pain inhibition are pronociceptive processes that increase pain risk; yet, little attention has focused on the influence of psychosocial factors. Discrimination is a psychosocial factor associated with increased pain in other minoritized groups; however, it is unclear whether it also promotes pain in NAs. This study analyzed data from 269 healthy, pain-free participants (N = 134 non-Hispanic whites [NHWs], N = 135 NAs) from the Oklahoma Study of Native American Pain Risk. Experienced discrimination was measured using the Everyday Discrimination Scale (EDS). Nociceptive processes were measured via static measures of spinal sensitivity (nociceptive flexion reflex [NFR] threshold, 3-stimulation NFR threshold), temporal summation of pain (TS-Pain) and nociceptive flexion reflex (TS-NFR), and conditioned pain modulation of pain (CPM-Pain) and NFR (CPM-NFR). Results demonstrated that greater discrimination was associated with enhanced TS-NFR and impaired CPM-NFR but not static measures of spinal sensitivity or measures of pain modulation (TS-Pain, CPM-Pain). Although the effects of discrimination on outcomes were similar in both groups (not moderated by ethnicity), NAs experienced higher levels of discrimination and therefore discrimination mediated a relationship between ethnicity and impaired CPM-NFR. This indicates experienced discrimination may promote a pain risk phenotype in NAs that involves spinal sensitization resulting from impaired inhibition of spinal nociception without sensitization of pain experience. PERSPECTIVE: This study found that discrimination was associated with spinal sensitization and impaired descending inhibition of spinal nociception. These findings bolster our understanding of how social stressors experienced disproportionately by minoritized groups can contribute to pain outcomes.

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.

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.

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.

Poor sleep quality is often comorbid with chronic pain. Research has also shown that poor and disrupted sleep may increase risk for chronic pain by promoting pronociceptive processes. This could occur through disrupted emotional modulation of pain since poor sleep can impact emotional experience and emotional experience modulates pain and nociception. To assess the pain system, nociceptive flexion reflexes (spinal level), pain-evoked potentials (supraspinal level), and perceived pain were recorded during an emotional picture-viewing task in which 37 healthy individuals received painful electric stimulations. The Pittsburgh Sleep Quality Index assessed sleep quality. Individuals with poor sleep quality were unable to inhibit signals at the spinal level in response to positive pictures, whereas emotional modulation of supraspinal nociception and pain perception remained unaffected by sleep quality. This suggests poor sleep quality may promote pronociception by impairing descending, emotional modulation of spinal nociception.

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.

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.

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.

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.

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.

Anger management styles (i.e., anger-in and anger-out) characterize a person's typical response to anger. Anger-in, the suppression of anger, and anger-out, the outward expression of anger, have been associated with increased acute and chronic pain. Previous research suggests that anger-in is related to pain because of its shared variance with negative affect; anger-out is believed to be related to pain because of a disruption of endogenous opioid systems. It is currently unknown whether anger management styles promote pain by facilitating central sensitization or spinal nociception. This study assessed the relationship between anger management styles and markers of central sensitization (i.e., temporal summation of pain [TS-pain] and nociception flexion reflex [TS-NFR]), spinal nociception (nociception flexion reflex [NFR] threshold), and measures of pain experience. One hundred nine healthy pain-free individuals completed the study. A bootstrapped mediation analysis was conducted to test whether negative affect mediated relationships with anger-in. Results suggested that anger-in and anger-out were associated with lower NFR thresholds (facilitated spinal nociception), but no other outcome. Negative affect did not mediate either of these relationships. These results suggest that anger management styles may amplify spinal nociceptive processes in healthy humans without altering central sensitization.

In healthy individuals, emotions modulate pain and spinal nociception according to a valence linear trend (ie, pain/nociception is highest during negative emotions and lowest during positive emotions). However, emerging evidence suggests that emotional modulation of pain (but not spinal nociception) is disrupted in fibromyalgia and disorders associated with chronic pain risk (eg, major depression, insomnia). The present study attempted to extend this work and to examine whether women with premenstrual dysphoric disorder (PMDD), a cyclical syndrome associated with debilitating affective symptoms during the late-luteal (premenstrual) phase of the menstrual cycle, is also associated with disrupted emotional modulation of pain. To do so, an affective picture-viewing procedure was used to study emotional modulation of pain and spinal nociception in 14 women with PMDD and 14 control women during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (verified by salivary hormone levels and luteinizing hormone tests). At each phase, mutilation, neutral, and erotic pictures were presented to manipulate emotion. During picture viewing, suprathreshold electrocutaneous stimuli were presented to evoke pain and the nociceptive flexion reflex (NFR; a physiological measure of spinal nociception). Statistically powerful linear mixed model analyses confirmed that pictures evoked the intended emotional states in both groups across all menstrual phases. Furthermore, emotion modulated pain and NFR according to a valence linear trend in both groups and across all menstrual phases. Thus, PMDD-related affective disturbance is not associated with a failure to emotionally modulate pain, suggesting that PMDD does not share this pain phenotype with major depression, insomnia, and fibromyalgia.

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.

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.

Sex hormones may contribute to inter- and intra-individual differences in pain by influencing emotional modulation of pain and nociception. To study this, a well-validated picture-viewing paradigm was used to assess emotional modulation of pain and the nociceptive flexion reflex (NFR; physiologic measure of nociception) during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle in healthy normally cycling women (n=40). Salivary estradiol, progesterone, and testosterone were assessed at each testing session. Emotional modulation of pain/NFR did not differ across menstrual phases, but low estradiol was associated with weaker emotional modulation of NFR (during all phases) and emotional modulation of pain (ovulatory and late-luteal phases). Given evidence that a failure to emotionally modulate pain might be a risk factor for chronic pain, low estradiol may promote chronic pain via this mechanism. However, future research is needed to extend these findings to women with disturbances of pain, emotion, and/or sex hormones.

Pain problems are more prevalent in Native Americans than in any other group in the U.S., and this might result from group differences in pain modulation. This study was designed to examine emotional modulation of pain and spinal nociception in healthy, pain-free Native Americans (n = 21) relative to non-Hispanic Whites (n = 20). To assess emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception), participants underwent a well-validated emotional picture-viewing paradigm during which suprathreshold pain stimuli were delivered to the ankle. Compared to Whites, Native Americans reported less pleasure to erotic pictures and failed to show corrugator reactivity to mutilation pictures. Unlike Whites, Native Americans only evidenced pain inhibition in response to erotica, but no pain facilitation (disinhibition) to mutilation pictures. Emotional modulation of NFR was similar in both groups. These preliminary findings suggest that Native Americans failed to disinhibit pain, perhaps due to over-activation of pain inhibitory mechanisms. Chronic over-activation of this system could ultimately exhaust it, thus putting Native Americans at future risk for chronic pain.

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

Pain is a tremendously malleable experience, and emotions are one of many psychological factors that modulate it. This chapter examines the emotion–pain relationship and provides a motivational framework for understanding it. It is suggested that a valence-by-arousal interaction characterizes the influence of emotions on pain in healthy humans. Specifically, positively valenced emotions generally inhibit pain, with greater inhibition resulting from greater positive arousal. By contrast, negatively valenced emotions with low-to-moderate arousal facilitate pain, with greater facilitation resulting from greater negative arousal. However, negatively valenced emotions with high arousal inhibit pain. Emerging evidence suggests that a failure to emotionally modulate pain could be a risk factor for the development of chronic pain; however, additional research is needed to confirm these preliminary data.

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 menstrual cycle influences pain, with symptoms often increasing during the premenstrual (late-luteal) phase. Deficiencies in endogenous inhibition of afferent nociception at the spinal level might contribute to menstrual phase-related changes in pain. This study assessed whether conditioned pain modulation (CPM) of spinal nociception differs between mid-follicular and late-luteal phases. CPM was evoked by a blood pressure cuff affixed to the right forearm and inflated to induce ischemia in 41 healthy women during both menstrual phases. Suprathreshold electric stimuli were delivered to the left sural nerve to evoke pain and the nociceptive flexion reflex (NFR) before, during, and after forearm ischemia. Forearm ischemia produced CPM of electrocutaneous pain and NFR, but inhibition did not differ across mid-follicular and late-luteal phases. Mechanisms contributing to changes in experimental pain across mid-follicular and late-luteal phases in healthy women are not due to deficits in CPM of spinal nociception.

The nociceptive flexion reflex (NFR) is a physiological tool to study spinal nociception. However, NFR assessment can take several minutes and expose participants to repeated suprathreshold stimulations. The 4 studies reported here assessed the reliability and validity of a brief method to assess NFR threshold that uses a single ascending series of stimulations (Peak 1 NFR), by comparing it to a well-validated method that uses 3 ascending/descending staircases of stimulations (Staircase NFR). Correlations between the NFR definitions were high, were on par with test-retest correlations of Staircase NFR, and were not affected by participant sex or chronic pain status. Results also indicated the test-retest reliabilities for the 2 definitions were similar. Using larger stimulus increments (4 mAs) to assess Peak 1 NFR tended to result in higher NFR threshold estimates than using the Staircase NFR definition, whereas smaller stimulus increments (2 mAs) tended to result in lower NFR threshold estimates than the Staircase NFR definition. Neither NFR definition was correlated with anxiety, pain catastrophizing, or anxiety sensitivity. In sum, a single ascending series of electrical stimulations results in a reliable and valid estimate of NFR threshold. However, caution may be warranted when comparing NFR thresholds across studies that differ in the ascending stimulus increments. Perspective This brief method to assess NFR threshold is reliable and valid; therefore, it should be useful to clinical pain researchers interested in quickly assessing inter- and intra-individual differences in spinal nociceptive processes.

Pain catastrophizing is associated with enhanced temporal summation of pain (TS-Pain). However, because prior studies have found that pain catastrophizing is not associated with a measure of spinal nociception (nociceptive flexion reflex [NFR] threshold), this association may not result from changes in spinal nociceptive processes. The goal of the present study in healthy participants was to examine the relationship between trait (traditional) and state (situation-specific) pain catastrophizing and temporal summation of NFR (TS-NFR) and TS-Pain. A secondary goal was to replicate prior findings concerning relationships between catastrophizing and NFR threshold, electrocutaneous pain threshold, and sensory and affective ratings of electrocutaneous stimuli. All analyses controlled for depression symptoms, pain-related anxiety, and participant sex. As expected, multiple regression analyses indicated that neither trait nor situation-specific catastrophizing was associated with NFR threshold, but that situation-specific catastrophizing was associated with pain ratings. Multilevel linear growth models of TS data indicated that situation-specific catastrophizing was associated with TS-Pain but not TS-NFR. Trait catastrophizing was not related to TS-Pain or TS-NFR. Together, these results confirm prior studies that indicate that catastrophizing enhances pain via supraspinal processes rather than spinal processes. Moreover, because catastrophizing was associated with TS-Pain but not TS-NFR, caution is warranted when using pain ratings to infer temporal summation of spinal nociceptive processes.

Research indicates pain may be influenced by the menstrual cycle. While the mechanisms underlying these effects are unclear, it is possible that menstrual phase-related changes in endogenous pain modulation contribute. The present study used well-validated methods to study affective modulation of pain and the nociceptive flexion reflex (NFR) in healthy women during two menstrual phases (mid-follicular vs. late-luteal). Women (N = 41) tracked their menstrual phases for three complete cycles and were asked to attend two laboratory testing sessions in the second and third cycles to assess affective modulation of pain and nociception (testing order counterbalanced). Menstrual phase was assessed from daily diaries, luteinizing hormone tests, and basal body temperature. At each session, emotionally charged pictures were presented and suprathreshold electrocutaneous stimulations were delivered during and in between pictures. Subjective and physiological emotional reactions were recorded in response to each picture and pain ratings and NFRs were recorded in response to each suprathreshold stimulus. Results suggested pictures effectively manipulated emotion in both menstrual phases. Moreover, arousing unpleasant pictures enhanced pain and NFR, whereas arousing pleasant pictures inhibited pain and NFR. These modulatory effects were similar in both menstrual phases. Together, these findings suggest that affective engagement of corticospinal mechanisms does not differ across these phases of the menstrual cycle. However, future research is needed to directly assess the relationship between affective modulation of pain/nociception and inter- and intra-individual differences in ovarian hormones and to extend these findings to women who suffer from menstrual cycle-related pain (e.g., premenstrual dysphoric disorder, fibromyalgia).

Physiological reactions to noxious stimuli are often used to make inferences about pain, but few studies have thoroughly examined the intra- and interindividual relationships between them. In the present study (N=104), multilevel analyses was used to assess relations between physiological (nociceptive flexion reflex magnitude [NFR], blink reflex magnitude, skin conductance response [SCR], heart rate [HR]) and subjective reactions to electrocutaneous stimuli. All physiological reactions were significant predictors of ratings when entered alone, explaining 1% (SCR) to 29% (NFR) of the variance; but only NFR, blink, and HR were significant in a multivariate predictor model. Significant interindividual variability in slopes was found for blink and HR, but not NFR. A final trimmed model that included NFR, blink, and the blink random slope explained 35% of the variance in ratings.

Prior research suggests emotional picture-viewing modulates motoric (nociceptive flexion reflex), autonomic (skin conductance response, heart rate acceleration), and subjective (pain rating) reactions to noxious electrodermal stimulation. The present study sought to determine whether emotional valence and arousal contribute to nociception modulation. To do so, pictures varying in emotional content (erotica, food, neutral, loss, attack) were chosen to manipulate emotional valence (pleasant = erotic and food; unpleasant = loss and attack) and arousal (low = food and loss; moderate = erotica and attack). Pictures were presented in pseudorandom order to elicit emotional processing while noxious electric stimulations were delivered to the sural nerve. Nociceptive flexion reflex (NFR) magnitude, skin conductance response (SCR), heart rate (HR) acceleration, and subjective pain ratings to each stimulation were measured, standardized, averaged by picture content, and analyzed. Results suggested that picture-viewing explained 52% of the variance in the multivariate combination of the nociceptive reactions and modulated them in parallel. Pleasant pictures inhibited reactions, whereas unpleasant pictures enhanced them. However, only erotica and attack pictures elicited significant modulation relative to neutral pictures, suggesting arousal also contributed. An exploratory multilevel analysis also supported this conclusion. Together, these data suggest emotional control of nociceptive reactions (ECON) is associated with a valence-byarousal interaction. Implications of these findings for how emotional picture-viewing can be used to study supraspinal modulation are discussed. � 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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.

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.

Impaired sleep enhances pain, perhaps by disrupting pain modulation. Given that emotion modulates pain, the present study examined whether emotional modulation of pain and nociception is impaired in persons with severe insomnia symptoms relative to controls. Insomnia group (n = 12) met the International Classification of Diseases, tenth revision symptoms for primary insomnia and controls (n = 13) reported no sleep impairment. Participants were shown emotionally evocative pictures (mutilation, neutral, and erotica) during which suprathreshold pain stimuli were delivered to evoke pain and the nociceptive flexion reflex (NFR; physiological correlate of spinal nociception). Emotional responses to pictures were similar in both groups, except that subjective valence/pleasure ratings were blunted in insomnia. Emotional modulation of pain and NFR was observed in controls, but only emotional modulation of NFR was observed in insomnia. Consistent with previous findings, pain modulation is disrupted in insomnia, which might promote pain. This may stem from disrupted supraspinal circuits not disrupted brain-to-spinal cord circuits.

Major depressive disorder (MDD) is associated with risk for chronic pain, but the mechanisms contributing to the MDD and pain relationship are unclear. To examine whether disrupted emotional modulation of pain might contribute, this study assessed emotional processing and emotional modulation of pain in healthy controls and unmedicated persons with MDD (14 MDD, 14 controls). Emotionally charged pictures (erotica, neutral, mutilation) were presented in 4 blocks. Two blocks assessed physiological-emotional reactions (pleasure/arousal ratings, corrugator electromyography (EMG), startle modulation, skin conductance) in the absence of pain and 2 blocks assessed emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations. Results indicated pictures generally evoked the intended emotional responses; erotic pictures elicited pleasure, subjective arousal, and smaller startle magnitudes, whereas mutilation pictures elicited displeasure, corrugator EMG activation, and subjective/physiological arousal. However, emotional processing was partially disrupted in MDD, as evidenced by a blunted pleasure response to erotica and a failure to modulate startle according to a valence linear trend. Furthermore, emotional modulation of pain was observed in controls but not MDD, even though there were no group differences in NFR threshold or emotional modulation of NFR. Together, these results suggest supraspinal processes associated with emotion processing and emotional modulation of pain may be disrupted in MDD, but brain to spinal cord processes that modulate spinal nociception are intact. Thus, emotional modulation of pain deficits may be a phenotypic marker for future pain risk in MDD.

Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (e.g., depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in four blocks; two blocks assessed only physiological-emotional reactions (i.e., pleasure/arousal ratings, corrugator EMG, startle modulation, skin conductance) in the absence of pain and two blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (e.g., reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all three groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes.

Objectives Understanding the relationship between the menstrual cycle and pain can contribute significantly to our knowledge of pain processing in women. Many early studies suggested that pain sensitivity was enhanced during the luteal phase of the menstrual cycle relative to the follicular phase; however, these studies were often limited by small sample sizes, lack of ovulation verification, focus on a single pain modality, inadequate assessment of menstrual cycle regularity, and low-powered statistical methods. The current study was designed to address these limitations and examine the difference in pain processing between the mid-follicular (days 5 to 8) and late-luteal (days 1 to 6 preceding menses) phases. Methods Forty-one healthy, regularly cycling women attended testing sessions that measured pain sensitivity from mechanical pain threshold, electrocutaneous pain threshold/tolerance, and ischemia pain threshold/tolerance, as well as McGill Pain Questionnaire qsensory and affective ratings of electric and ischemic stimuli. Electrocutaneous stimulation was also used to assess nociceptive flexion reflex threshold, a physiological measure of spinal nociception. Results When analyses were limited to data collected only in the targeted menstrual phases (N=30), results indicated no menstrual phase effect on any pain outcome (all P's>0.05), with the exception of lower electrocutaneous pain thresholds during the late-luteal phase. No outcomes differed by menstrual phase in the full sample (N=41). This indicates nociceptive responding varies little between the mid-follicular and late-luteal phases. Discussion The present study suggests that experimental pain processing does not significantly differ between the mid-follicular and late-luteal phases of the menstrual cycle in healthy women. This implies hormonal variation across these 2 phases (ie, progesterone) has a minimal effect on subjective and physiological responses to pain.

OBJECTIVES Anxiety sensitivity (AS) is the fear of anxiety-related sensations and its perceived harmful consequences. AS is associated with enhanced pain and worsened pain outcomes, suggesting it is a contributing factor in acute and chronic pain. However, the mechanisms that mediate the relationship between AS and pain are currently unknown. This study assessed the relationship between AS and 2 measures of spinal nociceptive processes (ie, nociceptive flexion reflex and temporal summation of nociceptive flexion reflex) and measures of subjective pain. This allowed us to determine whether AS engages descending cerebrospinal processes to facilitate pain signaling at spinal levels. METHODS AS was assessed in healthy men and women using the Anxiety Sensitivity Index-Revised. Then pain processing was assessed from electric pain threshold, nociceptive flexion reflex threshold, temporal summation of pain, temporal summation of nociceptive flexion reflex, and McGill Pain Questionnaire sensory and affective pain ratings. Associations among variables were assessed using Winsorized correlations (a robust and statistically powerful analytic method). RESULTS AS was positively associated with sensory pain ratings, affective pain ratings, and temporal summation of pain, but was unrelated to all other outcomes. DISCUSSION Given that AS was not significantly associated with measures of spinal nociception, these results suggest that AS may exert its influence on pain processing at the supraspinal, rather than the spinal level.

Emotion can modulate pain and spinal nociception, and correlational data suggest that cognitive-emotional processes can facilitate wind-up-like phenomena (ie, temporal summation of pain). However, there have been no experimental studies that manipulated emotion to determine whether within-subject changes in emotion influence temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR, a physiological measure of spinal nociception). The present study presented a series of emotionally charged pictures (mutilation, neutral, erotic) during which electric stimuli at 2 Hz were delivered to the sural nerve to evoke TS-pain and TS-NFR. Participants (n = 46 healthy; 32 female) were asked to rate their emotional reactions to pictures as a manipulation check. Pain outcomes were analyzed using statistically powerful multilevel growth curve models. Results indicated that emotional state was effectively manipulated. Further, emotion modulated the overall level of pain and NFR; pain and NFR were highest during mutilation and lowest during erotic pictures. Although pain and NFR both summated in response to the 2-Hz stimulation series, the magnitude of pain summation (TS-pain) and NFR summation (TS-NFR) was not modulated by picture-viewing. These results imply that, at least in healthy humans, within-subject changes in emotions do not promote central sensitization via amplification of temporal summation. However, future studies are needed to determine whether these findings generalize to clinical populations (eg, chronic pain).

Temporal summation of pain (TS-pain) is the progressive increase in pain ratings during a series of noxious stimulations. TS-pain has been used to make inferences about sensitization of spinal nociceptive processes; however, pain report can be biased thereby leading to problems with this inference. Temporal summation of the nociceptive flexion reflex (TS-NFR, a physiological measure of spinal nociception) can potentially overcome report bias, but there have been few attempts (generally with small Ns) to standardize TS-NFR procedures. In this study, 50 healthy participants received 25 series of noxious electric stimulations to evoke TS-NFR and TS-pain. Goals were to: 1) determine the stimulation frequency that best elicits TS-NFR and reduces electromyogram (EMG) contamination from muscle tension, 2) determine the minimum number of stimulations per series before NFR summation asymptotes, 3) compare NFR definition intervals (90-150ms vs. 70-150ms post-stimulation), and 4) compare TS-pain and TS-NFR when different stimulation frequencies are used. Results indicated TS-NFR should be elicited by a series of three stimuli delivered at 2.0Hz and TS-NFR should be defined from a 70-150ms post-stimulation scoring interval. Unfortunately, EMG contamination from muscle tension was greatest during 2.0Hz series. Discrepancies were noted between TS-NFR and TS-pain which raise concerns about using pain ratings to infer changes in spinal nociceptive processes. And finally, some individuals did not have reliable NFRs when the stimulation intensity was set at NFR threshold during TS-NFR testing; therefore, a higher intensity is needed. Implications of findings are discussed.

The present study examined whether a moderately aversive abdominal threat would lead to greater enhancement in affect- and pain-related defensive responding as indexed by the acoustic startle reflex (ASR) and nociceptive flexion reflex (NFR) in women compared to men. We also predicted sex differences in threat-related autonomic arousal measured by skin conductance responses (SCRs) to acoustic startle and noxious sural nerve stimulation. Unpredictable threat was manipulated by alternating 30-second safe ("no abdominal stimulation will be given") and threat ("abdominal stimulation may occur at anytime") periods. The experiment consisted of 2 blocks, each containing 4 safe and 4 threat periods in which the ASR or NFR was randomly probed 9-21 seconds following period onset. Unpredictable abdominal threat potentiated both ASR and NFR responses compared to periods signaling safety. SCRs to acoustic startle probes and noxious sural nerve stimulation were also significantly elevated during the threat vs safe periods. No sex differences in ASR or startle-evoked SCRs emerged. However, nociceptive responding was moderated by sex; females showed significant increases in NFR magnitudes across both safe and threat periods compared to males. Females also showed greater threat-potentiated SCRs to sural nerve stimulation than males. Our findings indicate that both affect- and pain-related defense and arousal systems are strongly influenced by threat of an aversive, unpredictable event, a situation associated with anticipatory anxiety. Females, compared to males, showed greater nociceptive responding and pain modulation when exposed to an unpredictable threatening context, whereas affect-driven ASR responses showed no such sex differentiation.

The short allele of the serotonin transporter gene (5-HTTLPR) is associated with greater negative emotionality. Given that emotion modulates pain, short allele carriers (s-carriers) may also demonstrate altered pain modulation. The present study used a well-validated emotional picture-viewing paradigm to modulate pain and the nociceptive flexion reflex (NFR, a measure of spinal nociception) in 144 healthy genotyped participants. As expected, pain/NFR responses were largest during unpleasant pictures and smallest during pleasant pictures. However, relative to l/l-carriers, s-carriers demonstrated greater pain inhibition during pleasant pictures and greater pain facilitation during unpleasant pictures. Neither emotional modulation of NFR nor NFR threshold was associated with 5-HTTLPR polymorphisms. Results also indicated that men who were s-carriers had a higher pain threshold and tolerance than other participants. Taken together, our results indicate 5-HTTLPR polymorphisms may influence pain modulation at the supraspinal (not spinal) level; however, the influence on pain sensitivity may be sex-specific.