Pain-induced Changes Research Articles

The effects of regular exercise on capsaicin-induced pulpal pain and pain-induced changes in passive avoidance learning and memory in rats.

BackgroundPulpal pain is one of the most common and severe orofacial pain conditions with considerable adverse effects on physiological processes including learning and memory. Regular exercise is known to be effective on cognitive function as well as pain processing in the central nervous system. Here, the possible effects of regular exercise on pulpal pain response as well as pain-induced changes in learning and memory efficiency in rats were investigated.MethodsTwenty-four male Wistar rats were randomly assigned to the control, capsaicin, exercise, and exercise plus capsaicin groups. Rats in exercise groups were forced to run on a treadmill with a moderate exercise protocol for 4 weeks. Capsaicin was used to induce dental pulp pain. Passive avoidance learning and memory performance was assessed by using a shuttle box apparatus.ResultsAccording to the results, regular exercise could decrease the time course of capsaicin-induced pulpal pain (P < 0.001). Moreover, in capsaicin-treated rats, passive avoidance acquisition was impaired as compared to the control (P < 0.05) and exercise (P < 0.001) groups. Additionally, regular exercise before capsaicin injection could attenuate capsaicin-induced memory impairments (P < 0.05).ConclusionsTaken together, the present data showed that regular exercise has inhibitory effects on capsaicin-induced pulpal pain as well as pain-induced cognitive dysfunction in rats.

Influence of social interaction on nociceptive-induced changes in locomotor activity in a mouse model of acute inflammatory pain: Use of novel thermal assays.

Most acute and chronic animal models of pain rely heavily on reflexive assays for evaluating levels of nociception, which involves removing the animal from its normal social environment. Here, we examine and characterize the influence of social interactions on inflammatory pain-evoked changes in movement in two different mouse strains. To produce inflammatory nociception, we injected CFA bilaterally into the hind paws of Balb/c and C3H mice and then recorded exploratory locomotor activity using an automated detector system to first evaluate the effects of social behavior on nociception. Secondly, we determined if carprofen administration altered the effects of social behavior on nociceptive-evoked movement. This methodology was expanded to create a novel thermal activity assay to objectively measure the effect of heat and cold on CFA-evoked animal movement in paired animals. Paired Balb/c and C3H mice exhibited significant hyper-locomotion that lasted for 3h post-injection in Balb/c, but only 1h post-injection in C3H. Single Balb/c mice only showed increased activity for 1h post-injection, while single C3H mice showed no increase. This CFA-induced increase in activity in paired animals was highly inversely correlated with mechanical allodynia as measured using standard Von Frey filaments. Carprofen administration completely blocked this CFA-induced hyperlocomotor activity. Both heat and cold induced a significant increase in locomotor activity in paired mice injected with CFA, while having no effect on activity in control mice injected with saline. The results presented here indicate that social interactions greatly influence inflammatory pain-induced changes in locomotor activity and indicate that the use of movement-based assays to evaluate nociception in paired mice may provide an alternative and more sensitive method to quantify nociception and characterize novel analgesic effects over time in the context of social interactions in rodent models of pain.

Slow-5 dynamic functional connectivity reflects the capacity to sustain cognitive performance during pain

Some individuals are more distracted by pain during a cognitive task than others, representing poor pain coping. We have characterized individuals as A-type (attention dominates) or P-type (pain dominates) based on how pain interferes with task speed. The ability to optimize behavior during pain may relate to the flexibility in communication at rest between the dorsolateral prefrontal cortex (DLPFC) of the executive control network, and the anterior mid-cingulate cortex (aMCC) of the salience network (SN) – regions involved in cognitive-interference. The aMCC and aIns (SN hub) also signify pain salience; flexible communication at rest between them possibly allowing prioritizing task performance during pain. We tested the hypotheses that pain-induced changes in task performance are related to resting-state dynamic functional connectivity (dFC) between these region pairs (DLPFC-aMCC; aMCC-aIns). We found that 1) pain reduces task consistency/speed in P-type individuals, but enhances performance in A-type individuals, 2) task consistency is related to the FC dynamics within DLPFC-aMCC and aMCC-aIns pairs, 3) brain-behavior relationships are driven by dFC within the slow-5 (0.01–0.027Hz) frequency band, and 4) dFC across the brain decreases at higher frequencies. Our findings point to neural communication dynamics at rest as being associated with prioritizing task performance over pain.

Evaluation of a Postoperative Pain‐Like State on Motivated Behavior in Rats: Effects of Plantar Incision on Progressive‐Ratio Food‐Maintained Responding

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional postoperative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hr, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior.

In vivo detection of acute pain-induced changes of GABA+ and Glx in the human brain by using functional 1H MEGA-PRESS MR spectroscopy

In vivo1H MR spectroscopic detection of pain associated metabolic changes in the human brain may allow for an objective evaluation of the perceived pain intensity and assessment of the involved neurotransmitters. Ultimately, it may lead to a deeper understanding of the mechanisms that underlie neuronal pain processing. The present study reports results of time-resolved measurements of acute heat pain induced changes of the excitatory (Glx) and inhibitory (GABA+) neurotransmitter turnover in the anterior cingulate cortex (ACC) and occipital cortex (OC) by using 1H MEGA-PRESS spectroscopy. In ACC and OC, the ratio Glx/tCr increased by median values of 21.5% (p<0.001) and 15.7% (p<0.001), respectively. At the same time, GABA+/tCr decreased by median values of 15.1% (p=0.114) in ACC and 12.7% (p<0.001) in OC. To our knowledge, this study demonstrates for the first time the possibility of quantifying pain-induced neurotransmitter changes in the brain by using functional 1H MEGA-PRESS. The increase of Glx/tCr may be ascribed to an elevated glutamatergic turnover, while the decrease of GABA+/tCr may reflect reduced activity of the inhibitory system in ACC and OC during pain processing.

Simultaneous fMRI–PET of the opioidergic pain system in human brain

MRI and PET provide complementary information for studying brain function. While the potential use of simultaneous MRI/PET for clinical diagnostic and disease staging has been demonstrated recently; the biological relevance of concurrent functional MRI–PET brain imaging to dissect neurochemically distinct components of the blood oxygenation level dependent (BOLD) fMRI signal has not yet been shown. We obtained sixteen fMRI–PET data sets from eight healthy volunteers. Each subject participated in randomized order in a pain scan and a control (nonpainful pressure) scan on the same day. Dynamic PET data were acquired with an opioid radioligand, [11C]diprenorphine, to detect endogenous opioid releases in response to pain. BOLD fMRI data were collected at the same time to capture hemodynamic responses. In this simultaneous human fMRI–PET imaging study, we show co-localized responses in thalamus and striatum related to pain processing, while modality specific brain networks were also found. Co-localized fMRI and PET signal changes in the thalamus were positively correlated suggesting that pain-induced changes in opioid neurotransmission contribute a significant component of the fMRI signal change in this region. Simultaneous fMRI–PET provides unique opportunities allowing us to relate specific neurochemical events to functional hemodynamic activation and to investigate the impacts of neurotransmission on neurovascular coupling of the human brain in vivo.

P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery.

The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (CNS) from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter, we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain-induced changes in P-gp trafficking are associated with changes in P-gp's association with caveolin-1, a key scaffolding/trafficking protein that colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization, and activation of P-gp "pools" between microvascular endothelial cell subcellular compartments. Since redox-sensitive processes may be involved in signaling disassembly of higher-order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface, providing improved CNS drug delivery. The advantage of therapeutic drug "relocalization" of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription.

Gabapentin and Diclofenac Reduce Opioid Consumption in Patients Undergoing Tonsillectomy: A Result of Altered CNS Drug Delivery?

Dear Editor, We have read with great interest the article by Mogadam and colleagues on utilization of gabapentin and diclofenac for management of post-operative pain in patients undergoing tonsillectomy (1). Perhaps the most intriguing aspect of this study was the observation that pre-operative administration of gabapentin or diclofenac resulted in reduced post-operative utilization of meperidine, an opioid analgesic. Optimal therapeutic efficacy of opioids requires that they cross the blood-brain barrier (BBB) and attain effective concentrations in the CNS (2). CNS delivery of opioids is determined by putative membrane transporters localized to the BBB endothelium (3, 4). Both pathophysiological factors (i.e., inflammatory signaling in pain) and pharmacological factors (i.e., use of ancillary pain medications) can modulate mechanisms involved in BBB opioid transport, an effect that can cause profound changes in CNS delivery of traditional opioids (i.e., morphine, meperidine). In fact, our research group has demonstrated that painful and/or inflammatory stimuli in the periphery can significantly change transport mechanisms for opioids at the BBB such as the drug efflux transporter P-glycoprotein (P-gp) (5) and the drug influx transporter organic anion transporting polypeptide 1a4 (6). Of particular note, we have also shown that diclofenac itself can attenuate pain-induced changes in BBB transporter activity (6). Our data suggest that a modulation in post-operative meperidine efficacy may, in part, be the result of altered CNS opioid delivery induced by diclofenac. An additional factor to consider is that some ancillary pain medications may act as chemical inhibitors of the same BBB transporters. In the context of the study by Mogadam and colleagues, this effect may involve the critical BBB efflux transporter P-gp. Specifically, gabapentin is a known P-gp inhibitor (7) while in vitro studies have suggested that meperidine is a P-gp transport substrate (8). Although in vivo studies in mdr1a knockout mice showed no difference in meperidine antinociception (9), a direct analysis of P-gp-mediated transport of meperidine in intact laboratory animals has not been undertaken. Furthermore, this study measured analgesic efficacy using only tail-pinch, a technique that may not have been sensitive enough to detect differences in meperidine analgesia between P-gp-deficient and P-gp-competent mice. Nonetheless, it is highly plausible that gabapentin blocked P-gp-mediated efflux transport at the BBB, an effect that effectively increased CNS meperidine delivery with the clinical manifestation of reduced opioid consumption in the post-operative period. Overall, results obtained from basic science studies of our laboratory and others point towards an explanation of modified post-operative opioid efficacy in terms of altered BBB transport and/or CNS delivery of meperidine induced by ancillary pain medications. Additionally, the paper by Mogadam and colleagues emphasizes the absolute importance of novel translational studies aimed at understanding specific mechanisms involved in CNS opioid delivery, opioid efficacy, and/or drug-opioid interactions.

Transient and Persistent Pain Induced Connectivity Alterations in Pediatric Complex Regional Pain Syndrome

Evaluation of pain-induced changes in functional connectivity was performed in pediatric complex regional pain syndrome (CRPS) patients. High field functional magnetic resonance imaging was done in the symptomatic painful state and at follow up in the asymptomatic pain free/recovered state. Two types of connectivity alterations were defined: (1) Transient increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb vs. unaffected limb in the CRPS state, but with normalized connectivity patterns in the recovered state; and (2) Persistent increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb as compared to the unaffected limb that persisted also in the recovered state (recovered affected limb versus recovered unaffected limb). The data support the notion that even after symptomatic recovery, alterations in brain systems persist, particularly in amygdala and basal ganglia systems. Connectivity analysis may provide a measure of temporal normalization of different circuits/regions when evaluating therapeutic interventions for this condition. The results add emphasis to the importance of early recognition and management in improving outcome of pediatric CRPS.

Temporal association between changes in primary sensory cortex and corticomotor output during muscle pain

BackgroundIntegration of information between multiple cortical regions is thought to underpin the experience of pain. Yet studies tend to focus on pain related changes in discrete cortical regions. Although altered processing in the primary motor (M1) and sensory cortex (S1) is implicated in pain, the temporal relationship between these regions is unknown and may provide insight into the interaction between them. MethodsWe used recordings of somatosensory-evoked potentials (SEPs) and transcranial magnetic stimulation to investigate the temporal relationship between altered excitability of the primary sensory cortex and corticomotor output during and after muscle pain induced by hypertonic saline infusion into the right first dorsal interosseous. SEPs and motor-evoked potentials (MEPs) were recorded in 12 healthy individuals. ResultsParticipants reported an average pain intensity of 5.4 (0.5) on a 10-cm visual analogue scale. The area of the N20–P25–N33 complex of the SEP was reduced during and after pain, but MEP amplitudes were suppressed only after pain had resolved. ConclusionsOur data show that pain reduces sensory processing before motor output is altered. This temporal dispersion, coupled with the lack of correlation between pain-induced changes in S1 and M1 excitability, imply either that independent processes are involved, or that reduced excitability of S1 during acute experimental muscle pain mediates latent reductions in motor output via processes that are non-linear and potentially involve activation of a wider brain network.

Functional roles of endogenous D-serine in pain-induced ultrasonic vocalization

The N-methyl-D-aspartate receptor (NMDAR) is crucial for pain-related behaviors. D-Serine is synthesized from L-serine by serine racemase (SR) and modulates NMDAR functions by acting as an agonist at the glycine-binding site. We analyzed noxious stimulus-induced ultrasonic vocalization and locomotor activity in the open-field test using SR knockout (SR-KO) mice to examine the role of endogenous D-serine in mammalian behaviors. SR-KO mice emitted less ultrasonic vocalization after noxious stimulation (VAS) than wild-type (WT) mice. The locomotor activity of WT mice decreased with repeated daily exposures to the open field, whereas that of SR-KO mice remained unchanged. VAS was significantly enhanced during arthritis in WT mice, whereas it was not enhanced during arthritis in SR-KO mice. These results indicate that mice lacking the ability to produce D-serine endogenously in the brain differ from normal mice with respect to the chronic pain-induced behavioral changes.

Visualizing the Complex Brain Dynamics of Chronic Pain

Chronic pain is now recognized as a disease state that involves changes in brain function. This concept is reinforced by data that document structural and morphological remapping of brain circuitry under conditions of chronic pain. Evidence for aberrant neurophysiology in the brain further confirms neuroplasticity at cellular and molecular levels. Proper detection of pain-induced changes using emerging non-invasive and cost-effective technologies, such as analytical electroencephalography methods, could yield objective diagnostic measures and may guide therapeutic interventions targeting the brain for effective management of chronic pain.

Functional roles of endogenous d-serine in the chronic pain-induced plasticity of NMDAR-mediated synaptic transmission in the central amygdala of mice

The amygdala is implicated in chronic pain-induced emotional changes. Chronic pain induces plastic changes of the N-methyl-d-aspartate receptor (NMDAR) functions in the brain including the amygdala. d-Serine is synthesized endogenously by serine racemase and modulates NMDAR-mediated synaptic transmission as a coagonist of glycine binding site. To clarify the functional roles of endogenous d-serine in chronic pain-induced plasticity of NMDAR mediated synaptic transmission, we investigated the NMDAR-mediated excitatory synaptic current (EPSC) of neurons in the latero-capsular division of the central amygdala (CeLC) using brain slices from serine racemase knockout (SR-KO) mice with chronic pain induced by monoarthritis. The decay time of NMDAR-mediated EPSC was significantly elongated by monoarthritis in wild type (WT) mice, but not in SR-KO mice. The d-serine application-induced increase of NMDAR-mediated EPSC was significantly facilitated by monoarthritis in WT mice, but not in SR-KO mice. These results suggest that endogenous d-serine facilitates chronic pain-induced plastic changes of NMDAR mediated synaptic transmission in CeLC.

Acute Pain and a Motivational Pathway in Adult Rats: Influence of Early Life Pain Experience

BackgroundThe importance of neonatal experience upon behaviour in later life is increasingly recognised. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood.Methodology/Principal FindingsRat pups received repeat plantar skin incisions (neonatal IN) or control procedures (neonatal anesthesia only, AN) at postnatal days (P)3, 10 and 17. When adult, rats with neonatal ‘pain history’ showed greater sensory sensitivity than control rats following acute plantar skin incision. Motivational behaviour in the two groups of rats was tested in a novelty-induced hypophagia (NIH) paradigm. The sensitivity of this paradigm to pain-induced changes in motivational behaviour was shown by significant increases in the time spent in the central zone of the arena (43.7±5.9% vs. 22.5±6.7%, p<0.05), close to centrally placed food treats, and decreased number of rears (9.5±1.4 vs. 19.2±2.3, p<0.001) in rats with acute plantar skin incision compared to naive, uninjured animals. Rats with a neonatal ‘pain history’ showed the same pain-induced behaviour in the novelty-induced hypophagia paradigm as controls. However, differences were observed in reward-related neural activity between the two groups. Two hours after behavioural testing, brains were harvested and neuronal activity mapped using c-Fos expression in lateral hypothalamic orexin neurons, part of a specific reward seeking pathway. Pain-induced activity in orexin neurons of control rats (18.4±2.8%) was the same as in uninjured naive animals (15.5±2.6%), but in those rats with a ‘pain history’, orexinergic activity was significantly increased (27.2±4.1%, p<0.01). Furthermore the extent of orexin neuron activation in individual rats with a ‘pain history’ was highly correlated with their motivational behaviour (r = −0.86, p = 0.01).Conclusions/SignificanceThese results show that acute pain alters motivational behaviour and that neonatal pain experience causes long-term changes in brain motivational orexinergic pathways, known to modulate mesolimbic dopaminergic reward circuitry.

The Lateral Pterygoid Muscle: Function and Dysfunction

The human lateral pterygoid muscle plays an important role in the control of jaw movements. This review provides an update on some aspects of the normal function of the lateral pterygoid muscle and its response to alterations, including mandibular advancement, occlusal changes, and experimental orofacial pain. Both the upper or superior head (SHLP) and the lower or inferior head (IHLP) of the lateral pterygoid insert predominantly into the neck of the condyle. A number of recent studies have carried out recordings of jaw movement and electromyographic (EMG) activity from the lateral pterygoid muscle, where verification of electrode location has been achieved through computer tomography imaging. From these studies, there is no evidence of background EMG activity within IHLP or SHLP when the jaw is in the clinically determined postural jaw position. There is little evidence for a reciprocal relation in activity between SHLP and IHLP, and both SHLP and IHLP play an important role in contralateral, protrusive, and jaw-opening movements and force generation. There is evidence for independent activation of subcompartments within the lateral pterygoid muscle to allow a range of force vectors to be delivered to the condyle. In terms of the role of the lateral pterygoid muscle in mandibular advancement and occlusal changes, the lack of studies of these issues, where verified recordings have been made from the lateral pterygoid muscle, means that there is no definitive evidence in humans for the "lateral pterygoid hypothesis," and there is also little reliable information as to the effect of occlusal variables on the activity of the lateral pterygoid muscle. There is also little information on the effect of pain on lateral pterygoid muscle activity, although recent studies demonstrate that the pattern of pain-induced changes in lateral pterygoid muscle EMG activity is not clear-cut but can vary with the task performed and jaw displacement magnitude. The lateral pterygoid muscle is a difficult muscle to access, and only verified recordings from the muscle will yield definitive conclusions.

Functional and structural imaging of pain-induced neuroplasticity

The understanding of the mechanisms underlying chronic pain is of major scientific and clinical interest. This review focuses on neuroimaging studies of pain-induced neuroplastic changes in the human brain and discusses five major categories of pain-induced neuroplastic changes. First, peripheral or central sensitization may result in increased nociceptive input to the brain and also changes the processing of nociceptive information within the brain. Second, chronic nociceptive input from the periphery or from lesions within the central nervous system may result in cortical reorganization and maladaptive neuroplasticity within somatosensory and motor systems. Thirdly, there is evidence for pain-induced changes in large-scale neuronal network connectivity. Fourth, in patients with chronic pain, structural brain changes may occur. Finally, there is discussion that in chronic pain patients the endogenous pain-modulatory system may function aberrantly. Recent work has substantially broadened our insights into neuroplastic changes that are involved in pain chronification. Future research will focus on the question of whether neuroimaging techniques can be used in the individual chronic pain patient as a biomarker that would allow for an objective diagnosis of different pain conditions and for the prediction of individual responses to specific therapies.

Pain-induced Changes in the Activity of the Cervical Extensor Muscles Evaluated by Muscle Functional Magnetic Resonance Imaging

To investigate the effect of experimental neck muscle pain on the activation of the cervical extensor muscles during the performance of a cervical extension exercise by the use of muscle functional magnetic resonance imaging. The activity of the multifidus, semispinalis cervicis, semispinalis capitis, and splenius capitis muscles was investigated bilaterally at 2 cervical levels (C2 to C3 and C7 to T1) in 15 healthy individuals. Measurements were taken at rest and after the performance of a cervical extension exercise without and with induced pain of the right upper trapezius (intramuscular injection of hypertonic saline). In the pain condition, the activity of the multifidus/semispinalis cervicis was reduced bilaterally at the C7 to T1 level (P=0.045). For the semispinalis capitis, there were no significant differences between both conditions. The splenius capitis showed a significantly higher T2 shift at the left side at the C2 to C3 level (P=0.008) and a lower T2 shift at the right side at the C7 to T1 level (P=0.023). This is the first study that has shown pain to immediately affect the activity of both deep and superficial cervical extensor muscle layers during a cervical extension exercise. The findings support recommendations for evaluation of cervical extensor muscle function early in the management of painful cervical spine injuries.

Erythropoietin Reduces Neuronal Cell Death and Hyperalgesia Induced by Peripheral Inflammatory Pain in Neonatal Rats

Painful stimuli during neonatal stage may affect brain development and contribute to abnormal behaviors in adulthood. Very few specific therapies are available for this developmental disorder. A better understanding of the mechanisms and consequences of painful stimuli during the neonatal period is essential for the development of effective therapies. In this study, we examined brain reactions in a neonatal rat model of peripheral inflammatory pain. We focused on the inflammatory insult-induced brain responses and delayed changes in behavior and pain sensation. Postnatal day 3 pups received formalin injections into the paws once a day for 3 days. The insult induced dysregulation of several inflammatory factors in the brain and caused selective neuronal cell death in the cortex, hippocampus and hypothalamus. On postnatal day 21, rats that received the inflammatory nociceptive insult exhibited increased local cerebral blood flow in the somatosensory cortex, hyperalgesia, and decreased exploratory behaviors. Based on these observations, we tested recombinant human erythropoietin (rhEPO) as a potential treatment to prevent the inflammatory pain-induced changes. rhEPO treatment (5,000 U/kg/day, i.p.), coupled to formalin injections, ameliorated neuronal cell death and normalized the inflammatory response. Rats that received formalin plus rhEPO exhibited normal levels of cerebral blood flow, pain sensitivity and exploratory behavior. Treatment with rhEPO also restored normal brain and body weights that were reduced in the formalin group. These data suggest that severe inflammatory pain has adverse effects on brain development and rhEPO may be a possible therapy for the prevention and treatment of this developmental disorder.

Gamma oscillations as a neuronal correlate of the attentional effects of pain

Successful behavior requires the attentional selection and preferred processing of behaviorally relevant sensory information. Painful stimuli are of utmost behavioral relevance and can therefore involuntarily affect attentional resources and interfere with ongoing behavior. However, the neuronal mechanisms which subserve the involuntary attentional effects of pain are largely unknown yet. Here, we therefore investigated the neuronal mechanisms of the attentional effects of pain by using electroencephalography during a visual attention task with the concurrent presentation of painful stimuli. Our results confirm that painful and visual stimuli induce gamma oscillations over central and occipital areas, respectively. Pain-induced gamma oscillations were correlated with pain-induced changes in visual gamma oscillations. Behaviorally, we observed variable effects of pain on visual reaction times, yielding an increase of reaction times for some subjects, as well as a decrease of reaction times for others. Most importantly, however, these changes in visual task performance were significantly related to pain-induced changes of visual gamma oscillations. These findings demonstrate that the variable attentional effects of pain are closely related to changes in neuronal gamma oscillations in the human brain. In the hypervigilant state of chronic pain, maladaptive changes in the attentional effects of pain may be associated with abnormal changes in neuronal gamma oscillations. Our findings may thus contribute to the understanding of the neuronal substrates of pain in health and may open a new window towards the understanding of pathological alterations of the pain experience in chronic pain syndromes.

Anger Suppression Predicts Pain, Emotional, and Cardiovascular Responses to the Cold Pressor

Manipulated anger suppression has been shown to heighten pain and anger responses to pain. We examined whether individual differences in self-reported anger suppression predicted pain, anger, and blood pressure responses to acute pain. Healthy participants (N = 47) underwent an anger-provoking speech task followed by a cold pressor pain task. Participants reported their degree of suppression of thoughts and feelings related to the speech. Pain intensity ratings were obtained throughout the cold pressor. Self-reported anger, anxiety and positive emotion, as well as ratings of sensory, general distress, and anger-specific elements of pain were obtained following the cold pressor. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded throughout. Self-reported suppression predicted greater pain intensity ratings, perception of sensory and anger-specific elements of pain, and self-reported anger in response to the cold pressor. Associations between self-reported suppression and pain intensity and ratings of anger-specific elements of pain were statistically mediated by pain-induced changes in self-reported anger, whereas the effect of suppression on sensory pain ratings was not. Self-reported suppression was also correlated inversely with SBP responses to the cold pressor. Consistent with an ironic process model and prior studies involving experimental manipulation of suppression, self-reported suppression of anger predicted greater pain intensity and perception of the anger-specific element of pain. Findings also suggest that suppression might attenuate homeostatic pressor responses to acute pain.