A life switch in pain

To determine the differences in pain, disability, depression, and pressure sensitivity between men and women with fibromyalgia syndrome (FMS), and to analyze the relationship between pain and pressure sensitivity in FMS. A cross-sectional study. Gender differences in pain sensitivity in individuals with FMS have not been yet clarified. Twenty-four men (age: 52 ± 6 years) and 24 age-matched women (age: 52 ± 5 years) with FMS diagnosed according to 1990 American College of Rheumatology criteria participated. Pressure pain thresholds (PPTs) over the 18 tender points and over the second metacarpal and tibialis anterior muscle were assessed. The intensity and duration of pain, tender point count, the Fibromyalgia Impact Questionnaire, and depression (Beck Depression Inventory-II) were calculated. Women reported higher intensity of pain, tender point count, and depression than men (P < 0.01). Men reported a longer history of pain and disability than women (P = 0.005). Women showed bilateral lower PPT over suboccipital, cervical spine, second rib, supraspinatus, lateral epicondyle, gluteal region, and second metacarpal than men (P < 0.05). Negative associations between tender point count and PPT were found in men and women. In men, negative correlations between the intensity of ongoing pain and PPT over the cervical spine were found. No significant association between PPT and other clinical outcome was seen. Women with FMS showed higher pain severity and lower PPT than men, whereas men exhibited longer duration of symptoms and disability. In men with FMS, the intensity of ongoing pain was positively correlated to pressure hyperalgesia over the neck. This study suggests that FMS could show a different phenotype in women and men and confirm that women exhibit lower PPT than men.

Fundamentals of Neurogastroenterology: Basic Science

This study aimed to evaluate the contributions of psychological status and cardiovascular responsiveness to racial/ethnic differences in experimental pain sensitivity. Data collected from 3,159 TMD-free individuals - non-Hispanic white (NHW): 1,637, African-American (AA): 1,012, Asian: 299, and Hispanic: 211 - from the OPPERA prospective cohort study were used. Variables analyzed included: quantitative sensory testing measures for pressure, mechanical cutaneous, and heat pain, cardiovascular responsiveness measures (BP, HR, HR/MAP ratio, and heart rate variability), and psychological status (depression, anxiety, stress, coping, and catastrophizing). Structural equation modeling was used for mediation analyses. Putative mediators that showed significant racial/ethnic differences were entered into the final models simultaneously with age, gender, BMI, geographic study site, and education and income level as covariates. Pain catastrophizing was a significant mediator for the associations between race and heat pain tolerance, heat pain ratings (HPR), heat pain aftersensations (HPA), mechanical cutaneous pain ratings and aftersensations (MCPRAS), and mechanical cutaneous pain temporal summation (MCPTS) for both Asians and AAs compared to NHWs. HR/MAP index showed a significant negative mediating effect on the association between race (AAs vs. NHWs) and heat pain tolerance. Coping negatively mediated the association between race and heat pain tolerance, HPR, and MCPTS in both AAs and Asians, compared to NHWs. Negative emotion was a significant mediator for the associations between race (Asians vs. NHWs) and mechanical cutaneous pain thresholds, HPR, HPA, and MCPRAS. Underlying factors responsible for racial differences in pain sensitivity are complex, but both psychological and cardiovascular factors appear to be relevant mediators. Further clinical and experimental research is required to increase our understanding of the suggested mechanisms explaining racial/ethnic differences in pain sensitivity found in the current study and to extend our findings to clinical pain populations.

BackgroundGenetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy.ResultsWe genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype.ConclusionThis study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.

Does neonatal surgery lead to increased pain sensitivity in later childhood?

Pain empathy is a complex form of psychological inference that enables us to understand how others feel in the context of pain. Since pain empathy may be grounded in our own pain experiences, it exhibits huge inter-individual variability. However, the neural mechanisms behind the individual differences in pain empathy and its association with pain perception are still poorly understood. In this study, we aimed to characterize brain mechanisms associated with individual differences in pain empathy in adult participants (n = 24). The 32-channel electroencephalography (EEG) was recorded at rest and during a pain empathy task, and participants viewed static visual stimuli of the limbs submitted to painful and nonpainful stimulation to solicit empathy. The pain sensitivity of each participant was measured using a series of direct current stimulations. In our results, the N2 of Fz and the LPP of P3 and P4 were affected by painful pictures. We found that both delta and alpha bands in the frontal and parietal cortex were involved in the regulation of pain empathy. For the delta band, a close relationship was found between average power, either in the resting or task state, and individual differences in pain empathy. It suggested that the spectral power in Fz's delta band may reflect subjective pain empathy across individuals. For the alpha band, the functional connectivity between Fz and P3 under painful picture stimulation was correlated to individuals' pain sensitivity. It indicated that the alpha band may reflect individual differences in pain sensitivity and be involved in pain empathy processing. Our results suggested the distinct role of the delta and alpha bands of EEG signals in pain empathy processing and may deepen our understanding of the neural mechanisms underpinning pain empathy.

Maternal Separation Leads to Persistent Reductions in Pain Sensitivity in Female Rats

The molecular genetic aspects of individual differences in thermoregulation and pain sensitivity that may be used to evaluate and predict the physical state of humans under contrast climate conditions, as well as during high physical and psychic loads, are reviewed. In response to abrupt changes in both external and internal temperature, the body activates internal resources that support homeostasis and adapts to the environment. Active movements are often associated with traumas accompanied by a sense of pain whose intensity and suppression depend on individual body characteristics. Understanding the functioning of the systems of thermoregulation and pain sensitivity at the molecular level and study of the polymorphism of genes involved in these processes is important for creation of optimal conditions for both rapid adaptation to the loads of everyday life and high physical activity and for success in sports.

Recent data suggest that interactions between systems involved in higher order knowledge and associative learning drive responses during value-based learning. However, it is unknown how these systems impact subjective responses, such as pain. We tested how instructions and reversal learning influence pain and pain-evoked brain activation. Healthy volunteers (n=40) were either instructed about contingencies between cues and aversive outcomes or learned through experience in a paradigm where contingencies reversed three times. We measured predictive cue effects on pain and heat-evoked brain responses using functional magnetic resonance imaging. Predictive cues dynamically modulated pain perception as contingencies changed, regardless of whether participants received contingency instructions. Heat-evoked responses in the insula, anterior cingulate, and other regions updated as contingencies changed, and responses in the prefrontal cortex mediated dynamic cue effects on pain, whereas responses in the brainstem's rostroventral medulla (RVM) were shaped by initial contingencies throughout the task. Quantitative modeling revealed that expected value was shaped purely by instructions in the Instructed Group, whereas expected value updated dynamically in the Uninstructed Group as a function of error-based learning. These differences were accompanied by dissociations in the neural correlates of value-based learning in the rostral anterior cingulate, thalamus, and posterior insula, among other regions. These results show how predictions dynamically impact subjective pain. Moreover, imaging data delineate three types of networks involved in pain generation and value-based learning: those that respond to initial contingencies, those that update dynamically during feedback-driven learning as contingencies change, and those that are sensitive to instruction. Together, these findings provide multiple points of entry for therapies designs to impact pain.

We examined the expression of preproenkephalin mRNA in pain-modulating regions of the rat's brainstem using in situ hybridization histochemistry. We found that neurones in the Kölliker-Fuse nucleus, which receives projections from spinal nociceptive-specific cells, express enkephalin mRNA, that this expression is increased by noxious pinch applied to the skin of awake animals, and that these enkephalinergic neurones are part of a descending system that terminates in the rostroventral medulla and the spinal cord. These findings show that natural noxious stimuli activate opioidergic bulbospinal neurones that could directly modulate spinal nociceptive transmission.

Considerable research suggests that females exhibit greater sensitivity to laboratory pain procedures than do males; however, whether the presence of acute clinical pain influences this sex difference in pain sensitivity has not been investigated. The present experiment investigated the effects of sex and acute dental pain on laboratory pain responses. Thermal pain onset and tolerance were determined in 46 dental patients (15 male, 31 female) experiencing pain due to acute irreversible pulpitis and in 33 healthy controls (13 male, 20 female). In addition, measures of mood and coping were obtained in all participants. All subjects participated in two experimental sessions. The first session took place immediately before the patients underwent endodontic treatment for relief of pulpal pain. The second session took place approximately 1-2 weeks later, when pulpitis patients were pain free after treatment. During each session, thermal pain onset and tolerance were assessed with a 1-cm2 contact thermode applied to the right volar forearm using an ascending method of limits. During both sessions, thermal pain onset and tolerance were lower in control females than in control males; however, male and female pulpitis patients did not differ in their thermal pain responses during either session. Pulpitis patients also showed greater affective distress than controls. These data suggest that the sex difference in thermal pain sensitivity frequently reported in pain-free subjects appears to be absent in patients presenting with acute dental pain. However, this effect cannot be explained solely based on the presence of clinical pain because the effect on pain threshold and tolerance persisted into session 2, when pulpitis patients were pain free. Potential explanations for these results are discussed.

Postnatally induced differences in adult pain sensitivity depend on genetics, gender and specific experiences: reversal of maternal deprivation effects by additional postnatal tactile stimulation or chronic imipramine treatment

Time dependant differences in pain sensitivity during unilateral ischemic pain provocation in healthy volunteers

The dorsolateral prefrontal cortex (DLPFC) is implicated in pain modulation through multiple psychological processes. Recent noninvasive brain stimulation studies suggest that interhemispheric DLPFC connectivity influences pain tolerance and discomfort by altering interhemispheric inhibition. The structure and role of interhemispheric DLPFC connectivity in pain processing have not been investigated. The present study used dynamic causal modeling (DCM) for fMRI to investigate transcallosal DLPFC connectivity during painful stimulation in healthy volunteers. DCM parameters were used to predict individual differences in sensitivity to noxious heat stimuli. Bayesian model selection results indicated that influences among the right DLPFC (rDLPFC) and left DLPFC (lDLPFC) are modulated during painful stimuli. Regression analyses revealed that greater rDLPFC→lDLPFC couplings were associated with higher suprathreshold pain temperatures. These results highlight the role of interhemispheric connectivity in pain modulation and support the preferential role of the right hemisphere in pain processing. Knowledge of these mechanisms may improve understanding of abnormal pain modulation in chronic pain populations.

The chapter provides a comprehensive review of the current knowledge concerning the anatomical, physiological, and neurochemical substrates that underlie both physiological and pathological pain. Thus, we describe in detail the pathways that underlie the transmission of inputs from the periphery to the CNS, the physiological properties of the neurons activated by painful stimuli, and the neurochemicals that mediate or modulate synaptic transmission in somatosensory pathways. A special effort has been made to identify critical advances in the field of pain research that point to the processes by which pathological pain develops following tissue or nerve injury, as well as how pain is modulated by various brain mechanisms. The review of the peripheral nervous system concentrates on differences in the properties of the primary afferent neurons that transduce and relay painful messages to the CNS, and how their responses are affected by injuries that produce inflammation. The review of spinal cord dorsal horn concentrates on what is known about the neurochemical influences on synaptic transmission, and how they are affected by inflammatory and nerve injuries in the periphery. The review of pain processing in the brain focuses on the role of various brain regions in the determination of the multidimensional nature of pain, as discerned by anatomical connectivity, physiological function, and brain imaging. Finally, insights are provided into the future of pain research, with a focus on molecular biology, and behavioral genetics as a means to understand individual differences in pain sensitivity and expression.