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Sample records for human experimental pain

  1. Experimental neck muscle pain impairs standing balance in humans.

    PubMed

    Vuillerme, Nicolas; Pinsault, Nicolas

    2009-02-01

    Impaired postural control has been reported in patients with chronic neck pain of both traumatic and non-traumatic etiologies, but whether painful stimulation of neck muscle per se can affect balance control during quiet standing in humans remains unclear. The purpose of the present experiment was thus to investigate the effect of experimental neck muscle pain on standing balance in young healthy adults. To achieve this goal, 16 male university students were asked to stand upright as still as possible on a force platform with their eyes closed in two conditions of No pain and Pain of the neck muscles elicited by experimental painful electrical stimulation. Postural control and postural performance were assessed by the displacements of the center of foot pressure (CoP) and of the center of mass (CoM), respectively. The results showed increased CoP and CoM displacements variance, range, mean velocity, and mean and median frequencies in the Pain relative to the No pain condition. The present findings emphasize the destabilizing effect of experimental neck muscle pain per se, and more largely stress the importance of intact neck neuromuscular function on standing balance.

  2. Pain referral and regional deep tissue hyperalgesia in experimental human hip pain models.

    PubMed

    Izumi, Masashi; Petersen, Kristian Kjær; Arendt-Nielsen, Lars; Graven-Nielsen, Thomas

    2014-04-01

    Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (P<.05). Referred pain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (P<.05). PPTs at the injection site were decreased after hypertonic saline injections into GMT and GMM compared with baseline, ALT injections, and isotonic saline. Cuff PPTs from the thigh were decreased after hypertonic saline injections into the ALT compared with baseline, GMT injections, and isotonic saline (P<.05). More subjects had positive joint pain provocation tests after hypertonic compared with isotonic saline injections (P<.05), indicating that this provocation test also assessed hyperalgesia in extra-articular soft tissues. The experimental models may open for better understanding of pain mechanisms associated with painful hip disorders.

  3. Human experimental pain models: A review of standardized methods in drug development

    PubMed Central

    Reddy, K. Sunil kumar; Naidu, M. U. R.; Rani, P. Usha; Rao, T. Ramesh Kumar

    2012-01-01

    Human experimental pain models are essential in understanding the pain mechanisms and appear to be ideally suited to test analgesic compounds. The challenge that confronts both the clinician and the scientist is to match specific treatments to different pain-generating mechanisms and hence reach a pain treatment tailored to each individual patient. Experimental pain models offer the possibility to explore the pain system under controlled settings. Standardized stimuli of different modalities (i.e., mechanical, thermal, electrical, or chemical) can be applied to the skin, muscles, and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using a multimodel-multistructure testing, the nociception arising from different body structures can be explored and modulation of specific biomarkers by new and existing analgesic drugs can be profiled. The value of human experimental pain models is to link animal and clinical pain studies, providing new possibilities for designing successful clinical trials. Spontaneous pain, the main compliant of the neuropathic patients, but currently there is no human model available that would mimic chronic pain. Therefore, current human pain models cannot replace patient studies for studying efficacy of analgesic compounds, although being helpful for proof-of-concept studies and dose finding. PMID:23626642

  4. Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research

    PubMed Central

    Oertel, Bruno Georg; Lötsch, Jörn

    2013-01-01

    The medical impact of pain is such that much effort is being applied to develop novel analgesic drugs directed towards new targets and to investigate the analgesic efficacy of known drugs. Ongoing research requires cost-saving tools to translate basic science knowledge into clinically effective analgesic compounds. In this review we have re-examined the prediction of clinical analgesia by human experimental pain models as a basis for model selection in phase I studies. The overall prediction of analgesic efficacy or failure of a drug correlated well between experimental and clinical settings. However, correct model selection requires more detailed information about which model predicts a particular clinical pain condition. We hypothesized that if an analgesic drug was effective in an experimental pain model and also a specific clinical pain condition, then that model might be predictive for that particular condition and should be selected for development as an analgesic for that condition. The validity of the prediction increases with an increase in the numbers of analgesic drug classes for which this agreement was shown. From available evidence, only five clinical pain conditions were correctly predicted by seven different pain models for at least three different drugs. Most of these models combine a sensitization method. The analysis also identified several models with low impact with respect to their clinical translation. Thus, the presently identified agreements and non-agreements between analgesic effects on experimental and on clinical pain may serve as a solid basis to identify complex sets of human pain models that bridge basic science with clinical pain research. PMID:23082949

  5. Genetic predictors for acute experimental cold and heat pain sensitivity in humans

    PubMed Central

    Kim, H; Mittal, D P; Iadarola, M J; Dionne, R A

    2006-01-01

    Background The genetic contribution to pain sensitivity underlies a complex composite of parallel pain pathways, multiple mechanisms, and diverse inter‐individual pain experiences and expectations. Methods Variations for genes encoding receptors related to cold and heat sensation, such as transient receptor potential A subtype 1 (TRPA1), M subtype 8 (TRPM8), V subtype 1 (TRPV1), δ opioid receptor subtype 1 (OPRD1), catechol O‐methyltransferase (COMT), and fatty acid amide hydrolyase (FAAH), were investigated in four major ethnic populations. Results We defined 13 haplotype blocks in European Americans, seven blocks in African Americans, seven blocks in Hispanic subjects, and 11 blocks in Asian Americans. Further study in European American subjects found significant associations between short duration cold pain sensitivity and variations in TRPA1, COMT, and FAAH in a gender dependent manner. Our observations demonstrate that genetic variations in TRPA1, COMT, and FAAH contribute gender specifically to individual variations in short duration cold pain sensitivity in a European American cohort. Conclusions The effects of TRPA1 variations on experimental short duration heat pain sensitivity may contribute to inter‐individual variation in pain sensitivity in humans. PMID:16882734

  6. The genetic influences on oxycodone response characteristics in human experimental pain.

    PubMed

    Olesen, Anne E; Sato, Hiroe; Nielsen, Lecia M; Staahl, Camilla; Droney, Joanne; Gretton, Sophy; Branford, Ruth; Drewes, Asbjørn M; Arendt-Nielsen, Lars; Riley, Julia; Ross, Joy

    2015-08-01

    Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P < 0.0001) and rs563649 (P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone.

  7. The effects of experimental muscle and skin pain on the static stretch sensitivity of human muscle spindles in relaxed leg muscles

    PubMed Central

    Birznieks, Ingvars; Burton, Alexander R; Macefield, Vaughan G

    2008-01-01

    Animal studies have shown that noxious inputs onto γ-motoneurons can cause an increase in the activity of muscle spindles, and it has been proposed that this causes a fusimotor-driven increase in muscle stiffness that is believed to underlie many chronic pain syndromes. To test whether experimental pain also acts on the fusimotor system in humans, unitary recordings were made from 19 spindle afferents (12 Ia, 7 II) located in the ankle and toe extensors or peronei muscles of awake human subjects. Muscle pain was induced by bolus intramuscular injection of 0.5 ml 5% hypertonic saline into tibialis anterior (TA); skin pain was induced by 0.2 ml injection into the overlying skin. Changes in fusimotor drive to the muscle spindles were inferred from changes in the mean discharge frequency and discharge variability of spindle endings in relaxed muscle. During muscle pain no afferents increased their discharge activity: seven afferents (5 Ia, 2 II) showed a decrease and six (4 Ia, 2 II) afferents were not affected. During skin pain of 13 afferents discharge rate increased in one (Ia) and decreased in two (1 Ia, 1 II). On average, the overall discharge rate decreased during muscle pain by 6.1% (P < 0.05; Wilcoxon), but remained essentially the same during skin pain. There was no detectable correlation between subjective pain level and the small change in discharge rate of muscle spindles. Irrespective of the type of pain, discharge variability parameters were not influenced (P > 0.05; Wilcoxon). We conclude that, contrary to the ‘vicious cycle’ hypothesis, acute activation of muscle or skin nociceptors does not cause a reflex increase in fusimotor drive in humans. Rather, our results are more aligned with the pain adaptation model, based on clinical studies predicting pain-induced reductions of agonist muscle activity. PMID:18403422

  8. Pain inhibits pain; human brainstem mechanisms.

    PubMed

    Youssef, A M; Macefield, V G; Henderson, L A

    2016-01-01

    Conditioned pain modulation is a powerful analgesic mechanism, occurring when a painful stimulus is inhibited by a second painful stimulus delivered at a different body location. Reduced conditioned pain modulation capacity is associated with the development of some chronic pain conditions and the effectiveness of some analgesic medications. Human lesion studies show that the circuitry responsible for conditioned pain modulation lies within the caudal brainstem, although the precise nuclei in humans remain unknown. We employed brain imaging to determine brainstem sites responsible for conditioned pain modulation in 54 healthy individuals. In all subjects, 8 noxious heat stimuli (test stimuli) were applied to the right side of the mouth and brain activity measured using functional magnetic resonance imaging. This paradigm was then repeated. However, following the fourth noxious stimulus, a separate noxious stimulus, consisting of an intramuscular injection of hypertonic saline into the leg, was delivered (conditioning stimulus). During this test and conditioning stimulus period, 23 subjects displayed conditioned pain modulation analgesia whereas 31 subjects did not. An individual's analgesic ability was not influenced by gender, pain intensity levels of the test or conditioning stimuli or by psychological variables such as pain catastrophizing or fear of pain. Brain images were processed using SPM8 and the brainstem isolated using the SUIT toolbox. Significant increases in signal intensity were determined during each test stimulus and compared between subjects that did and did not display CPM analgesia (p<0.05, small volume correction). The expression of analgesia was associated with reduction in signal intensity increases during each test stimulus in the presence of the conditioning stimulus in three brainstem regions: the caudalis subdivision of the spinal trigeminal nucleus, i.e., the primary synapse, the region of the subnucleus reticularis dorsalis and in the

  9. Vicarious pain while observing another in pain: an experimental approach

    PubMed Central

    Vandenbroucke, S.; Crombez, G.; Van Ryckeghem, D. M. L.; Brass, M.; Van Damme, S.; Goubert, L.

    2013-01-01

    Objective: This study aimed at developing an experimental paradigm to assess vicarious pain experiences. We further explored the putative moderating role of observer's characteristics such as hypervigilance for pain and dispositional empathy. Methods: Two experiments are reported using a similar procedure. Undergraduate students were selected based upon whether they reported vicarious pain in daily life, and categorized into a pain responder group or a comparison group. Participants were presented a series of videos showing hands being pricked whilst receiving occasionally pricking (electrocutaneous) stimuli themselves. In congruent trials, pricking and visual stimuli were applied to the same spatial location. In incongruent trials, pricking and visual stimuli were in the opposite spatial location. Participants were required to report on which location they felt a pricking sensation. Of primary interest was the effect of viewing another in pain upon vicarious pain errors, i.e., the number of trials in which an illusionary sensation was reported. Furthermore, we explored the effect of individual differences in hypervigilance to pain, dispositional empathy and the rubber hand illusion (RHI) upon vicarious pain errors. Results: Results of both experiments indicated that the number of vicarious pain errors was overall low. In line with expectations, the number of vicarious pain errors was higher in the pain responder group than in the comparison group. Self-reported hypervigilance for pain lowered the probability of reporting vicarious pain errors in the pain responder group, but dispositional empathy and the RHI did not. Conclusion: Our paradigm allows measuring vicarious pain experiences in students. However, the prevalence of vicarious experiences of pain is low, and only a small percentage of participants display the phenomenon. It remains however unknown which variables affect its occurrence. PMID:23781187

  10. Experimental manipulations of pain catastrophizing influence pain levels in patients with chronic pain and healthy volunteers.

    PubMed

    Kjøgx, Heidi; Kasch, Helge; Zachariae, Robert; Svensson, Peter; Jensen, Troels S; Vase, Lene

    2016-06-01

    Pain catastrophizing (PC) has been related to pain levels in both patients experiencing acute or chronic pain and in healthy volunteers exposed to experimental pain. Still, it is unclear whether high levels of pain catastrophizing lead to high levels of pain or vice versa. We therefore tested whether levels of pain catastrophizing could be increased and decreased in the same participant through hypnotic suggestions and whether the altered level of situation-specific pain catastrophizing was related to increased and decreased pain levels, respectively. Using the spontaneous pain of 22 patients with chronic tension-type headache and experimentally induced pain in 22 healthy volunteers, participants were tested in 3 randomized sessions where they received 3 types of hypnotic suggestions: Negative (based on the 13 items in the Pain Catastrophizing Scale), Positive (coping-oriented reversion of the Pain Catastrophizing Scale), and Neutral (neutral sentence) hypnotic suggestions. The hypnotic suggestions significantly increased and decreased situation-specific PC in both patients and healthy volunteers (P < 0.001). Also, the levels of pain intensity and pain unpleasantness were significantly altered in both patients and healthy volunteers (P < 0.001). Furthermore, regression analyses showed that changes in pain catastrophizing predicted changes in pain in patients (R = 0.204-0.304; P < 0.045) and in healthy volunteers (R = 0.328-0.252; P < 0.018). This is the first study to successfully manipulate PC in positive and negative directions in both patients with chronic pain and healthy volunteers and to show that these manipulations significantly influence pain levels. These findings may have important theoretical and clinical implications.

  11. Human models of pain for the prediction of clinical analgesia.

    PubMed

    Lötsch, Jörn; Oertel, Bruno G; Ultsch, Alfred

    2014-10-01

    Human experimental pain models are widely used to study drug effects under controlled conditions. However, efforts to improve both animal and human experimental model selection, on the basis of increased understanding of the underlying pathophysiological pain mechanisms, have been disappointing, with poor translation of results to clinical analgesia. We have developed an alternative approach to the selection of suitable pain models that can correctly predict drug efficacy in particular clinical settings. This is based on the analysis of successful or unsuccessful empirical prediction of clinical analgesia using experimental pain models. We analyzed statistically the distribution of published mutual agreements or disagreements between drug efficacy in experimental and clinical pain settings. Significance limits were derived by random permutations of agreements. We found that a limited subset of pain models predicts a large number of clinically relevant pain settings, including efficacy against neuropathic pain for which novel analgesics are particularly needed. Thus, based on empirical evidence of agreement between drugs for their efficacy in experimental and clinical pain settings, it is possible to identify pain models that reliably predict clinical analgesic drug efficacy in cost-effective experimental settings.

  12. Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

    PubMed Central

    Staahl, Camilla; Olesen, Anne Estrup; Andresen, Trine; Arendt-Nielsen, Lars; Drewes, Asbjørn Mohr

    2009-01-01

    AIM Experimental pain models may help to evaluate the mechanisms of action of analgesics and target the clinical indications for their use. This review addresses how the efficacy of opioids can be assessed in human volunteers using experimental pain models. The drawback with the different study designs is also discussed. METHOD A literature search was completed for randomized controlled studies which included human experimental pain models, healthy volunteers and opioids. RESULTS Opioids with a strong affinity for the µ-opioid receptor decreased the sensation in a variety of experimental pain modalities, but strong tonic pain was attenuated more than short lasting pain and non-painful sensations. The effects of opioids with weaker affinity for the µ-opioid receptor were detected by a more narrow range of pain models, and the assessment methods needed to be more sensitive. CONCLUSION The way the pain is induced, assessed and summarized is very important for the sensitivity of the pain models. This review gives an overview of how different opioids perform in experimental pain models. Generally experimental pain models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. This knowledge can aid the decisions needed to be taken when designing experimental pain studies for compounds entering phase 1 clinical trials. PMID:19694733

  13. A novel modelling and experimental technique to predict and measure tissue temperature during CO2 laser stimuli for human pain studies.

    PubMed

    Al-Saadi, Mohammed Hamed; Nadeau, V; Dickinson, M R

    2006-07-01

    Laser nerve stimulation is now accepted as one of the preferred methods for applying painful stimuli to human skin during pain studies. One of the main concerns, however, is thermal damage to the skin. We present recent work based on using a CO2 laser with a remote infrared (IR) temperature sensor as a feedback system. A model for predicting the subcutaneous skin temperature derived from the signal from the IR detector allows us to accurately predict the laser parameters, thus maintaining an optimum pain stimulus whilst avoiding dangerous temperature levels, which could result in thermal damage. Another aim is to relate the modelling of the CO2 fibre laser interaction to the pain response and compare these results with practical measurements of the pain threshold for various stimulus parameters. The system will also allow us to maintain a constant skin temperature during the stimulus. Another aim of the experiments underway is to review the psychophysics for pain in human subjects, permitting an investigation of the relationship between temperature and perceived pain.

  14. Pain assessment in human fetus and infants.

    PubMed

    Bellieni, Carlo Valerio

    2012-09-01

    In humans, painful stimuli can arrive to the brain at 20-22 weeks of gestation. Therefore several researchers have devoted their efforts to study fetal analgesia during prenatal surgery, and during painful procedures in premature babies. Aim of this paper is to gather from scientific literature the available data on the signals that the human fetus and newborns produce, and that can be interpreted as signals of pain. Several signs can be interpreted as signals of pain. We will describe them in the text. In infants, these signs can be combined to create specific and sensible pain assessment tools, called pain scales, used to rate the level of pain.

  15. Nature and Nurture of Human Pain

    PubMed Central

    2013-01-01

    Humans are very different when it comes to pain. Some get painful piercings and tattoos; others can not stand even a flu shot. Interindividual variability is one of the main characteristics of human pain on every level including the processing of nociceptive impulses at the periphery, modification of pain signal in the central nervous system, perception of pain, and response to analgesic strategies. As for many other complex behaviors, the sources of this variability come from both nurture (environment) and nature (genes). Here, I will discuss how these factors contribute to human pain separately and via interplay and how epigenetic mechanisms add to the complexity of their effects. PMID:24278778

  16. Nature and nurture of human pain.

    PubMed

    Belfer, Inna

    2013-01-01

    Humans are very different when it comes to pain. Some get painful piercings and tattoos; others can not stand even a flu shot. Interindividual variability is one of the main characteristics of human pain on every level including the processing of nociceptive impulses at the periphery, modification of pain signal in the central nervous system, perception of pain, and response to analgesic strategies. As for many other complex behaviors, the sources of this variability come from both nurture (environment) and nature (genes). Here, I will discuss how these factors contribute to human pain separately and via interplay and how epigenetic mechanisms add to the complexity of their effects.

  17. The effects of Botulinum Toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental human model of trigeminal sensitization.

    PubMed

    Gazerani, Parisa; Staahl, Camilla; Drewes, Asbjøn M; Arendt-Nielsen, Lars

    2006-06-01

    The trigeminovascular system is involved in migraine. Efficacy of Botulinum Toxin type A (BoNT-A) in migraine has been investigated in clinical studies but the mechanism of action remains unexplored. It is hypothesized that BoNT-A inhibits peripheral sensitization of nociceptive fibers and indirectly reduces central sensitization. We examined the effect of intramuscular injection of BoNT-A on an experimental human model of trigeminal sensitization induced by intradermal capsaicin injection to the forehead. BoNT-A (BOTOX) or saline was injected intramuscularly in precranial, neck and shoulder muscles to 32 healthy male volunteers in a double blind-randomized manner. Intradermally capsaicin-induced pain, flare and secondary hyperalgesia were obtained before and 1, 4 and 8 weeks after the above treatments. A significant suppressive effect of BoNT-A on pain, flare and hyperalgesia area was observed. The pain intensity area was significantly smaller in BoNT-A group (9.16+/-0.83 cm x s) compared to saline group (15.41+/-0.83cm x s) (P=0.011). The flare area was also reduced significantly in BoNT-A group (29.81+/-0.69 cm2) compared to saline group (39.71+/-0.69 cm2) (P<0.001). Similarly, the mean area of secondary hyperalgesia was significantly smaller in BoNT-A group (4.25+/-0.91 cm2) compared to saline group (7.03+/-0.91 cm2) (P=0.040). Post hoc analysis showed significant differences across the trials with a remarkable suppression effect of BoNT-A on capsaicin-induced sensory and vasomotor reactions as early as week1 (P<0.001). BoNT-A presented suppressive effects on the trigeminal/cervical nociceptive system activated by intradermal injection of capsaicin to the forehead. The effects are suggested to be caused by a local peripheral effect of BoNT-A on cutaneous nociceptors.

  18. IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP)

    PubMed Central

    Murphy, Stephen F.; Schaeffer, Anthony J.; Done, Joseph; Wong, Larry; Bell-Cohn, Ashlee; Roman, Kenny; Cashy, John; Ohlhausen, Michelle; Thumbikat, Praveen

    2015-01-01

    Chronic pelvic pain syndrome (CPPS) is the most common form of prostatitis, accounting for 90–95% of all diagnoses. It is a complex multi-symptom syndrome with unknown etiology and limited effective treatments. Previous investigations highlight roles for inflammatory mediators in disease progression by correlating levels of cytokines and chemokines with patient reported symptom scores. It is hypothesized that alteration of adaptive immune mechanisms results in autoimmunity and subsequent development of pain. Mouse models of CPPS have been developed to delineate these immune mechanisms driving pain in humans. Using the experimental autoimmune prostatitis (EAP) in C57BL/6 mice model of CPPS we examined the role of CD4+T-cell subsets in the development and maintenance of prostate pain, by tactile allodynia behavioral testing and flow cytometry. In tandem with increased CD4+IL17A+ T-cells upon EAP induction, prophylactic treatment with an anti-IL17 antibody one-day prior to EAP induction prevented the onset of pelvic pain. Therapeutic blockade of IL17 did not reverse pain symptoms indicating that IL17 is essential for development but not maintenance of chronic pain in EAP. Furthermore we identified a cytokine, IL7, to be associated with increased symptom severity in CPPS patients and is increased in patient prostatic secretions and the prostates of EAP mice. IL7 is fundamental to development of IL17 producing cells and plays a role in maturation of auto-reactive T-cells, it is also associated with autoimmune disorders including multiple sclerosis and type-1 diabetes. More recently a growing body of research has pointed to IL17’s role in development of neuropathic and chronic pain. This report presents novel data on the role of CD4+IL17+ T-cells in development and maintenance of pain in EAP and CPPS. PMID:25933188

  19. Heritability of pain catastrophizing and associations with experimental pain outcomes: a twin study.

    PubMed

    Trost, Zina; Strachan, Eric; Sullivan, Michael; Vervoort, Tine; Avery, Ally R; Afari, Niloofar

    2015-03-01

    This study used a twin paradigm to examine genetic and environmental contributions to pain catastrophizing and the observed association between pain catastrophizing and cold-pressor task (CPT) outcomes. Male and female monozygotic (n = 206) and dizygotic twins (n = 194) from the University of Washington Twin Registry completed a measure of pain catastrophizing and performed a CPT challenge. As expected, pain catastrophizing emerged as a significant predictor of several CPT outcomes, including cold-pressor Immersion Tolerance, Pain Tolerance, and Delayed Pain Rating. The heritability estimate for pain catastrophizing was found to be 37% with the remaining 63% of variance attributable to unique environmental influence. Additionally, the observed associations between pain catastrophizing and CPT outcomes were not found attributable to shared genetics or environmental exposure, which suggests a direct relationship between catastrophizing and experimental pain outcomes. This study is the first to examine the heritability of pain catastrophizing and potential processes by which pain catastrophizing is related to experimental pain response.

  20. Pain management: a fundamental human right.

    PubMed

    Brennan, Frank; Carr, Daniel B; Cousins, Michael

    2007-07-01

    This article surveys worldwide medical, ethical, and legal trends and initiatives related to the concept of pain management as a human right. This concept recently gained momentum with the 2004 European Federation of International Association for the Study of Pain (IASP) Chapters-, International Association for the Study of Pain- and World Health Organization-sponsored "Global Day Against Pain," where it was adopted as a central theme. We survey the scope of the problem of unrelieved pain in three areas, acute pain, chronic noncancer pain, and cancer pain, and outline the adverse physical and psychological effects and social and economic costs of untreated pain. Reasons for deficiencies in pain management include cultural, societal, religious, and political attitudes, including acceptance of torture. The biomedical model of disease, focused on pathophysiology rather than quality of life, reinforces entrenched attitudes that marginalize pain management as a priority. Strategies currently applied for improvement include framing pain management as an ethical issue; promoting pain management as a legal right, providing constitutional guarantees and statutory regulations that span negligence law, criminal law, and elder abuse; defining pain management as a fundamental human right, categorizing failure to provide pain management as professional misconduct, and issuing guidelines and standards of practice by professional bodies. The role of the World Health Organization is discussed, particularly with respect to opioid availability for pain management. We conclude that, because pain management is the subject of many initiatives within the disciplines of medicine, ethics and law, we are at an "inflection point" in which unreasonable failure to treat pain is viewed worldwide as poor medicine, unethical practice, and an abrogation of a fundamental human right.

  1. Human pain and genetics: some basics

    PubMed Central

    2013-01-01

    Human pain causes untold misery and suffering, with major impact on functioning and resources. Recent advances in genetics have revealed that subtle changes in DNA could partly explain the variation in individual differences in pain. Various genes encoding for receptors are now known to play a major role in the sensitivity, perception and expression of pain. The fields of epigenetics and proteomics hold promises in the way pain could be treated and managed in future. PMID:26516521

  2. A SCN10A SNP biases human pain sensitivity

    PubMed Central

    Duan, Guangyou; Han, Chongyang; Wang, Qingli; Guo, Shanna; Zhang, Yuhao; Ying, Ying; Huang, Penghao; Zhang, Li; Macala, Lawrence; Shah, Palak; Zhang, Mi; Li, Ningbo; Dib-Hajj, Sulayman D; Zhang, Xianwei

    2016-01-01

    Background: Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined. Results: Candidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity. We demonstrated an association between rs6795970 (G > A; p.Ala1073Val) and higher thresholds for mechanical pain in a discovery cohort (496 subjects) and confirmed it in a larger replication cohort (1005 female subjects). Functional assessments showed that although the minor allele shifts channel activation by −4.3 mV, a proexcitatory attribute, it accelerates inactivation, an antiexcitatory attribute, with the net effect being reduced repetitive firing of dorsal root ganglion neurons, consistent with lower mechanical pain sensitivity. Conclusions: At the association and mechanistic levels, the SCN10A single nucleotide polymorphism rs6795970 biases human pain sensitivity. PMID:27590072

  3. [Human beings in pain : A philosophical approach].

    PubMed

    Jantzen, A

    2011-12-01

    The philosophical discussion of the phenomenon of pain can help to increase the understanding of human beings in pain and to accompany them in such an experience. Pain affects a human being who has a body. The "I" of this human being cannot escape into painlessness. The pain imposes itself upon the human being who will try to withdraw from the pain but to withdraw from pain remains impossible because the human being cannot split himself up and therefore cannot establish a part of himself where his identity is not affected by pain.The pain shows how the experience of being in a body is connected to the experience of having an identity. Pain reduces the ability to act and narrows the possibility to interact with others; it affects the manner how the human is still or no longer able to address himself to others. In the reduction of his existence a human being experiences a basic condition of his existence: He is vulnerable.

  4. Pain relief is a human right.

    PubMed

    Daher, Michel

    2010-01-01

    For centuries, medical and surgical treatment has emphasized saving the life of the patient rather than ameliorating the patient's pain, particularly when there were few options for the latter. Today at the dawn of the 21st century, the best available evidence indicates a major gap between an increasingly understanding of the pathophysiology of pain and widespread inadequacy of its treatment. Epidemiologic evidence has proven that chronic pain is a widespread public health issue. Studies of cancer patients' pain control consistently reveal that up to half of patients receive inadequate analgesia and 30% do not receive appropriate drugs for their pain. Equally, for patients suffering HIV/AIDS, 60%-100% will experience pain at some stage in their illness. In the developed world, this gap has prompted a series of declarations and actions by national and international bodies advocating better pain control. One response to the worldwide undertreatment of pain has been to promote the concept that pain relief is a public health issue of such critical importance as to constitute an international imperative and fundamental human right. The importance of pain relief as the core of the medical ethic is clear. Pain clinicians promote the status of pain management beyond that of appropriate clinical practice or even an ethic of good medicine. They advocate a paradigm shift in the medical professions' perspective on pain management, from simply good practice to an imperative founded on patient rights. There is a need to promote policies which create conditions where human beings can bear even incurable illnesses and death in a dignified manner. This must help health professionals or lay groups to initiate a powerful agenda to reform local statutes. The essential components of such legislation are: 1. Reasonable pain management is a right. 2. Doctors have a duty to listen to and reasonably respond to a patient's report of pain. 3. Provision of necessary pain relief is immune from

  5. Pain-related emotions modulate experimental pain perception and autonomic responses.

    PubMed

    Rainville, Pierre; Bao, Quoc Viet Huynh; Chrétien, Pablo

    2005-12-05

    The effect of emotions on pain perception is generally recognized but the underlying mechanisms remain unclear. Here, emotions related to pain were induced in healthy volunteers using hypnosis, during 1-min immersions of the hand in painfully hot water. In Experiment 1, hypnotic suggestions were designed to induce various positive or negative emotions. Compared to a control condition with hypnotic-relaxation, negative emotions produced robust increases in pain. In Experiment 2, induction of pain-related anger and sadness were found to increase pain. Pain increases were associated with increases in self-rated desire for relief and decreases in expectation of relief, and with increases in arousal, negative affective valence and decreases in perceived control. In Experiment 3, hypnotic suggestions specifically designed to increase and decrease the desire for relief produced increases and decreases in pain, respectively. In all three experiments, emotion-induced changes in pain were most consistently found on ratings of pain unpleasantness compared to pain intensity. Changes in pain-evoked cardiac responses (R-R interval decrease), measured in experiments 2 and 3, were consistent with changes in pain unpleasantness. Correlation and multiple regression analyses suggest that negative emotions and desire for relief influence primarily pain affect and that pain-evoked autonomic responses are strongly associated with pain affect. These results confirm the hypothesized influence of the desire for relief on pain perception, and particularly on pain affect, and support the functional relation between pain affect and autonomic nociceptive responses. This study provides further experimental confirmation that pain-related emotions influence pain perception and pain-related physiological responses.

  6. A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile.

    PubMed

    Arendt-Nielsen, Lars; Harris, Steve; Whiteside, Garth T; Hummel, Michele; Knappenberger, Terri; OʼKeefe, Sarah; Kapil, Ram; Kyle, Don

    2016-09-01

    This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.

  7. Meta-analysis on brain representation of experimental dental pain.

    PubMed

    Lin, C-S; Niddam, D M; Hsu, M-L

    2014-02-01

    Functional magnetic resonance imaging (fMRI) has been widely used for investigating the brain representation associated with dental pain evoked by pulpal electrical stimulation. However, because of the heterogeneity of experimental designs and the small sample size of individual studies, the common brain representation regarding dental pain has remained elusive. We used imaging meta-analysis to investigate six dental pain-related fMRI studies (n = 87) and tested 3 hypotheses: (1) Dental pain is associated with the 'core' pain-related network; (2) pain-related brain activation is somatotopically organized in the somatosensory cortex; and (3) dental pain is associated with the cognitive-affective network related to pain. Qualitative and quantitative meta-analyses revealed: (1) common activation of the core pain-related network, including the somatosensory cortex, the insula, and the cingulate cortex; (2) inconsistency in somatotopically organized activation of the primary somatosensory cortex; and (3) common activation in the dorsolateral prefrontal cortex, suggesting a role of re-appraisal and coping in the experience of dental pain. In conclusion, fMRI combined with pulpal stimulation can effectively evoke activity in the pain-related network. The dental pain-related brain representation disclosed the mechanisms of how sensory and cognitive-affective factors shape dental pain, which will help in the development of more effective customized methods for central pain control.

  8. Spontaneous Chronic Pain After Experimental Thoracotomy Revealed by Conditioned Place Preference: Morphine Differentiates Tactile Evoked Pain From Spontaneous Pain.

    PubMed

    Hung, Ching-Hsia; Wang, Jeffrey Chi-Fei; Strichartz, Gary R

    2015-09-01

    Chronic pain after surgery limits social activity, interferes with work, and causes emotional suffering. A major component of such pain is reported as resting or spontaneous pain with no apparent external stimulus. Although experimental animal models can simulate the stimulus-evoked chronic pain that occurs after surgery, there have been no studies of spontaneous chronic pain in such models. Here the conditioned place preference (CPP) paradigm was used to reveal resting pain after experimental thoracotomy. Male Sprague Dawley rats received a thoracotomy with 1-hour rib retraction, resulting in evoked tactile hypersensitivity, previously shown to last for at least 9 weeks. Intraperitoneal injections of morphine (2.5 mg/kg) or gabapentin (40 mg/kg) gave equivalent 2- to 3-hour-long relief of tactile hypersensitivity when tested 12 to 14 days postoperatively. In separate experiments, single trial CPP was conducted 1 week before thoracotomy and then 12 days (gabapentin) or 14 days (morphine) after surgery, followed the next day by 1 conditioning session with morphine or gabapentin, both versus saline. The gabapentin-conditioned but not the morphine-conditioned rats showed a significant preference for the analgesia-paired chamber, despite the equivalent effect of the 2 agents in relieving tactile allodynia. These results show that experimental thoracotomy in rats causes spontaneous pain and that some analgesics, such as morphine, that reduce evoked pain do not also relieve resting pain, suggesting that pathophysiological mechanisms differ between these 2 aspects of long-term postoperative pain. Perspective: Spontaneous pain, a hallmark of chronic postoperative pain, is demonstrated here in a rat model of experimental postthoracotomy pain, further validating the use of this model for the development of analgesics to treat such symptoms. Although stimulus-evoked pain was sensitive to systemic morphine, spontaneous pain was not, suggesting different mechanistic

  9. Amantadine sulfate reduces experimental sensitization and pain in chronic back pain patients.

    PubMed

    Kleinböhl, Dieter; Görtelmeyer, Roman; Bender, Hans-Joachim; Hölzl, Rupert

    2006-03-01

    We investigated if established psychophysical measures of enhanced experimental sensitization in chronic musculoskeletal pain can be reduced by adjuvant treatment with a N-methyl-d-aspartate receptor antagonist, amantadine sulfate, and whether a reduction in sensitization might be accompanied by a concurrent improvement in clinical pain. Sensitization was evaluated by an experimental tonic heat model of short-term sensitization with concurrent subjective and behavioral psychophysical scaling. Twenty-six patients with chronic back pain were included in the randomized, double-blind, placebo-controlled study and received daily dosages of either placebo or 100 mg of amantadine sulfate during a 1-wk treatment. Participants completed quantitative sensory testing of pain thresholds and experimental sensitization before and after treatment and clinical pain ratings before, during, and after treatment. Experimental sensitization and clinical pain were reduced in patients receiving verum. Initially, experimental sensitization was enhanced in patients, with early sensitization at nonpainful intensities of contact heat and enhanced sensitization at painful intensities, as shown previously. After 1 wk of treatment, experimental sensitization was reduced with amantadine sulfate but not with placebo. We conclude that adjuvant chronic pain treatment with N-methyl-d-aspartate receptor antagonists might be beneficial for chronic pain if enhanced sensitization is involved and that the quantitative sensory test of temporal summation may be used to verify this.

  10. Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings

    PubMed Central

    Fillingim, Roger B.; King, Christopher D.; Ribeiro-Dasilva, Margarete C.; Rahim-Williams, Bridgett; Riley, Joseph L.

    2009-01-01

    Sex-related influences on pain and analgesia have become a topic of tremendous scientific and clinical interest, especially in the last 10 to 15 years. Members of our research group published reviews of this literature more than a decade ago, and the intervening time period has witnessed robust growth in research regarding sex, gender, and pain. Therefore, it seems timely to revisit this literature. Abundant evidence from recent epidemiologic studies clearly demonstrates that women are at substantially greater risk for many clinical pain conditions, and there is some suggestion that postoperative and procedural pain may be more severe among women than men. Consistent with our previous reviews, current human findings regarding sex differences in experimental pain indicate greater pain sensitivity among females compared with males for most pain modalities, including more recently implemented clinically relevant pain models such as temporal summation of pain and intramuscular injection of algesic substances. The evidence regarding sex differences in laboratory measures of endogenous pain modulation is mixed, as are findings from studies using functional brain imaging to ascertain sex differences in pain-related cerebral activation. Also inconsistent are findings regarding sex differences in responses to pharmacologic and non-pharmacologic pain treatments. The article concludes with a discussion of potential biopsychosocial mechanisms that may underlie sex differences in pain, and considerations for future research are discussed. Perspective This article reviews the recent literature regarding sex, gender, and pain. The growing body of evidence that has accumulated in the past 10 to 15 years continues to indicate substantial sex differences in clinical and experimental pain responses, and some evidence suggests that pain treatment responses may differ for women versus men. PMID:19411059

  11. The influence of experimentally induced pain on shoulder muscle activity.

    PubMed

    Diederichsen, Louise Pyndt; Winther, Annika; Dyhre-Poulsen, Poul; Krogsgaard, Michael R; Nørregaard, Jesper

    2009-04-01

    Muscle function is altered in painful shoulder conditions. However, the influence of shoulder pain on muscle coordination of the shoulder has not been fully clarified. The aim of the present study was to examine the effect of experimentally induced shoulder pain on shoulder muscle function. Eleven healthy men (range 22-27 years), with no history of shoulder or cervical problems, were included in the study. Pain was induced by 5% hypertonic saline injections into the supraspinatus muscle or subacromially. Seated in a shoulder machine, subjects performed standardized concentric abduction (0 degrees -105 degrees) at a speed of approximately 120 degrees/s, controlled by a metronome. During abduction, electromyographic (EMG) activity was recorded by intramuscular wire electrodes inserted in two deeply located shoulder muscles and by surface-electrodes over six superficially located shoulder muscles. EMG was recorded before pain, during pain and after pain had subsided and pain intensity was continuously scored on a visual analog scale (VAS). During abduction, experimentally induced pain in the supraspinatus muscle caused a significant decrease in activity of the anterior deltoid, upper trapezius and the infraspinatus and an increase in activity of lower trapezius and latissimus dorsi muscles. Following subacromial injection a significantly increased muscle activity was seen in the lower trapezius, the serratus anterior and the latissimus dorsi muscles. In conclusion, this study shows that acute pain both subacromially and in the supraspinatus muscle modulates coordination of the shoulder muscles during voluntary movements. During painful conditions, an increased activity was detected in the antagonist (latissimus), which support the idea that localized pain affects muscle activation in a way that protects the painful structure. Further, the changes in muscle activity following subacromial pain induction tend to expand the subacromial space and thereby decrease the load

  12. Administrative Aspects of Human Experimentation.

    ERIC Educational Resources Information Center

    Irvine, George W.

    1992-01-01

    The following administrative aspects of scientific experimentation with human subjects are discussed: the definition of human experimentation; the distinction between experimentation and treatment; investigator responsibility; documentation; the elements and principles of informed consent; and the administrator's role in establishing and…

  13. Verbally reinforcing pain reports: an experimental test of the operant model of chronic pain.

    PubMed

    Jolliffe, Christopher D; Nicholas, Michael K

    2004-01-01

    Effective treatments for chronic pain have been based on the operant model for chronic pain, which holds that pain behaviours can be operantly controlled by various reinforcers. Support for the operant model comes primarily from treatment/outcome studies which report significant reductions in pain behaviours in chronic pain patients, but fail to demonstrate the underlying operant thesis that various reinforcers play a significant role in the establishment and maintenance of pain behaviours. In an experimental test of this hypothesis, the pain reports of forty-six healthy undergraduate students were measured over two sets of fifteen trials, in which the pressure from a blood-pressure cuff applied to their arm either remained stable or decreased over time. Half of the subjects received positive verbal reinforcement from the experimenter after each trial if their report of pain intensity exceeded that of the previous trial. Overall, the mean pain reports of reinforced subjects were significantly greater than those of the non-reinforced subjects both when the intensity of the cuff was stable over trials, and when it decreased, as expected. These results provide support for the operant model of chronic pain. The clinical and theoretical implications of these results for the operant model of chronic pain are discussed, and suggestions for future research are made.

  14. The effect of experimentally-induced subacromial pain on proprioception.

    PubMed

    Sole, Gisela; Osborne, Hamish; Wassinger, Craig

    2015-02-01

    Shoulder injuries may be associated with proprioceptive deficits, however, it is unknown whether these changes are due to the experience of pain, tissue damage, or a combination of these. The aim of this study was to investigate the effect of experimentally-induced sub-acromial pain on proprioceptive variables. Sub-acromial pain was induced via hypertonic saline injection in 20 healthy participants. Passive joint replication (PJR) and threshold to detection of movement direction (TTDMD) were assessed with a Biodex System 3 Pro isokinetic dynamometer for baseline control, experimental pain and recovery control conditions with a starting position of 60° shoulder abduction. The target angle for PJR was 60° external rotation, starting from 40°. TTDMD was tested from a position of 20° external rotation. Repeated measures ANOVAs were used to determine differences between PJR absolute and variable errors and TTDMD for the control and experimental conditions. Pain was elicited with a median 7 on the Numeric Pain Rating Scale. TTDMD was significantly decreased for the experimental pain condition compared to baseline and recovery conditions (≈30%, P = 0.003). No significant differences were found for absolute (P = 0.152) and variable (P = 0.514) error for PJR. Movement sense was enhanced for the experimental sub-acromial pain condition, which may reflect protective effects of the central nervous system in response to the pain. Where decreased passive proprioception is observed in shoulders with injuries, these may be due to a combination of peripheral tissue injury and neural adaptations that differ from those due to acute pain.

  15. Effect of experimental chewing on masticatory muscle pain onset

    PubMed Central

    CONTI, Paulo César Rodrigues; SILVA, Rafael dos Santos; de ARAUJO, Carlos dos Reis Pereira; ROSSETI, Leylha Maria N.; YASSUDA, Shigueharu; da SILVA, Renato Oliveira Ferreira; PEGORARO, Luiz Fernando

    2011-01-01

    Objectives To evaluate the effect of a chewing exercise on pain intensity and pressurepain threshold in patients with myofascial pain. Methods Twenty-nine consecutive women diagnosed with myofascial pain (MFP) according to the Research Diagnostic Criteria comprised the experimental group and 15 healthy age-matched female were used as controls. Subjects were asked to chew a gum stick for 9 min and to stay at rest for another 9 min afterwards. Pain intensity was rated on a visual analog scale (VAS) every 3 min. At 0, 9 and 18 min, the pressure-pain threshold (PPT) was measured bilaterally on the masseter and the anterior, medium, and posterior temporalis muscles. Results Patients with myofascial pain reported increase (76%) and no change (24%) on the pain intensity measured with the VAS. A reduction of the PPT at all muscular sites after the exercise and a non-significant recovery after rest were also observed. Conclusion The following conclusions can be drawn: 1. there are at least two subtypes of patients with myofascial pain that respond differently to experimental chewing; 2. the chewing protocol had an adequate discriminative ability in distinguishing patients with myofascial pain from healthy controls. PMID:21437467

  16. Brain and human pain: topographic EEG amplitude and coherence mapping.

    PubMed

    Chen, A C; Rappelsberger, P

    1994-01-01

    Nineteen young healthy volunteers (8 males and 11 females) participated in an experimental ice-cube cold pressor test to study topographic changes of EEG parameters in response to painful stimulation. EEG was recorded with 19 electrodes and quantified by amplitude and coherence analyses. Mean amplitudes and values for local (between adjacent electrodes) and interhemispheric (between electrodes on homologous sites of both hemispheres) coherences were computed for six frequency bands. For the evaluation of changes between EEG at rest (baseline) and EEG during painful stimulation (right or left hand), non-parametric paired Wilcoxon tests were performed. The obtained descriptive error probabilities were presented in probability maps. In the behavioural pain tolerance and subjective pain ratings, no difference in gender or stimulation condition was observed. Under painful stimulation the results showed: (A) most pronounced decrease of Alpha amplitude in the central areas and some increase of high Beta amplitude; (B) increase of local coherence for Alpha and Beta 2 mainly in central regions and centro-frontal leads; and (C) increase of interhemispheric coherence for Alpha and Beta 2 in the central areas. The results of this study indicate clearly that peripheral painful stimulation is reflected by EEG changes. Decrease of EEG amplitude and simultaneous increase of EEG coherence in the central regions can be cortical correlates of human pain.

  17. Pain and stress in the human fetus.

    PubMed

    White, Michelle C; Wolf, Andrew R

    2004-06-01

    It is not known if the fetus can actually feel pain, but noxious stimulation during fetal life does cause detectable stress responses. These responses cause both short and long-term changes in the central nervous system, which can affect subsequent pain behaviour. Reducing the stress response is known to be beneficial in children and adults and recent evidence suggests this is also true for the fetus. However, the optimal amount of suppression required and the best method of achieving this (opioid or regional anaesthesia techniques) remain unknown. Prevention and treatment of pain is a basic human right, regardless of age, and if the technique of fetal surgery is to progress then a greater understanding of nociception and the stress response is required.

  18. Dissociable Learning Processes Underlie Human Pain Conditioning.

    PubMed

    Zhang, Suyi; Mano, Hiroaki; Ganesh, Gowrishankar; Robbins, Trevor; Seymour, Ben

    2016-01-11

    Pavlovian conditioning underlies many aspects of pain behavior, including fear and threat detection [1], escape and avoidance learning [2], and endogenous analgesia [3]. Although a central role for the amygdala is well established [4], both human and animal studies implicate other brain regions in learning, notably ventral striatum and cerebellum [5]. It remains unclear whether these regions make different contributions to a single aversive learning process or represent independent learning mechanisms that interact to generate the expression of pain-related behavior. We designed a human parallel aversive conditioning paradigm in which different Pavlovian visual cues probabilistically predicted thermal pain primarily to either the left or right arm and studied the acquisition of conditioned Pavlovian responses using combined physiological recordings and fMRI. Using computational modeling based on reinforcement learning theory, we found that conditioning involves two distinct types of learning process. First, a non-specific "preparatory" system learns aversive facial expressions and autonomic responses such as skin conductance. The associated learning signals-the learned associability and prediction error-were correlated with fMRI brain responses in amygdala-striatal regions, corresponding to the classic aversive (fear) learning circuit. Second, a specific lateralized system learns "consummatory" limb-withdrawal responses, detectable with electromyography of the arm to which pain is predicted. Its related learned associability was correlated with responses in ipsilateral cerebellar cortex, suggesting a novel computational role for the cerebellum in pain. In conclusion, our results show that the overall phenotype of conditioned pain behavior depends on two dissociable reinforcement learning circuits.

  19. Interaction between histamine-induced itch and experimental muscle pain.

    PubMed

    Wasner, G; Schwarz, K; Schattschneider, J; Binder, A; Jensen, T S; Baron, R

    2004-06-01

    Itch sensation can be inhibited by simultaneously applied cutaneous pain at the same skin site via a central mechanism. Deep muscle pain is often associated with sensory changes in the corresponding dermatome. We investigated whether experimentally induced muscle pain has any influence on histamine-induced itch and vice versa in a double blind placebo-controlled study. Experiments were performed in 18 healthy subjects. In nine individuals control iontophoresis of histamine into the forearm produced a distinct itch sensation. Another nine individuals participated in an additional experiment in which histamine and saline were iontophoresed on the forearm in a randomized double-blinded two-way crossover design after intramuscular injection of capsaicin into the ipsilateral brachioradial muscle. Capsaicin-induced muscle pain reduced itch sensation significantly. In contrast, capsaicin-induced muscle pain increased significantly after cutaneous histamine application compared to muscle pain after iontophoresis of saline (placebo). These novel data indicate that muscle pain inhibits itch and histamine increases muscle pain. A bi-directional interaction between cutaneous histamine-sensitive afferents and nociceptive muscle afferents via central mechanisms is suggested.

  20. Decreased pain sensitivity among people with schizophrenia: a meta-analysis of experimental pain induction studies.

    PubMed

    Stubbs, Brendon; Thompson, Trevor; Acaster, Sarah; Vancampfort, Davy; Gaughran, Fiona; Correll, Christoph U

    2015-11-01

    Patients with schizophrenia report reduced pain sensitivity in clinical studies, but experimental studies are required to establish pain sensitivity as a potential endophenotype. We conducted a systematic review of electronic databases from database inception until April 15, 2015, including experimental studies investigating pain among patients with schizophrenia spectrum disorder vs healthy controls. A random-effect meta-analysis yielding Hedges' g ±95% confidence intervals (CIs) as the effect size (ES) measure was conducted. Primary outcome was a pooled composite of pain threshold and pain tolerance; secondary outcomes included these parameters individually, plus sensory threshold, physiological pain response, and pain intensity or unpleasantness. Across 17 studies, patients with schizophrenia spectrum disorder (n = 387; age, 30.7 ± 6.9 years; females, 31.9%; illness duration, 7.0 ± 5.7 years) were compared with controls (n = 483; age, 29.5 ± 7.4 years; females, 31.0%). Patients had elevated pain threshold/pain tolerance vs controls (ES = 0.583; 95% CI, 0.212-0.954; P = 0.002; studies = 15). Results were similar in antipsychotic-free individuals (ES = 0.599; 95% CI, 0.291-0.907; P < 0.0001; studies = 8), with trend-level significance in antipsychotic-treated individuals (ES = 0.566; 95% CI, -0.007 to 1.125; P = 0.047; studies = 9). Likewise, patients with schizophrenia had increased pain tolerance (ES = 0.566; 95% CI, 0.235-0.897; P = 0.0001; studies = 6), sensory threshold (ES = 1.16; 95% CI, 0.505-1.727; P < 0.0001; studies = 5), and pain threshold (ES = 0.696; 95% CI, 0.407-0.986; P < 0.001; studies = 9), as well as reduced physiological response to noxious stimuli (ES = 0.456; 95% CI, 0.131-0.783; P = 0.006) and pain intensity/unpleasantness ratings (ES = 0.547; 95% CI, 0.146-0.949; P = 0.008). Findings were similarly significant in antipsychotic-free patients with schizophrenia (analysable parameters = 4) and antipsychotic-treated individuals (analysable

  1. Gender role affects experimental pain responses: a systematic review with meta-analysis.

    PubMed

    Alabas, O A; Tashani, O A; Tabasam, G; Johnson, M I

    2012-10-01

    Gender role refers to the culturally and socially constructed meanings that describe how women and men should behave in certain situations according to feminine and masculine roles learned throughout life. The aim of this meta-analysis was to evaluate the relationship between gender role and experimental pain responses in healthy human participants. We searched computerized databases for studies published between January 1950 and May 2011 that had measured gender role in healthy human adults and pain response to noxious stimuli. Studies were entered into a meta-analysis if they calculated a correlation coefficient (r) for gender role and experimental pain. Searches yielded 4465 'hits' and 13 studies were eligible for review. Sample sizes were 67-235 participants and the proportion of female participants was 45-67%. Eight types of gender role instrument were used. Meta-analysis of six studies (406 men and 539 women) found a significant positive correlation between masculine and feminine personality traits and pain threshold and tolerance, with a small effect size (r = 0.17, p = 0.01). Meta-analysis of four studies (263 men and 297 women) found a significant negative correlation between gender stereotypes specific to pain and pain threshold and tolerance, with a moderate effect size (r = -0.41, p < 0.001). In conclusion, individuals who considered themselves more masculine and less sensitive to pain than the typical man showed higher pain thresholds and tolerances. Gender stereotypes specific to pain scales showed stronger associations with sex differences in pain sensitivity response than masculine and feminine personality trait scales.

  2. Pain tolerance predicts human social network size

    PubMed Central

    Johnson, Katerina V.-A.; Dunbar, Robin I. M.

    2016-01-01

    Personal social network size exhibits considerable variation in the human population and is associated with both physical and mental health status. Much of this inter-individual variation in human sociality remains unexplained from a biological perspective. According to the brain opioid theory of social attachment, binding of the neuropeptide β-endorphin to μ-opioid receptors in the central nervous system (CNS) is a key neurochemical mechanism involved in social bonding, particularly amongst primates. We hypothesise that a positive association exists between activity of the μ-opioid system and the number of social relationships that an individual maintains. Given the powerful analgesic properties of β-endorphin, we tested this hypothesis using pain tolerance as an assay for activation of the endogenous μ-opioid system. We show that a simple measure of pain tolerance correlates with social network size in humans. Our results are in line with previous studies suggesting that μ-opioid receptor signalling has been elaborated beyond its basic function of pain modulation to play an important role in managing our social encounters. The neuroplasticity of the μ-opioid system is of future research interest, especially with respect to psychiatric disorders associated with symptoms of social withdrawal and anhedonia, both of which are strongly modulated by endogenous opioids. PMID:27121297

  3. Effects of hypnotic analgesia and hypnotizability on experimental ischemic pain.

    PubMed

    DeBenedittis, G; Panerai, A A; Villamira, M A

    1989-01-01

    Mechanisms of hypnotic analgesia are still poorly understood and conflicting data are reported regarding the underlying neurochemical correlates. The present study was designed to investigate the effects of hypnotically induced analgesia and hypnotizability on experimental ischemic pain, taking into account pain and distress tolerance as well as the neurochemical correlates. 11 high hypnotizable Ss and 10 low hypnotizable Ss, as determined by scores on the Stanford Hypnotic Susceptibility Scale, Form C (Weitzenhoffer & E. R. Hilgard, 1962), were administered an ischemic pain test in both waking and hypnotic conditions. The following variables were measured: (a) pain and distress tolerance, (b) anxiety levels, and (c) plasma concentrations of beta-endorphin and adrenocorticotropic hormone (ACTH). Results confirmed significant increases of pain and distress tolerance during hypnosis as compared to the waking state, with positive correlations between pain and distress relief and hypnotizability. Moreover, a hypnotically induced dissociation between the sensory-discriminative and the affective-motivational dimensions of pain experience was found, but only in high hypnotizable Ss. Hypnotic analgesia was unrelated to anxiety reduction and was not mediated either by endorphins or by ACTH.

  4. Virtual human technology: capturing sex, race, and age influences in individual pain decision policies.

    PubMed

    Hirsh, Adam T; Alqudah, Ashraf F; Stutts, Lauren A; Robinson, Michael E

    2008-11-15

    Pain assessment is subject to bias due to characteristics of the individual in pain and of the observing person. Few research studies have examined pain assessment biases in an experimental setting. This study employs innovative virtual human technology to achieve greater experimental control. A lens model design was used to capture decision-making policies at the idiographic and nomothetic level. Seventy-five undergraduates viewed virtual humans (VH) that varied in sex, race, age, and pain expression. Participants provided computerized ratings with Visual Analogue Scales on the VH's pain intensity, pain unpleasantness, negative mood, coping, and need for medical treatment. Idiographic analyses revealed that individuals used pain expression most frequently as a significant cue. Nomothetic analyses showed that higher pain expression VH and female VH were viewed as having higher pain intensity, higher pain unpleasantness, greater negative mood, worse coping, and a greater need to seek medical treatment than lower pain expression VH and male VH, respectively. Older VH were viewed as having worse coping and a greater need to seek medical treatment than younger VH. This innovative paradigm involving VH technology and a lens model design was shown to be highly effective and could serve as a model for future studies investigating pain-related decision making in healthcare providers.

  5. Nonpainful wide-area compression inhibits experimental pain.

    PubMed

    Honigman, Liat; Bar-Bachar, Ofrit; Yarnitsky, David; Sprecher, Elliot; Granovsky, Yelena

    2016-09-01

    Compression therapy, a well-recognized treatment for lymphoedema and venous disorders, pressurizes limbs and generates massive non-noxious afferent sensory barrages. The aim of this study was to study whether such afferent activity has an analgesic effect when applied on the lower limbs, hypothesizing that larger compression areas will induce stronger analgesic effects, and whether this effect correlates with conditioned pain modulation (CPM). Thirty young healthy subjects received painful heat and pressure stimuli (47°C for 30 seconds, forearm; 300 kPa for 15 seconds, wrist) before and during 3 compression protocols of either SMALL (up to ankles), MEDIUM (up to knees), or LARGE (up to hips) compression areas. Conditioned pain modulation (heat pain conditioned by noxious cold water) was tested before and after each compression protocol. The LARGE protocol induced more analgesia for heat than the SMALL protocol (P < 0.001). The analgesic effect interacted with gender (P = 0.015). The LARGE protocol was more efficient for females, whereas the MEDIUM protocol was more efficient for males. Pressure pain was reduced by all protocols (P < 0.001) with no differences between protocols and no gender effect. Conditioned pain modulation was more efficient than the compression-induced analgesia. For the LARGE protocol, precompression CPM efficiency positively correlated with compression-induced analgesia. Large body area compression exerts an area-dependent analgesic effect on experimental pain stimuli. The observed correlation with pain inhibition in response to robust non-noxious sensory stimulation may suggest that compression therapy shares similar mechanisms with inhibitory pain modulation assessed through CPM.

  6. Nonpainful wide-area compression inhibits experimental pain

    PubMed Central

    Honigman, Liat; Bar-Bachar, Ofrit; Yarnitsky, David; Sprecher, Elliot; Granovsky, Yelena

    2016-01-01

    Abstract Compression therapy, a well-recognized treatment for lymphoedema and venous disorders, pressurizes limbs and generates massive non-noxious afferent sensory barrages. The aim of this study was to study whether such afferent activity has an analgesic effect when applied on the lower limbs, hypothesizing that larger compression areas will induce stronger analgesic effects, and whether this effect correlates with conditioned pain modulation (CPM). Thirty young healthy subjects received painful heat and pressure stimuli (47°C for 30 seconds, forearm; 300 kPa for 15 seconds, wrist) before and during 3 compression protocols of either SMALL (up to ankles), MEDIUM (up to knees), or LARGE (up to hips) compression areas. Conditioned pain modulation (heat pain conditioned by noxious cold water) was tested before and after each compression protocol. The LARGE protocol induced more analgesia for heat than the SMALL protocol (P < 0.001). The analgesic effect interacted with gender (P = 0.015). The LARGE protocol was more efficient for females, whereas the MEDIUM protocol was more efficient for males. Pressure pain was reduced by all protocols (P < 0.001) with no differences between protocols and no gender effect. Conditioned pain modulation was more efficient than the compression-induced analgesia. For the LARGE protocol, precompression CPM efficiency positively correlated with compression-induced analgesia. Large body area compression exerts an area-dependent analgesic effect on experimental pain stimuli. The observed correlation with pain inhibition in response to robust non-noxious sensory stimulation may suggest that compression therapy shares similar mechanisms with inhibitory pain modulation assessed through CPM. PMID:27152691

  7. The human brain response to dental pain relief.

    PubMed

    Meier, M L; Widmayer, S; Abazi, J; Brügger, M; Lukic, N; Lüchinger, R; Ettlin, D A

    2015-05-01

    Local anesthesia has made dental treatment more comfortable since 1884, but little is known about associated brain mechanisms. Functional magnetic resonance imaging is a modern neuroimaging tool widely used for investigating human brain activity related to sensory perceptions, including pain. Most brain regions that respond to experimental noxious stimuli have recently been found to react not only to nociception alone, but also to visual, auditory, and other stimuli. Thus, presumed functional attributions have come under scrutiny regarding selective pain processing in the brain. Evidently, innovative approaches are warranted to identify cerebral regions that are nociceptive specific. In this study, we aimed at circumventing known methodological confounders by applying a novel paradigm in 14 volunteers: rather than varying the intensity and thus the salience of painful stimuli, we applied repetitive noxious dental stimuli at constant intensity to the left mandibular canine. During the functional magnetic resonance imaging paradigm, we suppressed the nociceptive barrage by a mental nerve block. Brain activity before and after injection of 4% articaine was compared intraindividually on a group level. Dental pain extinction was observed to correspond to activity reduction in a discrete region of the left posterior insular cortex. These results confirm previous reports demonstrating that direct electrical stimulation of this brain region-but not of others-evokes bodily pain sensations. Hence, our investigation adds further evidence to the notion that the posterior insula plays a unique role in nociceptive processing.

  8. TRPA1 and TRPV1 Antagonists Do Not Inhibit Human Acidosis-Induced Pain.

    PubMed

    Schwarz, Matthias G; Namer, Barbara; Reeh, Peter W; Fischer, Michael J M

    2017-01-03

    Acidosis occurs in a variety of pathophysiological and painful conditions where it is thought to excite or contribute to excitation of nociceptive neurons. Despite potential clinical relevance the principal receptor for sensing acidosis is unclear, but several receptors have been proposed. We investigated the contribution of the acid-sensing ion channels, transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1) to peripheral pain signaling. We first established a human pain model using intraepidermal injection of the TRPA1 agonist carvacrol. This resulted in concentration-dependent pain sensations, which were reduced by experimental TRPA1 antagonist A-967079. Capsaicin-induced pain was reduced by the TRPV1 inhibitor BCTC. Amiloride was used to block acid-sensing ion channels. Testing these antagonists in a double-blind and randomized experiment, we probed the contribution of the respective channels to experimental acidosis-induced pain in 15 healthy human subjects. A continuous intraepidermal injection of pH 4.3 was used to counter the buffering capacity of tissue and generate a prolonged painful stimulation. In this model, addition of A-967079, BCTC or amiloride did not reduce the reported pain. In conclusion, target-validated antagonists, applied locally in human skin, have excluded the main hypothesized targets and the mechanism of the human acidosis-induced pain remains unclear.

  9. Experimentally induced pain perception is acutely reduced by aerobic exercise in people with chronic low back pain.

    PubMed

    Hoffman, Martin D; Shepanski, Melissa A; Mackenzie, Sean P; Clifford, Philip S

    2005-01-01

    This study examined whether subjects with chronic low back pain demonstrate exercise-induced analgesia to experimentally induced pressure pain. We employed a repeated measures design to study eight subjects with chronic low back pain (mean +/- standard deviation age = 40 +/- 10, duration of pain = 7 +/- 4 years). Pain ratings were measured immediately before and 2 minutes and 32 minutes after 25 minutes of cycle ergometry (5 minutes at 50% peak oxygen uptake, then 20 minutes at 70% peak oxygen uptake). We based the pain ratings on subject input on a visual analog scale at 10-second intervals during the 2-minute pressure pain stimulus to the nondominant index finger. Compared with preexercise values, pain ratings were significantly (p < 0.05) decreased after exercise at both 2 and 32 minutes postexercise. We conclude that pressure pain perception can be reduced for more than 30 minutes following aerobic exercise from leg cycling among people with chronic low back pain.

  10. Inflammation-induced pain sensitization in men and women: does sex matter in experimental endotoxemia?

    PubMed

    Wegner, Alexander; Elsenbruch, Sigrid; Rebernik, Laura; Roderigo, Till; Engelbrecht, Elisa; Jäger, Marcus; Engler, Harald; Schedlowski, Manfred; Benson, Sven

    2015-10-01

    A role of the innate immune system is increasingly recognized as a mechanism contributing to pain sensitization. Experimental administration of the bacterial endotoxin lipopolysaccharide (LPS) constitutes a model to study inflammation-induced pain sensitization, but all existing human evidence comes from male participants. We assessed visceral and musculoskeletal pain sensitivity after low-dose LPS administration in healthy men and women to test the hypothesis that women show greater LPS-induced hyperalgesia compared with men. In this randomized, double-blind, placebo-controlled crossover study, healthy men (n = 20) and healthy women using oral contraceptives (n = 20) received an intravenous injection of 0.4 ng/kg body weight LPS or placebo. Pain sensitivity was assessed with established visceral and musculoskeletal pain models (ie, rectal pain thresholds; pressure pain thresholds for different muscle groups), together with a heartbeat perception (interoceptive accuracy) task. Plasma cytokines (tumor necrosis factor-α and interleukin-6) were measured along with state anxiety at baseline and up to 6-hour postinjection. Lipopolysaccharide application led to significant increases in plasma cytokines and state anxiety and decreased interoceptive awareness in men and women (P < 0.001, condition effects), with more pronounced LPS-induced cytokine increases in women (P < 0.05, interaction effects). Although both rectal and pressure pain thresholds were significantly decreased in the LPS condition (all P < 0.05, condition effect), no sex differences in endotoxin-induced sensitization were observed. In summary, LPS-induced systemic immune activation leads to visceral and musculoskeletal hyperalgesia, irrespective of biological sex. These findings support the broad applicability of experimental endotoxin administration as a translational preclinical model of inflammation-induced pain sensitization in both sexes.

  11. The effect of paracetamol and tropisetron on pain: experimental studies and a review of published data.

    PubMed

    Tiippana, Elina; Hamunen, Katri; Kontinen, Vesa; Kalso, Eija

    2013-02-01

    Experimental studies suggest that paracetamol-induced analgesia is mediated via central serotonergic pathways and attenuated by 5-HT3-antagonists. However, clinical studies do not support this, and 5-HT3-antagonists are expected to reduce pain by blocking the descending pronociceptive pathway. The current project tested whether tropisetron attenuates analgesia by paracetamol. Two randomized, double-blind, crossover studies with 18 healthy male volunteers in each were performed. Pain stimuli were cold water immersion (cold pressor test), contact heat pain (study 1) and electrical stimulation (study 2). In both studies, tropisetron 5 mg i.v. or saline was administered, followed by paracetamol 2 g i.v. 30 min. later. Individual changes in heat and cold pain intensity, cold pain tolerance and unpleasantness were recorded. The same thresholds were also expressed as scores (% of the individual score at baseline). Additionally, previously published findings on the effects of paracetamol and its interaction with 5HT3-antagonists in human experimental pain models were reviewed. After calculation of the sensory and pain scores (%), tropisetron seemed to amplify the analgesic action of paracetamol. Paracetamol 2 g i.v. did not show any statistically significant analgesia in thermal tests (study 1), or differences in sensory, pain detection or moderate pain thresholds of the electrical stimulus (study 2). As paracetamol did not have a measurable analgesic effect in these tests, no conclusions can be drawn about the interaction between paracetamol and tropisetron. However, tropisetron may have an analgesic effect of its own. Clinicians should not avoid using these drugs together, unless larger clinical studies indicate otherwise.

  12. Human Biology: Experimental.

    ERIC Educational Resources Information Center

    New York City Board of Education, Brooklyn, NY. Bureau of Curriculum Development.

    Education is a process of adapting to change, and the rate of change is especially rapid in science today. This curriculum in human biology is an alternative to the New York State courses in general and Regents biology, and it has been designed to focus on change from the standpoint of the urban student. It is designed to provide students with…

  13. Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy.

    PubMed

    Marshall, Andrew G; Lee-Kubli, Corinne; Azmi, Shazli; Zhang, Michael; Ferdousi, Maryam; Mixcoatl-Zecuatl, Teresa; Petropoulos, Ioannis N; Ponirakis, Georgios; Fineman, Mark S; Fadavi, Hassan; Frizzi, Katie; Tavakoli, Mitra; Jeziorska, Maria; Jolivalt, Corinne G; Boulton, Andrew J M; Efron, Nathan; Calcutt, Nigel A; Malik, Rayaz A

    2017-02-15

    Impaired rate dependent depression (RDD) of the Hoffman-reflex is associated with reduced dorsal spinal cord potassium chloride co-transporter expression and impaired spinal GABAA receptor function, indicative of spinal inhibitory dysfunction. We have investigated the pathogenesis of impaired RDD in diabetic rodents exhibiting features of painful neuropathy and the translational potential of this marker of spinal inhibitory dysfunction in human painful diabetic neuropathy. Impaired RDD and allodynia were present in type 1 and type 2 diabetic rats but not in rats with type 1 diabetes receiving insulin supplementation that did not restore normoglycemia. Impaired RDD in diabetic rats was rapidly normalized by spinal delivery of duloxetine acting via 5HT2A receptors and temporally coincident with the alleviation of allodynia. Deficits in RDD and corneal nerve density were demonstrated in patients with painful diabetic neuropathy when compared to healthy control subjects and patients with painless diabetic neuropathy. Spinal inhibitory dysfunction and peripheral small fibre pathology may contribute to the clinical phenotype in painful diabetic neuropathy. Deficits in RDD may help to identify patients with spinally mediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.

  14. Ultrasound guided, painful electrical stimulation of lumbar facet joint structures: an experimental model of acute low back pain.

    PubMed

    O'Neill, Søren; Graven-Nielsen, Thomas; Manniche, Claus; Arendt-Nielsen, Lars

    2009-07-01

    Quantitative sensory testing has indicated generalized muscle hyperalgesia in patients with chronic low back pain. The temporal development of such hyperalgesia is not well understood. The aim of the present study was to demonstrate whether generalized muscle hyperalgesia can develop within minutes of acute low back pain using a new experimental model of lumbar facet joint pain. Thirteen healthy volunteers were included and baseline pressure pain thresholds were assessed at eight separate sites, outside the area of evoked low back and referred pain. Using ultrasonography, two electrode needles were placed either side of a lumbar facet joint (right L3-4) and used to induce experimental low back pain for 10 min with continuous stimulation. Thresholds, stimulus-response relationships, distribution and quality of the electrically induced pain were recorded. Electrical facet joint stimulation induced low back pain and pain referral into the anterior leg, ipsilaterally, proximal to the knee, similar to what is observed clinically. Pressure pain thresholds did not change significantly before, during and after facet joint stimulation. In conclusion, we describe a novel model of acute experimental low back pain and demonstrate that generalized hyperalgesia did not develop within minutes of acute low back pain.

  15. Experimentation on humans and nonhumans.

    PubMed

    Pluhar, Evelyn B

    2006-01-01

    In this article, I argue that it is wrong to conduct any experiment on a nonhuman which we would regard as immoral were it to be conducted on a human, because such experimentation violates the basic moral rights of sentient beings. After distinguishing the rights approach from the utilitarian approach, I delineate basic concepts. I then raise the classic "argument from marginal cases" against those who support experimentation on nonhumans but not on humans. After next replying to six important objections against that argument, I contend that moral agents are logically required to accord basic moral rights to every sentient being. I conclude by providing criteria for distinguishing ethical from unethical experimentation.

  16. Relative Valuation of Pain in Human Orbitofrontal Cortex

    PubMed Central

    Vlaev, Ivo; Seymour, Ben; Chater, Nick; Dolan, Raymond J.

    2014-01-01

    The valuation of health-related states, including pain, is a critical issue in clinical practice, health economics, and pain neuroscience. Surprisingly the monetary value people associate with pain is highly context-dependent, with participants willing to pay more to avoid medium-level pain when presented in a context of low-intensity, rather than high-intensity, pain. Here, we ask whether context impacts upon the neural representation of pain itself, or alternatively the transformation of pain into valuation-driven behavior. While undergoing fMRI, human participants declared how much money they would be willing to pay to avoid repeated instances of painful cutaneous electrical stimuli delivered to the foot. We also implemented a contextual manipulation that involved presenting medium-level painful stimuli in blocks with either low- or high-level stimuli. We found no evidence of context-dependent activity within a conventional “pain matrix,” where pain-evoked activity reflected absolute stimulus intensity. By contrast, in right lateral orbitofrontal cortex, a strong contextual dependency was evident, and here activity tracked the contextual rank of the pain. The findings are in keeping with an architecture where an absolute pain valuation system and a rank-dependent system interact to influence willing to pay to avoid pain, with context impacting value-based behavior high in a processing hierarchy. This segregated processing hints that distinct neural representations reflect sensory aspects of pain and components that are less directly nociceptive whose integration also guides pain-related actions. A dominance of the latter might account for puzzling phenomena seen in somatization disorders where perceived pain is a dominant driver of behavior. PMID:25355207

  17. Suggestions to Reduce Clinical Fibromyalgia Pain and Experimentally Induced Pain Produce Parallel Effects on Perceived Pain but Divergent Functional MRI–Based Brain Activity

    PubMed Central

    Derbyshire, Stuart W.G.; Whalley, Matthew G.; Seah, Stanley T.H.; Oakley, David A.

    2017-01-01

    ABSTRACT Objective Hypnotic suggestion is an empirically validated form of pain control; however, the underlying mechanism remains unclear. Methods Thirteen fibromyalgia patients received suggestions to alter their clinical pain, and 15 healthy controls received suggestions to alter experimental heat pain. Suggestions were delivered before and after hypnotic induction with blood oxygen level–dependent (BOLD) activity measured concurrently. Results Across groups, suggestion produced substantial changes in pain report (main effect of suggestion, F2, 312 = 585.8; p < .0001), with marginally larger changes after induction (main effect of induction, F1, 312 = 3.6; p = .060). In patients, BOLD response increased with pain report in regions previously associated with pain, including thalamus and anterior cingulate cortex. In controls, BOLD response decreased with pain report. All changes were greater after induction. Region-of-interest analysis revealed largely linear patient responses with increasing pain report. Control responses, however, were higher after suggestion to increase or decrease pain from baseline. Conclusions Based on behavioral report alone, the mechanism of suggestion could be interpreted as largely similar regardless of the induction or type of pain experience. The functional magnetic resonance imaging data, however, demonstrated larger changes in brain activity after induction and a radically different pattern of brain activity for clinical pain compared with experimental pain. These findings imply that induction has an important effect on underlying neural activity mediating the effects of suggestion, and the mechanism of suggestion in patients altering clinical pain differs from that in controls altering experimental pain. Patient responses imply that suggestions altered pain experience via corresponding changes in pain-related brain regions, whereas control responses imply suggestion engaged cognitive control. PMID:27490850

  18. Experimental pain phenotyping in community-dwelling individuals with knee osteoarthritis.

    PubMed

    Cardoso, Josue S; Riley, Joseph L; Glover, Toni; Sibille, Kimberly T; Bartley, Emily J; Goodin, Burel R; Bulls, Hailey W; Herbert, Matthew; Addison, Adriana S; Staud, Roland; Redden, David T; Bradley, Laurence A; Fillingim, Roger B; Cruz-Almeida, Yenisel

    2016-09-01

    Pain among individuals with knee osteoarthritis (OA) is associated with significant disability in older adults, and recent evidence demonstrates enhanced experimental pain sensitivity. Although previous research showed considerable heterogeneity in the OA clinical pain presentation, less is known regarding the variability in responses to experimental pain. The present study included individuals with knee OA (n = 292) who participated in the Understanding Pain and Limitations in Osteoarthritic Disease study and completed demographic and psychological questionnaires followed by a multimodal quantitative sensory testing (QST) session. Quantitative sensory testing measures were subjected to variable reduction procedures to derive pain sensitivity index scores, which in turn were entered into a cluster analysis. Five clusters were significantly different across all pain sensitivity index variables (P < 0.001) and were characterized by: (1) low pain sensitivity to pressure pain (N = 39); (2) average pain sensitivity across most modalities (N = 88); (3) high temporal summation of punctate pain (N = 38); (4) high cold pain sensitivity (N = 80); and (5) high sensitivity to heat pain and temporal summation of heat pain (N = 41). Clusters differed significantly by race, gender, somatic reactivity, and catastrophizing (P < 0.05). Our findings support the notion that there are distinct subgroups or phenotypes based on experimental pain sensitivity in community-dwelling older adults with knee OA, expanding previous findings of similar cluster characterizations in healthy adults. Future research is needed to further understand the pathophysiological mechanisms underlying pain within these subgroups, which may be of added value in tailoring effective treatments for people with OA.

  19. Experimental pain responses in children with chronic pain and in healthy children: How do they differ?

    PubMed Central

    Tsao, Jennie CI; Evans, Subhadra; Seidman, Laura C; Zeltzer, Lonnie K

    2012-01-01

    BACKGROUND: Extant research comparing laboratory pain responses of children with chronic pain with healthy controls is mixed, with some studies indicating lower pain responsivity for controls and others showing no differences. Few studies have included different pain modalities or assessment protocols. OBJECTIVES: To compare pain responses among 26 children (18 girls) with chronic pain and matched controls (mean age 14.8 years), to laboratory tasks involving thermal heat, pressure and cold pain. Responses to cold pain were assessed using two different protocols: an initial trial of unspecified duration and a second trial of specified duration. METHODS: Four trials of pressure pain and of thermal heat pain stimuli, all of unspecified duration, were administered, as well as the two cold pain trials. Heart rate and blood pressure were assessed at baseline and after completion of the pain tasks. RESULTS: Pain tolerance and pain intensity did not differ between children with chronic pain and controls for the unspecified trials. For the specified cold pressor trial, 92% of children with chronic pain completed the entire trial compared with only 61.5% of controls. Children with chronic pain exhibited a trend toward higher baseline and postsession heart rate and reported more anxiety and depression symptoms compared with control children. CONCLUSIONS: Contextual factors related to the fixed trial may have exerted a greater influence on pain tolerance in children with chronic pain relative to controls. Children with chronic pain demonstrated a tendency toward increased arousal in anticipation of and following pain induction compared with controls. PMID:22518373

  20. Parallels in sources of trauma, pain, distress, and suffering in humans and nonhuman animals.

    PubMed

    Ferdowsian, Hope; Merskin, Debra

    2012-01-01

    It is widely accepted that animals often experience pain and distress as a result of their use in scientific experimentation. However, unlike human suffering, the wide range of acute, recurrent, and chronic stressors and trauma on animals is rarely evaluated. In order to better understand the cumulative effects of captivity and laboratory research conditions on animals, we explore parallels between human experiences of pain and psychological distress and those of animals based on shared brain structures and physiological mechanisms. We review anatomical, physiological, and behavioral similarities between humans and other animals regarding the potential for suffering. In addition, we examine associations between research conditions and indicators of pain and distress. We include 4 case studies of common animal research protocols in order to illustrate incidental and experimental factors that can lead to animal suffering. Finally, we identify parallels between established traumatic conditions for humans and existing laboratory conditions for animals.

  1. Testing Assumptions in Human Pain Models: Psychophysical Differences Between First and Second Pain.

    PubMed

    Eckert, Nathanial R; Vierck, Charles J; Simon, Corey B; Cruz-Almeida, Yenisel; Fillingim, Roger B; Riley, Joseph L

    2017-03-01

    Acute pain arises from activation of myelinated (A delta) and unmyelinated (C) nociceptive afferents, leading to first (A-fiber) or second (C-fiber) pain sensations. The current study sought to investigate first and second pain within glabrous and hairy skin sites in human upper limbs. Fifty healthy adults (25 male/25 female, 18-30 years old, mean = 20.5 ± 1.4 years) participated in a psychophysical study investigating electronically rated, thermal first and second pain sensations within the glabrous skin at the palm and hairy skin of the forearm. Repeated measures analysis of variance indicated that the threshold for first pain was lower (more sensitive) than for second pain (P = .004), for glabrous as well as hairy skin, and thresholds at glabrous skin were higher than for hairy skin (P = .001). Hairy skin presented a steeper slope for testing, whereas there were no differences in slope between first and second pain. The study findings support assumptions associated with mechanistic differences between first and second pain sensations, while offering a novel method for producing first and second pain with the same thermal stimulus. Efforts to understand abnormalities among people with clinical pain and development of new therapeutic agents will benefit from specific psychophysical methods.

  2. Experimental reduction of pain catastrophizing modulates pain report but not spinal nociception as verified by mediation analyses.

    PubMed

    Terry, Ellen L; Thompson, Kathryn A; Rhudy, Jamie L

    2015-08-01

    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.

  3. Pain perception in people with Down syndrome: a synthesis of clinical and experimental research

    PubMed Central

    McGuire, Brian E.; Defrin, Ruth

    2015-01-01

    People with an intellectual disability experience both acute and chronic pain with at least the same frequency as the general population. However, considerably less is known about the pain perception of people with Down syndrome. In this review paper, we evaluated the available clinical and experimental evidence. Some experimental studies of acute pain have indicated that pain threshold was higher than normal but only when using a reaction time method to measure pain sensitivity. However, when reaction time is not part of the calculation of the pain threshold, pain sensitivity in people with Down syndrome is in fact lower than normal (more sensitive to pain). Clinical studies of chronic pain have shown that people with an intellectual disability experience chronic pain and within that population, people with Down syndrome also experience chronic pain, but the precise prevalence of chronic pain in Down syndrome has yet to be established. Taken together, the literature suggests that people with Down syndrome experience pain, both acute and chronic, with at least the same frequency as the rest of the population. Furthermore, the evidence suggests that although acute pain expression appears to be delayed, once pain is registered, there appears to be a magnified pain response. We conclude by proposing an agenda for future research in this area. PMID:26283936

  4. Endogenous Opioid Antagonism in Physiological Experimental Pain Models: A Systematic Review

    PubMed Central

    Werner, Mads U.; Pereira, Manuel P.; Andersen, Lars Peter H.; Dahl, Jørgen B.

    2015-01-01

    Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu-opioid-receptor (MOR) antagonists in placebo-controlled, double-blind studies using ʻinhibitoryʼ or ʻsensitizingʼ, physiological test paradigms in healthy human subjects. The databases PubMed and Embase were searched according to predefined criteria. Out of a total of 2,142 records, 63 studies (1,477 subjects [male/female ratio = 1.5]) were considered relevant. Twenty-five studies utilized ʻinhibitoryʼ test paradigms (ITP) and 38 studies utilized ʻsensitizingʼ test paradigms (STP). The ITP-studies were characterized as conditioning modulation models (22 studies) and repetitive transcranial magnetic stimulation models (rTMS; 3 studies), and, the STP-studies as secondary hyperalgesia models (6 studies), ʻpainʼ models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP-studies, including stress-induced analgesia and rTMS. In the remaining 14 conditioning modulation studies either absence of effects or ambiguous effects by MOR-antagonists, were observed. In the STP-studies, no effect of the opioid-blockade could be demonstrated in 5 out of 6 secondary hyperalgesia studies. The direction of MOR-antagonist dependent effects upon pain ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 ʻpainʼ model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR-antagonist demonstrated a consistent effect, presumably mediated by an EOS-dependent mechanisms of analgesia and hyperalgesia. PMID:26029906

  5. Pain modulatory phenotypes differentiate subgroups with different clinical and experimental pain sensitivity.

    PubMed

    Vaegter, Henrik B; Graven-Nielsen, Thomas

    2016-07-01

    Pain biomarkers are warranted for individualized pain management. Based on different pain modulatory phenotypes, the objectives of this study were to explore the existence of subgroups within patients with nonmalignant chronic pain and to investigate differences in clinical pain and pain hypersensitivity between subgroups. Cuff algometry was performed on lower legs in 400 patients with chronic pain to assess pressure pain threshold, pressure pain tolerance, temporal summation of pain (TSP: increase in pain scores to 10 repeated stimulations), and conditioned pain modulation (CPM: increase in cuff pressure pain threshold during cuff pain conditioning on the contralateral leg). Heat detection and heat pain thresholds at clinical painful and nonpainful body areas were assessed. Based on TSP and CPM, 4 distinct groups were formed: group 1 (n = 85) had impaired CPM and facilitated TSP; group 2 (n = 148) had impaired CPM and normal TSP; group 3 (n = 45) had normal CPM and facilitated TSP; and group 4 (n = 122) had normal CPM and normal TSP. Group 1 showed more pain regions than the other 3 groups (P < 0.001), indicating that impaired CPM and facilitated TSP play an important role in widespread pain. Groups 1 and 2 compared with group 4 had lower heat pain threshold at nonpainful areas and lower cuff pressure pain tolerance (P < 0.02), indicating that CPM plays a role for widespread hyperalgesia. Moreover, group 1 demonstrated higher clinical pain scores than group 4 (P < 0.05). Although not different between subgroups, patients were profiled on demographics, disability, pain catastrophizing, and fear of movement. Future research should investigate interventions tailored towards these subgroups.

  6. Sex differences in experimental measures of pain sensitivity and endogenous pain inhibition

    PubMed Central

    Bulls, Hailey W; Freeman, Emily L; Anderson, Austen JB; Robbins, Meredith T; Ness, Timothy J; Goodin, Burel R

    2015-01-01

    It has been suggested that increased pain sensitivity and disruption of endogenous pain inhibitory processes may account, at least in part, for the greater prevalence and severity of chronic pain in women compared to men. However, previous studies addressing this topic have produced mixed findings. This study examined sex differences in pain sensitivity and inhibition using quantitative sensory testing (QST), while also considering the influence of other important factors such as depressive symptoms and sleep quality. Healthy men (n=24) and women (n=24) each completed a QST battery. This battery included an ischemic pain task (IPT) that used a submaximal effort tourniquet procedure as well as a conditioned pain modulation (CPM) procedure for the assessment of endogenous pain inhibition. Prior to QST, participants completed the Center for Epidemiologic Studies Depression Scale and the Pittsburgh Sleep Quality Index. Analyses revealed significant sex differences for the ischemic pain task and the conditioned pain modulation procedure, such that women tolerated the ischemic pain for a shorter amount of time and demonstrated less pain inhibition compared with men. This remained true even when accounting for sex differences in depressive symptoms and sleep quality. The results of this study suggest that women may be more pain sensitive and possess less-efficient endogenous pain inhibitory capacity compared with men. Whether interventions that decrease pain sensitivity and enhance pain inhibition in women ultimately improve their clinical pain outcomes is an area of research that deserves additional attention in the future. PMID:26170713

  7. Human surrogate models of neuropathic pain: validity and limitations.

    PubMed

    Binder, Andreas

    2016-02-01

    Human surrogate models of neuropathic pain in healthy subjects are used to study symptoms, signs, and the hypothesized underlying mechanisms. Although different models are available, different spontaneous and evoked symptoms and signs are inducible; 2 key questions need to be answered: are human surrogate models conceptually valid, ie, do they share the sensory phenotype of neuropathic pain states, and are they sufficiently reliable to allow consistent translational research?

  8. Infusion pressure and pain during microneedle injection into skin of human subjects.

    PubMed

    Gupta, Jyoti; Park, Sohyun S; Bondy, Brian; Felner, Eric I; Prausnitz, Mark R

    2011-10-01

    Infusion into skin using hollow microneedles offers an attractive alternative to hypodermic needle injections. However, the fluid mechanics and pain associated with injection into skin using a microneedle have not been studied in detail before. Here, we report on the effect of microneedle insertion depth into skin, partial needle retraction, fluid infusion flow rate and the co-administration of hyaluronidase on infusion pressure during microneedle-based saline infusion, as well as on associated pain in human subjects. Infusion of up to a few hundred microliters of fluid required pressures of a few hundred mmHg, caused little to no pain, and showed weak dependence on infusion parameters. Infusion of larger volumes up to 1 mL required pressures up to a few thousand mmHg, but still usually caused little pain. In general, injection of larger volumes of fluid required larger pressures and application of larger pressures caused more pain, although other experimental parameters also played a significant role. Among the intradermal microneedle groups, microneedle length had little effect; microneedle retraction lowered infusion pressure but increased pain; lower flow rate reduced infusion pressure and kept pain low; and use of hyaluronidase also lowered infusion pressure and kept pain low. We conclude that microneedles offer a simple method to infuse fluid into the skin that can be carried out with little to no pain.

  9. Sex differences in experimental pain among healthy children: a systematic review and meta-analysis.

    PubMed

    Boerner, Katelynn E; Birnie, Kathryn A; Caes, Line; Schinkel, Meghan; Chambers, Christine T

    2014-05-01

    Sex differences in response to experimental pain are commonly reported in systematic reviews in the adult literature. The objective of the present research was to conduct a systematic review and meta-analysis of sex differences in healthy children's responses to experimental pain (e.g., cold pressor, heat pain, pressure pain) and, where possible, to conduct analyses separately for children and adolescents. A search was conducted of electronic databases for published papers in English of empirical research using experimental pain tasks to examine pain-related outcomes in healthy boys and girls between 0 and 18 years of age. Eighty articles were eligible for inclusion and were coded to extract information relevant to sex differences. The systematic review indicated that, across different experimental pain tasks, the majority of studies reported no significant differences between boys and girls on pain-related outcomes. However, the meta-analysis of available combined data found that girls reported significantly higher cold pressor pain intensity compared to boys in studies where the mean age of participants was greater than 12 years. Additionally, a meta-analysis of heat pain found that boys had significantly higher tolerance than girls overall, and boys had significantly higher heat pain threshold than girls in studies where the mean age of participants was 12 years or younger. These findings suggest that developmental stage may be relevant for understanding sex differences in pain.

  10. Assessment of knee joint pain in experimental rodent models of osteoarthritis.

    PubMed

    Piel, Margaret J; Kroin, Jeffrey S; Im, Hee-Jeong

    2015-01-01

    Pain assessment in animal models of osteoarthritis is integral to interpretation of a model's utility in representing the clinical condition, and enabling accurate translational medicine. Here we describe two methods for behavioral pain assessments available for use in animal models of experimental osteoarthritic pain: Von Frey filaments and spontaneous activity monitoring.

  11. Psychophysiological responses to pain identify reproducible human clusters.

    PubMed

    Farmer, Adam D; Coen, Steven J; Kano, Michiko; Paine, Peter A; Shwahdi, Mustafa; Jafari, Jafar; Kishor, Jessin; Worthen, Sian F; Rossiter, Holly E; Kumari, Veena; Williams, Steven C R; Brammer, Michael; Giampietro, Vincent P; Droney, Joanne; Riley, Julia; Furlong, Paul L; Knowles, Charles H; Lightman, Stafford L; Aziz, Qasim

    2013-11-01

    Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≤ 0.01); greater sympathetic tone (P<0.05); and higher cortisol levels (P ≤ 0.001). During pain, less stimulus was tolerated (P ≤ 0.01), and there was an increase in parasympathetic tone (P ≤ 0.05). The 5-HTTLPR short allele was over-represented (P ≤ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≤ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies.

  12. Pain perception and its genesis in the human brain.

    PubMed

    C N Chen, Andrew

    2008-10-25

    In the past two decades, pain perception in the human brain has been studied with EEG/MEG brain topography and PET/fMRI neuroimaging techniques. A host of cortical and subcortical loci can be activated by various nociceptive conditions. The activation in pain perception can be induced by physical (electrical, thermal, mechanical), chemical (capsacin, ascoric acid), psychological (anxiety, stress, nocebo) means, and pathological (e.g. migraine, neuropathic) diseases. This article deals mainly on the activation, but not modulation, of human pain in the brain. The brain areas identified are named pain representation, matrix, neuraxis, or signature. The sites are not uniformly isolated across various studies, but largely include a set of cores sites: thalamus and primary somatic area (SI), second somatic area (SII), insular cortex (IC), prefrontal cortex (PFC), cingulate, and parietal cortices. Other areas less reported and considered important in pain perception include brainstem, hippocampus, amygdala and supplementary motor area (SMA). The issues of pain perception basically encompass both the site and the mode of brain function. Although the site issue is delineared to a large degree, the mode issue has been much less explored. From the temporal dynamics, IC can be considered as the initial stage in genesis of pain perception as conscious suffering, the unique aversion in the human brain.

  13. Sex differences in parent and child pain ratings during an experimental child pain task.

    PubMed

    Moon, E C; Chambers, C T; Larochette, Anne-Claire; Hayton, K; Craig, K D; McGrath, P J

    2008-01-01

    Research in the field of pediatric pain has largely ignored the role of fathers in their children's pain experiences. The first objective of the present study was to examine the effect of the presence of mothers versus fathers on children's subjective ratings, facial expressions and physiological responses to acute pain. The second objective was to examine whether child and parent sex influence parents' proxy ratings of their children's pain. The final objective was to compare levels of agreement between mothers' and fathers' assessments of their children's pain. Participants included 73 children (37 boys, 36 girls), four to 12 years of age, along with 32 fathers and 41 mothers. Children undertook the cold pressor pain task while observed by one of their parents. During the task, the children's heart rates and facial expressions were recorded. Children provided self-reports and parents provided proxy reports of child pain intensity using the seven-point Faces Pain Scale. Neither child nor parent sex had a significant impact on children's subjective reports, facial expressions or heart rates in response to acute pain. Fathers gave their sons higher pain ratings than their daughters, whereas mothers' ratings of their sons' and daughters' pain did not differ. Kappa statistics and t tests revealed that fathers tended to be more accurate judges of their children's pain than mothers. Overall, this research highlights the importance of examining both parent and child sex differences in pediatric pain research.

  14. The role of experimentally-induced subacromial pain on shoulder strength and throwing accuracy.

    PubMed

    Wassinger, Craig A; Sole, Gisela; Osborne, Hamish

    2012-10-01

    Shoulder injuries often comprise two separate yet related components, structural tissue damage and pain. The role of each of these components on shoulder function is difficult to ascertain. Experimental pain models allow the assessment of consequences of localized pain when applied to healthy individuals. By understanding the role of pain on shoulder function, clinicians will be able to more efficiently assess and treat shoulder injuries. The objective of the study was to evaluate the role of experimentally-induced sub-acromial pain on shoulder isokinetic rotational strength and throwing accuracy. This was a block counterbalanced, crossover, repeated measures study design utilizing 20 individuals without self-reported shoulder or cervical pathology. Shoulder function was measured with and without experimental pain injection (2 mL of 5% hypertonic saline) in the sub-acromial space. Functional tasks consisted of shoulder rotational strength utilizing isokinetic testing and throwing accuracy via the functional throwing performance index. The hypertonic saline induced moderate pain levels in all participants (4.3-5.1/10). Normalized shoulder internal (t = 3.76, p = 0.001) and external (t = 3.12, p = 0.006) rotation strength were both diminished in the painful condition compared to the pain free condition. Throwing accuracy was also reduced while the participants experienced pain (t = 3.99, p = 0.001). Moderate levels of experimental shoulder pain were sufficient to negatively influence shoulder strength and throwing accuracy in participants without shoulder pathology.

  15. Adult attachment and reports of pain in experimentally-induced pain.

    PubMed

    Andrews, Nicole Emma; Meredith, Pamela Joy; Strong, Jenny

    2011-05-01

    Attachment theory has been proposed as a framework for understanding the development of chronic pain, with evidence supporting the overrepresentation of insecure attachment styles in chronic pain populations and links between insecure attachment and factors known to impact one's ability to cope with pain. The present study sought to extend two earlier studies exploring the relationships between adult attachment and communication of an acute pain experience, in anticipation of providing insight into individual differences in vulnerability in development of chronic pain. It was hypothesised that: (a) fearful attachment would be associated with perceptions of the pain as less intense, and (b) anxious attachment would be associated with lower pain thresholds. A convenience sample of 82 healthy adults completed self-report measures of attachment, neuroticism, and negative affect prior to taking part in a coldpressor pain inducement task. Results demonstrated that fearful attachment was associated with lower levels of pain intensity throughout the coldpressor task. In addition, dismissing attachment was also associated with less intense pain, as well as increased coldpressor endurance (tolerance) in the presence of a known assessor. These associations were retained after controlling for measures of neuroticism, negative affect, age, and social desirability. The results of this study are consistent with the proposition that fearful and dismissing individuals tend to mask their underlying distress caused by the pain experience, potentially leading to difficulties coping with pain over time.

  16. Pain and motor processing in the human cerebellum.

    PubMed

    Coombes, Stephen A; Misra, Gaurav

    2016-01-01

    Pain-related adaptations in movement require a network architecture that allows for integration across pain and motor circuits. Previous studies addressing this issue have focused on cortical areas such as the midcingulate cortex. Here, we focus on pain and motor processing in the human cerebellum. The goal of this study was to identify areas of activation in the cerebellum, which are common to pain and motor processing, and to determine whether the activation is limited to the superior and inferior cerebellar motor maps or extends into multimodal areas of the posterior cerebellum. Our observations identified overlapping activity in left and right lobules VI and VIIb during pain and motor processing. Activation in these multimodal regions persisted when pain and motor processes were combined within the same trial, and activation in contralateral left lobule VIIb persisted when stimulation was controlled for. Functional connectivity analyses revealed significant correlations in the BOLD time series between multimodal cerebellar regions and sensorimotor regions in the cerebrum including anterior midcingulate cortex, supplementary motor area, and thalamus. The current findings are the first to show multimodal processing in lobules VI and VIIb for motor control and pain processing and suggest that the posterior cerebellum may be important in understanding pain-related adaptations in motor control.

  17. Multiple Representations of Pain in Human Cerebral Cortex

    NASA Astrophysics Data System (ADS)

    Talbot, Jeanne D.; Marrett, Sean; Evans, Alan C.; Meyer, Ernst; Bushnell, M. Catherine; Duncan, Gary H.

    1991-03-01

    The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However, with the use of magnetic resonance imaging and positron emission tomography in humans, it has now been demonstrated that painful heat causes significant activation of the contralateral anterior cingulate, secondary somatosensory, and primary somatosensory cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in similar experiments. Furthermore, the unilateral cingulate activation indicates that this forebrain area, thought to regulate emotions, contains an unexpectedly specific representation of pain.

  18. Pain and stress in the human fetus.

    PubMed

    Smith, R P; Gitau, R; Glover, V; Fisk, N M

    2000-09-01

    Invasive diagnostic and therapeutic techniques are increasingly applied to the fetus. It is not known if the fetus feels pain during such procedures, but the fetus does mount significant stress hormonal and circulatory changes in response to these from 18-20 weeks. Perinatal stress may have long-term neurodevelopmental implications. During open fetal surgery, maternal general anaesthesia provides fetal anaesthesia. However, in closed procedures, fetal analgesia presents difficulties. The optimal drug, dose, and route of administration remain to be determined.

  19. Effects of coping statements on experimental pain in chronic pain patients.

    PubMed

    Roditi, Daniela; Robinson, Michael E; Litwins, Nola

    2009-08-19

    The present study measured the effects of catastrophizing self-statements and positive coping self-statements on cold pressor-induced pain. Participants were 58 adult chronic pain patients with current facial pain. It was hypothesized that catastrophizing would lead to a decrease in pain endurance whereas positive coping would lead to an increase in pain endurance. It was also hypothesized that catastrophizing would lead to an increase in peak pain intensity whereas positive coping would lead to a decrease in peak pain intensity. At pretest, participants submerged their nondominant hand in the cold pressor. Pain sensitivity ranges (PSR) were subsequently determined by calculating the difference between tolerance and threshold times. Ratings of peak pain intensity were measured using a pressure sensitive bladder/transducer. Participants underwent random assignment to either a catastrophizing group or a positive coping self-statement group. ANCOVA results revealed that on average, participants employing catastrophizing statements as a coping strategy experienced significantly lower PSR (M = 35.53, SD = 39.71) compared to participants employing positive coping self-statements (M = 73.70, SD = 86.14) when controlling for pretest PSR. Group assignment had no significant influence on peak pain intensity ratings. Thus, our results reveal that manipulation of coping causes changes in pain endurance.

  20. Pharmacology of human experimental anxiety.

    PubMed

    Graeff, F G; Parente, A; Del-Ben, C M; Guimarães, F S

    2003-04-01

    This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.

  1. Gender, variation in opioid receptor genes and sensitivity to experimental pain

    PubMed Central

    2013-01-01

    Background Pain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included. Results Nineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain. Conclusion This is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions. PMID:23570317

  2. Periodontal CGRP contributes to orofacial pain following experimental tooth movement in rats.

    PubMed

    Long, Hu; Liao, Lina; Gao, Meiya; Ma, Wenqiang; Zhou, Yang; Jian, Fan; Wang, Yan; Lai, Wenli

    2015-08-01

    Calcitonin-related gene peptide (CGRP) plays an important role in orofacial inflammatory pain. The aim of this study was to determine whether periodontal CGRP contributes to orofacial pain induced by experimental tooth movement in rats. Male Sprague-Dawley rats were used in this study. Closed coil springs were used to deliver forces. Rats were euthanized on 0d, 1d, 3d, 5d, 7d, and 14d following experimental tooth movement. Then, alveolar bones were obtained for immunostaining of periodontal tissues against CGRP. Two hours prior to euthanasia on each day, orofacial pain levels were assessed through rat grimace scale. CGRP and olcegepant (CGRP receptor antagonist) were injected into periodontal tissues to verify the roles of periodontal CGRP in orofacial pain induced by experimental tooth movement. Periodontal CGRP expression levels and orofacial pain levels were elevated on 1d, 3d, 5d, and 7d following experimental tooth movement. The two indices were significantly correlated with each other and fitted into a dose-response model. Periodontal administration of CGRP could elevate periodontal CGRP expressions and exacerbate orofacial pain. Moreover, olcegepant administration could decrease periodontal CGRP expressions and alleviate orofacial pain. Therefore, periodontal CGRP plays an important role in pain transmission and modulation following experimental tooth movement. We suggest that it may participate in a positive feedback aiming to amplify orofacial pain signals.

  3. Tonic muscle pain does not increase fusimotor drive to human leg muscles: implications for chronic muscle pain.

    PubMed

    Fazalbhoy, Azharuddin; Macefield, Vaughan G; Birznieks, Ingvars

    2013-06-01

    Experimental pain induced in animals has shown that noxious stimulation of group III and IV afferents increases the firing of muscle spindles via a reflex excitation of fusimotor (γ) motoneurones. Chronic muscle pain has been hypothesized to develop as a result of a vicious cycle involving this mechanism. In order to explore the effects of long-lasting muscle pain on the fusimotor system, single unit muscle spindle afferents were recorded from 15 subjects. Afferent activity was recorded from foot and ankle extensor muscles whilst infusing hypertonic saline into the tibialis anterior muscle of the ipsilateral leg, producing moderate-strong pain lasting for ∼60 min. A change in fusimotor drive was inferred by observing changes in the mean discharge rate of spontaneously active muscle spindle afferents. Homonymous and heteronymous muscles remained relaxed and showed no increase in activity, arguing against any fusimotor-driven increase in motor activity, and there was no net change in the firing of muscle spindle afferents. We conclude that long-lasting stimulation of group III and IV afferents fails to excite fusimotor neurones and increase muscle spindle discharge. Accordingly, the vicious cycle theory has no functional basis for the development of myalgia in human subjects.

  4. Experimental pain processing in individuals with cognitive impairment: current state of the science.

    PubMed

    Defrin, Ruth; Amanzio, Martina; de Tommaso, Marina; Dimova, Violeta; Filipovic, Sasa; Finn, David P; Gimenez-Llort, Lydia; Invitto, Sara; Jensen-Dahm, Christina; Lautenbacher, Stefan; Oosterman, Joukje M; Petrini, Laura; Pick, Chaim G; Pickering, Gisele; Vase, Lene; Kunz, Miriam

    2015-08-01

    Cognitive impairment (CI) can develop during the course of ageing and is a feature of many neurological and neurodegenerative diseases. Many individuals with CI have substantial, sustained, and complex health care needs, which frequently include pain. However, individuals with CI can have difficulty communicating the features of their pain to others, which in turn presents a significant challenge for effective diagnosis and treatment of their pain. Herein, we review the literature on responsivity of individuals with CI to experimental pain stimuli. We discuss pain responding across a large number of neurological and neurodegenerative disorders in which CI is typically present. Overall, the existing data suggest that pain processing is altered in most individuals with CI compared with cognitively intact matched controls. The precise nature of these alterations varies with the type of CI (or associated clinical condition) and may also depend on the type of pain stimulation used and the type of pain responses assessed. Nevertheless, it is clear that regardless of the etiology of CI, patients do feel noxious stimuli, with more evidence for hypersensitivity than hyposensitivity to these stimuli compared with cognitively unimpaired individuals. Our current understanding of the neurobiological mechanisms underpinning these alterations is limited but may be enhanced through the use of animal models of CI, which also exhibit alterations in nociceptive responding. Further research using additional behavioural indices of pain is warranted. Increased understanding of altered experimental pain processing in CI will facilitate the development of improved diagnostic and therapeutic approaches for pain in individuals with CI.

  5. Pain assessment and treatment disparities: a virtual human technology investigation.

    PubMed

    Hirsh, Adam T; George, Steven Z; Robinson, Michael E

    2009-05-01

    Pain assessment and treatment is influenced by patient demographic characteristics and nonverbal expressions. Methodological challenges have limited the empirical investigation of these issues. The current analogue study employed an innovative research design and novel virtual human (VH) technology to investigate disparities in pain-related clinical decision-making. Fifty-four nurses viewed vignettes consisting of a video clip of the VH patient and clinical summary information describing a post-surgical context. Participants made assessment (pain intensity and unpleasantness) and treatment (non-opioid and opioid medications) decisions on computerized visual analogue scales. VH demographic cues of sex, race, and age, as well as facial expression of pain, were systematically manipulated and hypothesized to influence decision ratings. Idiographic and nomothetic statistical analyses were conducted to test these hypotheses. Idiographic results indicated that sex, race, age, and pain expression cues accounted for significant, unique variance in decision policies among many nurses. Pain expression was the most salient cue in this context. Nomothetic results indicated differences within VH cues of interest; the size and consistency of these differences varied across policy domains. This study demonstrates the application of VH technology and lens model methodology to the study of disparities in pain-related decision-making. Assessment and treatment of acute post-surgical pain often varies based on VH demographic and facial expression cues. These data contribute to the existing literature on disparities in pain practice and highlight the potential of a novel approach that may serve as a model for future investigation of these critical issues.

  6. Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain

    PubMed Central

    Vale, Mariana L; Benevides, Verônica M; Sachs, Daniela; Brito, Gerly A C; da Rocha, Francisco A C; Poole, Stephen; Ferreira, Sérgio H; Cunha, Fernando Q; Ribeiro, Ronaldo A

    2004-01-01

    The antihyperalgesic effect of pentoxifylline was investigated in three experimental pain models. Pentoxifylline (0.5–1.6 mg kg−1) given 30 min before the stimulus significantly inhibited the writhing response induced by the intraperitoneal (i.p.) administration of either acetic acid (−90%) or zymosan (−83%), but not that of iloprost, in mice, as well as the zymosan-induced articular hyperalgesia in the zymosan arthritis in rats (−50%). Pentoxifylline also inhibited the mechanical hypernociception in rats induced by the intraplantar injection of either carrageenin (−81%), bradykinin (−56%) or tumor necrosis factor α (TNF-α; −46%), but not that induced by interleukin-1β (IL-1β) or prostaglandin E2 (PGE2). Pentoxifylline did not inhibit the nociceptive response in the hot plate test in mice. Further, the antinociceptive effect of pentoxifylline in the writhing test in mice and the zymosan-induced articular hyperalgesia were not reversed by the coadministration of the opioid receptor antagonist naloxone. Thus, pentoxifylline antinociceptive effect is probably not mediated at a central level. Pentoxifylline significantly reduced TNF-α (−43%) and IL-1β (−42%) concentrations in the joint exudates of rats stimulated by intra-articular injection of zymosan and the production of both cytokines (−66 and −86%, respectively) by mouse peritoneal macrophages stimulated in vivo with zymosan as well as the expression of TNF-α at the tissue level in carrageenin-injected rat paws. In conclusion, the antinociceptive activity of pentoxifylline is associated with the inhibition of the release of both TNF-α and IL-1β. PMID:15520047

  7. Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain.

    PubMed

    Vale, Mariana L; Benevides, Verônica M; Sachs, Daniela; Brito, Gerly A C; da Rocha, Francisco A C; Poole, Stephen; Ferreira, Sérgio H; Cunha, Fernando Q; Ribeiro, Ronaldo A

    2004-12-01

    The antihyperalgesic effect of pentoxifylline was investigated in three experimental pain models. Pentoxifylline (0.5-1.6 mg kg(-1)) given 30 min before the stimulus significantly inhibited the writhing response induced by the intraperitoneal (i.p.) administration of either acetic acid (-90%) or zymosan (-83%), but not that of iloprost, in mice, as well as the zymosan-induced articular hyperalgesia in the zymosan arthritis in rats (-50%). Pentoxifylline also inhibited the mechanical hypernociception in rats induced by the intraplantar injection of either carrageenin (-81%), bradykinin (-56%) or tumor necrosis factor alpha (TNF-alpha; -46%), but not that induced by interleukin-1beta (IL-1beta) or prostaglandin E(2) (PGE(2)). Pentoxifylline did not inhibit the nociceptive response in the hot plate test in mice. Further, the antinociceptive effect of pentoxifylline in the writhing test in mice and the zymosan-induced articular hyperalgesia were not reversed by the coadministration of the opioid receptor antagonist naloxone. Thus, pentoxifylline antinociceptive effect is probably not mediated at a central level. Pentoxifylline significantly reduced TNF-alpha (-43%) and IL-1beta (-42%) concentrations in the joint exudates of rats stimulated by intra-articular injection of zymosan and the production of both cytokines (-66 and -86%, respectively) by mouse peritoneal macrophages stimulated in vivo with zymosan as well as the expression of TNF-alpha at the tissue level in carrageenin-injected rat paws. In conclusion, the antinociceptive activity of pentoxifylline is associated with the inhibition of the release of both TNF-alpha and IL-1beta.

  8. Sex differences in pain: a brief review of clinical and experimental findings

    PubMed Central

    Bartley, E. J.; Fillingim, R. B.

    2013-01-01

    Summary Recent years have witnessed substantially increased research regarding sex differences in pain. The expansive body of literature in this area clearly suggests that men and women differ in their responses to pain, with increased pain sensitivity and risk for clinical pain commonly being observed among women. Also, differences in responsivity to pharmacological and non-pharmacological pain interventions have been observed; however, these effects are not always consistent and appear dependent on treatment type and characteristics of both the pain and the provider. Although the specific aetiological basis underlying these sex differences is unknown, it seems inevitable that multiple biological and psychosocial processes are contributing factors. For instance, emerging evidence suggests that genotype and endogenous opioid functioning play a causal role in these disparities, and considerable literature implicates sex hormones as factors influencing pain sensitivity. However, the specific modulatory effect of sex hormones on pain among men and women requires further exploration. Psychosocial processes such as pain coping and early-life exposure to stress may also explain sex differences in pain, in addition to stereotypical gender roles that may contribute to differences in pain expression. Therefore, this review will provide a brief overview of the extant literature examining sex-related differences in clinical and experimental pain, and highlights several biopsychosocial mechanisms implicated in these male–female differences. The future directions of this field of research are discussed with an emphasis aimed towards further elucidation of mechanisms which may inform future efforts to develop sex-specific treatments. PMID:23794645

  9. Asians differ from non-Hispanic Whites in experimental pain sensitivity.

    PubMed

    Rowell, Lauren N; Mechlin, Beth; Ji, Ellen; Addamo, Michael; Girdler, Susan S

    2011-08-01

    This study examined differences between Asians and non-Hispanic Whites (Whites) in pain sensitivity, and its relationship to mean arterial pressure (MAP) and heart rate (HR). In 30 Whites (50% female) and 30 Asians (50% female), experimental pain sensitivity was assessed with a hand cold pressor task, yielding measures of pain threshold, tolerance, intensity, and unpleasantness. Mean arterial pressure and HR measurements taken at rest and in response to speech stress were assessed. Perceived stress, anxiety, perfectionism, parental criticism, parental expectations and depressive symptoms were also measured. The results indicated that for the cold pain test, Asians demonstrated significantly lower pain threshold and tolerance levels than Whites. Although no ethnic differences were seen for MAP or HR responses to stress, for Whites higher stress MAP levels were correlated with reduced pain sensitivity, while for Asians higher baseline and stress HR levels were correlated with reduced pain sensitivity. Asians reported higher parental expectations and greater parental criticism than Whites. For Asians only, higher levels of perfectionism were related to more depressive symptoms, anxiety and perceived stress. These results indicate that Asian Americans are more sensitive to experimental pain than Whites and suggest ethnic differences in endogenous pain regulatory mechanisms (e.g. MAP and HR). The results may also have implications for understanding ethnic differences in clinical pain.

  10. Is experimentally induced pain associated with socioeconomic status? Do poor people hurt more?

    PubMed Central

    Miljković, Ana; Stipčić, Ana; Braš, Marijana; Đorđević, Veljko; Brajković, Lovorka; Hayward, Caroline; Pavić, Arsen; Kolčić, Ivana; Polašek, Ozren

    2014-01-01

    Background The association of pain and socioeconomic status is widely reported, yet much less clearly understood. The aim of this study was to investigate the association of experimentally induced pain threshold and tolerance with socioeconomic status. Material/Methods The study sample consisted of 319 adult subjects from the population of the island of Vis, Croatia, which was previously shown to have a high level of social homogeneity. A manual dolorimeter was used to measure mechanical pressure pain threshold (least stimulus intensity) and pain tolerance (maximum tolerance stimulus intensity) on both hands. Pain tolerance interval was defined as the difference between pain tolerance and threshold. Years of schooling and material status were used as socioeconomic estimates. Results Both of the socioeconomic estimates were significantly correlated with pain threshold, tolerance, and tolerance interval (P<0.001). The mixed modeling analysis, controlled for the effects of age, gender, and 4 psychological variables, indicated that education was not a significant predictor in any of the 3 models. However, lower material status was significantly associated with lower pain tolerance (P=0.038) and narrower pain tolerance interval (P=0.032), but not with pain threshold (P=0.506). The overall percentages of explained variance were lower in the tolerance interval model (20.2%) than in pain tolerance (23.1%) and threshold (33.1%), suggesting the increasing share of other confounding variables in pain tolerance and even more so in tolerance interval model. Conclusions These results suggest a significant association between experimentally induced pain tolerance and tolerance interval with material status, suggesting that poor people indeed do hurt more. PMID:25029965

  11. Adaptability to pain is associated with potency of local pain inhibition, but not conditioned pain modulation: a healthy human study.

    PubMed

    Zheng, Zhen; Wang, Kelun; Yao, Dongyuan; Xue, Charlie C L; Arendt-Nielsen, Lars

    2014-05-01

    This study investigated the relationship between pain sensitivity, adaptability, and potency of endogenous pain inhibition, including conditioned pain modulation (CPM) and local pain inhibition. Forty-one healthy volunteers (20 male, 21 female) received conditioning stimulation (CS) over 2 sessions in a random order: tonic heat pain (46 °C) on the right leg for 7 minutes and cold pressor pain (1 °C to 4 °C) on the left hand for 5 minutes. Participants rated the intensity of pain continuously using a 0 to 10 electronic visual analogue scale. The primary outcome measures were pressure pain thresholds (PPT) measured at the heterotopic and homotopic location to the CS sites before, during, and 20 minutes after CS. Two groups of participants, pain adaptive and pain nonadaptive, were identified based on their response to pain in the cold pressor test. Pain-adaptive participants showed a pain reduction between peak pain and pain at end of the test by at least 2 of 10 (n=16); whereas the pain-nonadaptive participants reported unchanged peak pain during 5-minute CS (n=25). Heterotopic PPTs during the CS did not differ between the 2 groups. However, increased homotopic PPTs measured 20 minutes after CS correlated with the amount of pain reduction during CS. These results suggest that individual sensitivity and adaptability to pain does not correlate with the potency of CPM. Adaptability to pain is associated with longer-lasting local pain inhibition.

  12. Pains of probation: effective practice and human rights.

    PubMed

    Durnescu, Ioan

    2011-06-01

    This article explores the experience of offenders while under probation supervision and analyses the "pains of probation" in connection to rehabilitation aspirations. The article has two main parts. In the first part of the article, the experiences of probationers are examined using thematic analysis, and eight different pains of probation are identified. In the second part of the article, these pains of probation are examined from two different perspectives: human rights and the Good Lives Model. The conclusion is that these two perspectives support each other and can help reduce the frustrations and deprivations experienced by individuals on probation. By implementing these two perspectives, probation services may overcome the obstacles toward desistance and earn more legitimacy in the eyes of probation recipients.

  13. Tryptase - PAR2 axis in Experimental Autoimmune Prostatitis, a model for Chronic Pelvic Pain Syndrome

    PubMed Central

    Roman, Kenny; Done, Joseph D.; Schaeffer, Anthony J.; Murphy, Stephen F.; Thumbikat, Praveen

    2014-01-01

    Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined for the presence of mast cell degranulation products. Tryptase-β and PAR2 expression were examined in murine experimental autoimmune prostatitis (EAP). Pelvic pain and inflammation were assessed in the presence or absence of PAR2 expression and upon PAR2 neutralization. Tryptase-β and carboxypeptidase A3 were elevated in CP/CPPS compared to healthy volunteers. Tryptase-β was capable of inducing pelvic pain and was increased in EAP along with its receptor PAR2. PAR2 was required for the development of chronic pelvic pain in EAP. PAR2 signaling in dorsal root ganglia lead to ERK1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS. PMID:24726923

  14. Side effects of pain and analgesia in animal experimentation.

    PubMed

    Jirkof, Paulin

    2017-03-22

    This review highlights selected effects of untreated pain and of widely used analgesics such as opioids, non-steroid anti-inflammatory drugs and antipyretics, to illustrate the relevance of carefully planned, appropriate and controlled analgesia for greater reproducibility in animal experiments involving laboratory rodents.

  15. Antinociceptive Interaction of Tramadol with Gabapentin in Experimental Mononeuropathic Pain.

    PubMed

    Miranda, Hugo F; Noriega, Viviana; Prieto, Juan Carlos; Zanetta, Pilar; Castillo, Rodrigo; Aranda, Nicolás; Sierralta, Fernando

    2016-08-01

    Neuropathic pain is the result of injury to the nervous system, and different animal models have been established to meet the manifestations of neuropathy. The pharmacotherapy for neuropathic pain includes gabapentin and tramadol, but these are only partially effective when given alone. The aim of this study was to assess the antinociceptive interaction between both drugs using the isobolographic analysis and changes of the IL-1β concentration in a mouse model of neuropathic pain (partial sciatic nerve ligation or PSNL). The i.p. administration of gabapentin (5-100 mg/kg) or tramadol (12.5-100 mg/kg) displayed a dose-dependent antinociception in the hot plate assay of PSNL mice, and effects induced by gabapentin with tramadol were synergistic. Administration of gabapentin or tramadol reversed significantly the increase in the concentration of IL-1β induced by PSNL after either 7 or 14 days and their combination was significantly more potent in reversing the elevated concentration of IL-1β. The synergism obtained by the co-administration of gabapentin and tramadol is proposed to result from action on different mechanisms in pain pathways. Gabapentin or tramadol or their combination modulates the expression of pro-inflammatory cytokine, IL-1β, in a model of mice PSNL which could be due to an inhibition of glial function.

  16. Experimenter Effects on Pain Reporting in Women Vary across the Menstrual Cycle

    PubMed Central

    Vigil, Jacob M.; DiDomenico, Jared; Strenth, Chance; Coulombe, Patrick; Kruger, Eric; Mueller, Andrea A.; Guevara Beltran, Diego; Adams, Ian

    2015-01-01

    Background. Separate lines of research have shown that menstrual cycling and contextual factors such as the gender of research personnel influence experimental pain reporting. Objectives. This study examines how brief, procedural interactions with female and male experimenters can affect experimentally reported pain (cold pressor task, CPT) across the menstrual cycle. Methods. Based on the menstrual calendars 94 naturally cycling women and 38 women using hormonal contraceptives (Mage = 19.83,  SD = 3.09) were assigned to low and high fertility groups. This assignment was based on estimates of their probability of conception given their current cycle day. Experimenters (12 males, 7 females) engaged in minimal procedural interactions with participants before the CPT was performed in solitude. Results. Naturally cycling women in the high fertility group showed significantly higher pain tolerance (81 sec, d = .79) following interactions with a male but not a female experimenter. Differences were not found for women in the low fertility or contraceptive groups. Discussion. The findings illustrate that menstrual functioning moderates the effect that experimenter gender has on pain reporting in women. Conclusion. These findings have implications for standardizing pain measurement protocols and understanding how basic biopsychosocial mechanisms (e.g., person-perception systems) can modulate pain experiences. PMID:25892990

  17. Effects of restricted environmental stimulation: enhancement of hypnotizability for experimental and chronic pain control.

    PubMed

    Barabasz, A F; Barabasz, M

    1989-07-01

    Enhancement of hypnotizability and pain tolerance has been demonstrated using restricted environmental stimulation therapy (REST) with university students as Ss (A. F. Barabasz, 1982). The purpose of the present study was to determine whether or not similar results could be obtained with chronic pain patients. Ss consisted of outpatients in treatment for conditions in which pain is prominent who also demonstrated low hypnotizability after repeated hypnosis plateau sessions. 2 groups of Ss were exposed to REST. Situational demand characteristics (Orne, 1962) favored an increase in hypnotizability for REST Group 1 (high demand). REST Group 2 (low demand) was exposed to situational demand characteristics designed to disguise the experimental hypothesis. 2 groups of control Ss were exposed to the same alternative demand characteristic manipulations as the experimental groups, but environmental stimulation was maintained. The Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) of Weitzenhoffer and E. R. Hilgard (1962), including a posthypnotic suggestion for an anesthetic reaction, and an ischemic pain test were administered prior to treatment and again immediately following treatment. After 6 hours of REST, significant increases in SHSS:C scores were found for high-demand and low-demand experimental Ss, as well as for high-demand control Ss. No such increase was found for low-demand controls. Significant decreases in pain scores were found for both high- and low-demand experimental groups. No significant pain score decreases were found for either control group, suggesting a relatively weak effect of demand characteristics. An independent postexperimental inquiry suggested all Ss believed they received active treatments. The inquiry, conducted 10-15 days after the experiment, also revealed a majority of experimental Ss were using hypnosis on a daily basis to reduce pain with a substantial decrease in pain medication. Only 2 control Ss (highest in hypnotizability

  18. Statins alleviate experimental nerve injury-induced neuropathic pain.

    PubMed

    Shi, Xiang Qun; Lim, Tony K Y; Lee, Seunghwan; Zhao, Yuan Qing; Zhang, Ji

    2011-05-01

    The statins are a well-established class of drugs that lower plasma cholesterol levels by inhibiting HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase. They are widely used for the treatment of hypercholesterolemia and for the prevention of coronary heart disease. Recent studies suggest that statins have anti-inflammatory effects beyond their lipid-lowering properties. We sought to investigate whether statins could affect neuropathic pain by mediating nerve injury-associated inflammatory responses. The effects of hydrophilic rosuvastatin and lipophilic simvastatin were examined in the mouse partial sciatic nerve ligation model. Systemic daily administration of either statin from days 0 to 14 completely prevented the development of mechanical allodynia and thermal hyperalgesia. When administered from days 8 to 14 after injury, both statins dose-dependently reduced established hypersensitivity. After treatment, the effects of the statins were washed out within 2 to 7 days, depending on dose. Effects of both statins in alleviating mechanical allodynia were further confirmed in a different injury-associated neuropathic pain model, mental nerve chronic constriction, in rats. Both statins were able to abolish interleukin-1β expression in sciatic nerve triggered by nerve ligation. Additionally, quantitative analysis with Iba-1 and glial fibrillary acid protein immunoreactivity demonstrated that rosuvastatin and simvastatin significantly reduced the spinal microglial and astrocyte activation produced by sciatic nerve injury. The increase of interleukin-1β mRNA in the ipsilateral side of spinal cords was also reduced by the treatment of either statin. We identified a potential new application of statins in the treatment of neuropathic pain. The pain-alleviating effects of statins are likely attributable to their immunomodulatory effects.

  19. Sex differences in how social networks and relationship quality influence experimental pain sensitivity.

    PubMed

    Vigil, Jacob M; Rowell, Lauren N; Chouteau, Simone; Chavez, Alexandre; Jaramillo, Elisa; Neal, Michael; Waid, David

    2013-01-01

    This is the first study to examine how both structural and functional components of individuals' social networks may moderate the association between biological sex and experimental pain sensitivity. One hundred and fifty-two healthy adults (mean age = 22yrs., 53% males) were measured for cold pressor task (CPT) pain sensitivity (i.e., intensity ratings) and core aspects of social networks (e.g., proportion of friends vs. family, affection, affirmation, and aid). Results showed consistent sex differences in how social network structures and intimate relationship functioning modulated pain sensitivity. Females showed higher pain sensitivity when their social networks consisted of a higher proportion of intimate types of relationship partners (e.g., kin vs. non kin), when they had known their network partners for a longer period of time, and when they reported higher levels of logistical support from their significant other (e.g., romantic partner). Conversely, males showed distinct patterns in the opposite direction, including an association between higher levels of logistical support from one's significant other and lower CPT pain intensity. These findings show for the first time that the direction of sex differences in exogenous pain sensitivity is likely dependent on fundamental components of the individual's social environment. The utility of a social-signaling perspective of pain behaviors for examining, comparing, and interpreting individual and group differences in experimental and clinical pain reports is discussed.

  20. Neural correlates of heat-evoked pain memory in humans

    PubMed Central

    Gui, Peng; Li, Lei; Ku, Yixuan; Bodner, Mark; Fan, Gaojie; Zhou, Yong-Di; Dong, Xiao-Wei

    2016-01-01

    The neural processes underlying pain memory are not well understood. To explore these processes, contact heat-evoked potentials (CHEPs) were recorded in humans with electroencephalography (EEG) technique during a delayed matching-to-sample task, a working memory task involving presentations of two successive painful heat stimuli (S-1 and S-2) with different intensities separated by a 2-s interval (the memorization period). At the end of the task, the subject was required to discriminate the stimuli by indicating which (S-1 or S-2) induced more pain. A control task was used, in which no active discrimination was required between stimuli. All event-related potential (ERP) analysis was aligned to the onset of S-1. EEG activity exhibited two successive CHEPs: an N2-P2 complex (∼400 ms after onset of S-1) and an ultralate component (ULC, ∼900 ms). The amplitude of the N2-P2 at vertex, but not the ULC, was significantly correlated with stimulus intensity in these two tasks, suggesting that the N2-P2 represents neural coding of pain intensity. A late negative component (LNC) in the frontal recording region was observed only in the memory task during a 500-ms period before onset of S-2. LNC amplitude differed between stimulus intensities and exhibited significant correlations with the N2-P2 complex. These indicate that the frontal LNC is involved in maintenance of intensity of pain in working memory. Furthermore, alpha-band oscillations observed in parietal recording regions during the late delay displayed significant power differences between tasks. This study provides in the temporal domain previously unidentified neural evidence showing the neural processes involved in working memory of painful stimuli. PMID:26740529

  1. Social comparison performance standards, threat, and tolerance for experimentally-induced pain.

    PubMed

    Jackson, Todd; Phillips, Heath

    2011-11-01

    Social modelling experiments have illustrated how upward social comparisons (i.e., observing pain tolerant role models) can facilitate tolerance relative to downward social comparison (i.e., observing pain intolerant alternatives). However, because clinical studies suggest that people prefer to make downward social comparisons with less fortunate others when they are threatened or overwhelmed with pain or illness, it seems plausible that upward social comparisons confer fewer benefits when pain is appraised as threatening. To address this issue, we assessed effects of verbally-presented upward and downward social comparison standards on tolerance for cold pressor pain among 124 Australian adults (44 men, 80 women) primed with either more or less threatening orienting information about task-related pain sensations. As predicted, participants exposed to the lower threat orienting prime and upward comparison performance standard were significantly more pain tolerant than peers in all other conditions. Conversely, the average tolerance time for participants presented with the higher threat orienting prime and upward comparison standard did not differ from that of either downward comparison group. The research highlighted powerful situational influences on tolerance for experimental pain and identified conditions under which verbally-presented upward social comparison standards may facilitate and hinder the capacity to bear pain.

  2. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome.

    PubMed

    Roman, Kenny; Done, Joseph D; Schaeffer, Anthony J; Murphy, Stephen F; Thumbikat, Praveen

    2014-07-01

    Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined for the presence of mast cell degranulation products. Tryptase-β and PAR2 expression were examined in murine EAP. Pelvic pain and inflammation were assessed in the presence or absence of PAR2 expression and upon PAR2 neutralization. Tryptase-β and carboxypeptidase A3 were elevated in CP/CPPS compared to healthy volunteers. Tryptase-β was capable of inducing pelvic pain and was increased in EAP along with its receptor PAR2. PAR2 was required for the development of chronic pelvic pain in EAP. PAR2 signaling in dorsal root ganglia led to extracellular signal-regulated kinase (ERK)1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS.

  3. Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

    PubMed Central

    Wang, I-Ching; Chung, Chen-Yen; Liao, Fang; Chen, Chih-Cheng; Lee, Cheng-Han

    2017-01-01

    Multiple sclerosis (MS)-induced neuropathic pain deteriorates quality of life in patients but is often refractory to treatment. In experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, animals develop neuropathy and inflammation-induced tissue acidosis, which suggests the involvement of acid-sensing ion channels (ASICs). Also, peripheral neuropathy is reported in MS patients. However, the involvement of the peripheral nervous system (PNS) in MS neuropathic pain remains elusive. This study investigated the contribution of ASICs and peripheral neuropathy in MS-induced neuropathic pain. Elicited pain levels were as high in Asic1a−/−, Asic2−/− and Asic3−/− mice as wild-type mice even though only Asic1a−/− mice showed reduced EAE disease severity, which indicates that pain in EAE was independent of disease severity. We thus adopted an EAE model without pertussis toxin (EAEnp) to restrain activated immunity in the periphery and evaluate the PNS contribution to pain. Both EAE and EAEnp mice showed similar pain behaviors and peripheral neuropathy in nerve fibers and DRG neurons. Moreover, pregabalin significantly reduced neuropathic pain in both EAE and EAEnp mice. Our findings highlight the essential role of the PNS in neuropathic pain in EAE and pave the way for future development of analgesics without side effects in the CNS. PMID:28181561

  4. No relevant modulation of TRPV1-mediated trigeminal pain by intranasal carbon dioxide in healthy humans

    PubMed Central

    2013-01-01

    Background Nasal insufflation of CO2 has been shown to exert antinociceptive respectively antihyperalgesic effects in animal pain models using topical capsaicin with activation of TRPV1-receptor positive nociceptive neurons. Clinical benefit from CO2 inhalation in patients with craniofacial pain caused by a putative activation of TRPV1 receptor positive trigeminal neurons has also been reported. These effects are probably mediated via an activation of TRPV1 receptor - positive neurons in the nasal mucosa with subsequent central inhibitory effects (such as conditioned pain modulation). In this study, we aimed to examine the effects of intranasal CO2 on a human model of craniofacial pain elicited by nasal application of capsaicin. Methods In a first experiment, 48 healthy volunteers without previous craniofacial pain received intranasal capsaicin to provoke trigeminal pain elicited by activation of TRVP1 positive nociceptive neurons. Then, CO2 or air was insufflated alternatingly into the nasal cavity at a flow rate of 1 l/min for 60 sec each. In the subsequent experiment, all participants were randomized into 2 groups of 24 each and received either continuous nasal insufflation of CO2 or placebo for 18:40 min after nociceptive stimulation with intranasal capsaicin. In both experiments, pain was rated on a numerical rating scale every 60 sec. Results Contrary to previous animal studies, the effects of CO2 on experimental trigeminal pain were only marginal. In the first experiment, CO2 reduced pain ratings only minimally by 5.3% compared to air if given alternatingly with significant results for the main factor GROUP (F1,47 = 4.438; p = 0.041) and the interaction term TIME*GROUP (F2.6,121.2 = 3.3; p = 0.029) in the repeated-measures ANOVA. However, these effects were abrogated after continuous insufflation of CO2 or placebo with no significant changes for the main factors or the interaction term. Conclusions Although mild modulatory effects of low

  5. Transcriptional regulator PRDM12 is essential for human pain perception.

    PubMed

    Chen, Ya-Chun; Auer-Grumbach, Michaela; Matsukawa, Shinya; Zitzelsberger, Manuela; Themistocleous, Andreas C; Strom, Tim M; Samara, Chrysanthi; Moore, Adrian W; Cho, Lily Ting-Yin; Young, Gareth T; Weiss, Caecilia; Schabhüttl, Maria; Stucka, Rolf; Schmid, Annina B; Parman, Yesim; Graul-Neumann, Luitgard; Heinritz, Wolfram; Passarge, Eberhard; Watson, Rosemarie M; Hertz, Jens Michael; Moog, Ute; Baumgartner, Manuela; Valente, Enza Maria; Pereira, Diego; Restrepo, Carlos M; Katona, Istvan; Dusl, Marina; Stendel, Claudia; Wieland, Thomas; Stafford, Fay; Reimann, Frank; von Au, Katja; Finke, Christian; Willems, Patrick J; Nahorski, Michael S; Shaikh, Samiha S; Carvalho, Ofélia P; Nicholas, Adeline K; Karbani, Gulshan; McAleer, Maeve A; Cilio, Maria Roberta; McHugh, John C; Murphy, Sinead M; Irvine, Alan D; Jensen, Uffe Birk; Windhager, Reinhard; Weis, Joachim; Bergmann, Carsten; Rautenstrauss, Bernd; Baets, Jonathan; De Jonghe, Peter; Reilly, Mary M; Kropatsch, Regina; Kurth, Ingo; Chrast, Roman; Michiue, Tatsuo; Bennett, David L H; Woods, C Geoffrey; Senderek, Jan

    2015-07-01

    Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

  6. No effect of a single session of transcranial direct current stimulation on experimentally induced pain in patients with chronic low back pain--an exploratory study.

    PubMed

    Luedtke, Kerstin; May, Arne; Jürgens, Tim P

    2012-01-01

    Transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability. A small number of studies suggested that tDCS modulates the response to experimental pain paradigms. No trials have been conducted to evaluate the response of patients already suffering from pain, to an additional experimental pain before and after tDCS. The present study investigated the effect of a single session of anodal, cathodal and sham stimulation (15 mins/1 mA) over the primary motor cortex on the perceived intensity of repeated noxious thermal and electrical stimuli and on elements of quantitative sensory testing (thermal pain and perception thresholds) applied to the right hand in 15 patients with chronic low back pain. The study was conducted in a double-blind sham-controlled and cross-over design. No significant alterations of pain ratings were found. Modalities of quantitative sensory testing remained equally unchanged. It is therefore hypothesized that a single 15 mins session of tDCS at 1 mA may not be sufficient to alter the perception of experimental pain and in patients with chronic pain. Further studies applying repetitive tDCS to patients with chronic pain are required to fully answer the question whether experimental pain perception may be influenced by tDCS over the motor cortex.

  7. No Effect of a Single Session of Transcranial Direct Current Stimulation on Experimentally Induced Pain in Patients with Chronic Low Back Pain – An Exploratory Study

    PubMed Central

    Luedtke, Kerstin; May, Arne; Jürgens, Tim P.

    2012-01-01

    Transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability. A small number of studies suggested that tDCS modulates the response to experimental pain paradigms. No trials have been conducted to evaluate the response of patients already suffering from pain, to an additional experimental pain before and after tDCS. The present study investigated the effect of a single session of anodal, cathodal and sham stimulation (15 mins/1 mA) over the primary motor cortex on the perceived intensity of repeated noxious thermal and electrical stimuli and on elements of quantitative sensory testing (thermal pain and perception thresholds) applied to the right hand in 15 patients with chronic low back pain. The study was conducted in a double-blind sham-controlled and cross-over design. No significant alterations of pain ratings were found. Modalities of quantitative sensory testing remained equally unchanged. It is therefore hypothesized that a single 15 mins session of tDCS at 1 mA may not be sufficient to alter the perception of experimental pain and in patients with chronic pain. Further studies applying repetitive tDCS to patients with chronic pain are required to fully answer the question whether experimental pain perception may be influenced by tDCS over the motor cortex. PMID:23189136

  8. Effect of Catechol-O-methyltransferase-gene (COMT) Variants on Experimental and Acute Postoperative Pain in 1,000 Women undergoing Surgery for Breast Cancer

    PubMed Central

    Kambur, Oleg; Kaunisto, Mari A.; Tikkanen, Emmi; Leal, Suzanne M.; Ripatti, Samuli; Kalso, Eija A.

    2016-01-01

    Background Catechol-O-methyltransferase (COMT) metabolizes catecholamines in different tissues. Polymorphisms in COMT gene can attenuate COMT activity and increase sensitivity to pain. Human studies exploring the effect of COMT polymorphisms on pain sensitivity have mostly included small, heterogeneous samples and have ignored several important single nucleotide polymorphisms (SNPs). This study examines the effect of COMT polymorphisms on experimental and postoperative pain phenotypes in a large ethnically homogeneous female patient cohort. Methods Intensity of cold (+2–4°C) and heat (+48°C) pain and tolerance to cold pain were assessed in 1,000 patients scheduled for breast cancer surgery. Acute postoperative pain and oxycodone requirements were recorded. Twenty-two COMT SNPs were genotyped and their association with six pain phenotypes analyzed with linear regression. Results There was no association between any of the tested pain phenotypes and SNP rs4680. The strongest association signals were seen between rs165774 and heat pain intensity as well as rs887200 and cold pain intensity. In both cases, minor allele carriers reported less pain. Neither of these results remained significant after strict multiple testing corrections. When analyzed further, the effect of rs887200 was, however, shown to be significant and consistent throughout the cold pressure test. No evidence of association between the SNPs and postoperative oxycodone consumption was found. Conclusions SNPs rs887200 and rs165774 located in the untranslated regions of the gene had the strongest effects on pain sensitivity. Their effect on pain is described here for the first time. These results should be confirmed in further studies and the potential functional mechanisms of the variants studied. PMID:24343288

  9. Neuronal and immunological basis of action of antidepressants in chronic pain - clinical and experimental studies.

    PubMed

    Mika, Joanna; Zychowska, Magdalena; Makuch, Wioletta; Rojewska, Ewelina; Przewlocka, Barbara

    2013-01-01

    The current knowledge of the pharmacological actions of the tricyclic antidepressants (TCAs) has slowly evolved through their over 40-year history. Chronic pain represents one of the most important public health problems, and antidepressants are an essential part of the therapeutic strategy in addition to classical analgesics. This article reviews the available evidence on the efficacy and safety of antidepressants in chronic pain conditions; namely, headaches, low back pain, fibromyalgia, cancer pain and especially neuropathic pain. TCAs are traditionally the main type of depression medication used to treat chronic pain. Recently, new antidepressants were introduced into clinical use, with a significant reduction in side effects and equivalent efficacy on mood disorders. These new drugs that are effective for chronic pain belong to the tetracyclic antidepressants (TeCAs) group (amoxapine, maprotiline), the serotonin and noradrenaline reuptake inhibitors (SNRIs) group (duloxetine, venlafaxine, milnacipran) and the atypical antidepressants group (bupropion, trazodone, mirtazapine, nefazodone). In this review, we present the available publications on TCAs (amitriptyline, doxepin, imipramine, desipramine, nortriptyline), TeCAs (amoxapine, maprotiline), selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, paroxetine), SNRIs (duloxetine, venlafaxine, milnacipran) and atypical antidepressants (bupropion) for the treatment of neuropathic pain. We also review analgesics acting as both opioid receptor agonists and also acting as aminergic reuptake inhibitors. Existing data are insufficient to conclude which of these new classes of antidepressants has the best clinical profile and will be the most effective in the treatment of neuropathic pain; in addition, a lower incidence of side effects should be considered. Increased experimental and translational research is a key for further improvement of the treatment of chronic pain with antidepressants. However

  10. Antihypernociceptive activity of anethole in experimental inflammatory pain.

    PubMed

    Ritter, Alessandra M V; Domiciano, Talita P; Verri, Waldiceu A; Zarpelon, Ana Carla; da Silva, Lorena G; Barbosa, Carmem P; Natali, Maria Raquel M; Cuman, Roberto K N; Bersani-Amado, Ciomar A

    2013-04-01

    Anethole has been reported to have antioxidant, antibacterial, antifungal, antiinflammatory, and anesthetic properties. In the present study, we evaluated the effects of anethole in two pain models of inflammatory origin: acute inflammation induced by carrageenan and persistent inflammation induced by Complete Freund's adjuvant. We evaluated the effects of anethole (125, 250, and 500 mg/kg) on the development of paw oedema and mechanical hypernociception. The liver was collected for histological analysis. Paw skin was collected to determine the levels of the cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-17 (IL-17), and myeloperoxidase activity. Blood was collected to assess alanine transaminase (ALT) and aspartate transaminase (AST). The chemical composition of star anise oil was determined by gas chromatography/mass spectrometry (GC/MS), showing a presence of anethole of 98.1%. Oral pretreatment with anethole in mice inhibited paw oedema, mechanical pernociception, myelopewroxidase activity, TNF-α, IL-1β and IL-17 levels in acute and persistent inflammation models. Additionally, anethole treatment did not alter prostaglandin E2-induced mechanical hypernociception. Possible side effects were also examined. Seven-day anethole treatment did not alter plasma AST and ALT levels, and the histological profile of liver tissue was normal. The present study provides evidence of the antiinflammatory and analgesic activities of anethole in acute and persistent inflammation models.

  11. Adult stem cell as new advanced therapy for experimental neuropathic pain treatment.

    PubMed

    Franchi, Silvia; Castelli, Mara; Amodeo, Giada; Niada, Stefania; Ferrari, Daniela; Vescovi, Angelo; Brini, Anna Teresa; Panerai, Alberto Emilio; Sacerdote, Paola

    2014-01-01

    Neuropathic pain (NP) is a highly invalidating disease resulting as consequence of a lesion or disease affecting the somatosensory system. All the pharmacological treatments today in use give a long lasting pain relief only in a limited percentage of patients before pain reappears making NP an incurable disease. New approaches are therefore needed and research is testing stem cell usage. Several papers have been written on experimental neuropathic pain treatment using stem cells of different origin and species to treat experimental NP. The original idea was based on the capacity of stem cell to offer a totipotent cellular source for replacing injured neural cells and for delivering trophic factors to lesion site; soon the researchers agreed that the capacity of stem cells to contrast NP was not dependent upon their regenerative effect but was mostly linked to a bidirectional interaction between the stem cell and damaged microenvironment resident cells. In this paper we review the preclinical studies produced in the last years assessing the effects induced by several stem cells in different models of neuropathic pain. The overall positive results obtained on pain remission by using stem cells that are safe, of easy isolation, and which may allow an autologous transplant in patients may be encouraging for moving from bench to bedside, although there are several issues that still need to be solved.

  12. Experimental muscle pain decreases the frequency threshold of electrically elicited muscle cramps.

    PubMed

    Serrao, Mariano; Arendt-Nielsen, Lars; Ge, Hong-You; Pierelli, Francesco; Sandrini, Giorgio; Farina, Dario

    2007-09-01

    This study in humans tested the hypothesis that nociceptive muscle afferent input facilitates the occurrence of muscle cramps. In 13 healthy adults, muscle cramps were experimentally induced in the foot by stimulating the tibialis posterior nerve at the ankle with 2-s bursts of stimuli separated by 30 s, with stimulation frequency increasing by 2-Hz increments from 10 Hz until the cramp appeared. The minimum stimulation frequency that induced the cramp was defined "cramp frequency threshold". In 2 days, elicitation of the cramp was performed in the two-feet with and without (baseline condition) injection of hypertonic (painful condition) or isotonic (control condition) saline into the deep midportion of the flexor hallucis brevis muscle, from where surface EMG signals were recorded. The cramp frequency threshold was lower for the painful condition with respect to its baseline (mean +/- SE, hypertonic saline: 25.7 +/- 2.1 Hz, corresponding baseline: 31.2 +/- 2.8 Hz; P < 0.01) while there was no difference between the threshold with isotonic injection with respect to baseline. EMG average rectified value and power spectral frequency were higher during the cramp than immediately before the stimulation that elicited the cramp (pre-cramp: 13.9 +/- 1.6 muV and 75.4 +/- 3.8 Hz, respectively; post-cramp: 19.9 +/- 3.2 muV and 101.6 +/- 6.0 Hz; P < 0.05). The results suggest that nociceptive muscle afferent activity induced by injection of hypertonic saline facilitates the generation of electrically elicited muscle cramps.

  13. The effect of experimental low back pain on lumbar muscle activity in people with a history of clinical low back pain: a muscle functional MRI study.

    PubMed

    Danneels, Lieven; Cagnie, Barbara; D'hooge, Roseline; De Deene, Yves; Crombez, Geert; Vanderstraeten, Guy; Parlevliet, Thierry; Van Oosterwijck, Jessica

    2016-02-01

    In people with a history of low back pain (LBP), structural and functional alterations have been observed at several peripheral and central levels of the sensorimotor pathway. These existing alterations might interact with the way the sensorimotor system responds to pain. We examined this assumption by evaluating the lumbar motor responses to experimental nociceptive input of 15 participants during remission of unilateral recurrent LBP. Quantitative T2 images (muscle functional MRI) were taken bilaterally of multifidus, erector spinae, and psoas at several segmental levels (L3 upper and L4 upper and lower endplate) and during several conditions: 1) at rest, 2) upon trunk-extension exercise without pain, and 3) upon trunk-extension exercise with experimental induced pain at the clinical pain-side (1.5-ml intramuscular hypertonic saline injections in erector spinae). Following experimental pain induction, muscle activity levels similarly reduced for all three muscles, on both painful and nonpainful sides, and at multiple segmental levels (P = 0.038). Pain intensity and localization from experimental LBP were similar as during recalled clinical LBP episodes. In conclusion, unilateral and unisegmental experimental LBP exerts a generalized and widespread decrease in lumbar muscle activity during remission of recurrent LBP. This muscle response is consistent with previous observed patterns in healthy people subjected to the same experimental pain paradigm. It is striking that similar inhibitory patterns in response to pain could be observed, despite the presence of preexisting alterations in the lumbar musculature during remission of recurrent LBP. These results suggest that motor output can modify along the course of recurrent LBP.

  14. Higher cortical modulation of pain perception in the human brain: Psychological determinant.

    PubMed

    Chen, Andrew Cn

    2009-10-01

    Pain perception and its genesis in the human brain have been reviewed recently. In the current article, the reports on pain modulation in the human brain were reviewed from higher cortical regulation, i.e. top-down effect, particularly studied in psychological determinants. Pain modulation can be examined by gene therapy, physical modulation, pharmacological modulation, psychological modulation, and pathophysiological modulation. In psychological modulation, this article examined (a) willed determination, (b) distraction, (c) placebo, (d) hypnosis, (e) meditation, (f) qi-gong, (g) belief, and (h) emotions, respectively, in the brain function for pain modulation. In each, the operational definition, cortical processing, neuroimaging, and pain modulation were systematically deliberated. However, not all studies had featured the brain modulation processing but rather demonstrated potential effects on human pain. In our own studies on the emotional modulation on human pain, we observed that emotions could be induced from music melodies or pictures perception for reduction of tonic human pain, mainly in potentiation of the posterior alpha EEG fields, likely resulted from underneath activities of precuneous in regulation of consciousness, including pain perception. To sum, higher brain functions become the leading edge research in all sciences. How to solve the information bit of thinking and feeling in the brain can be the greatest challenge of human intelligence. Application of higher cortical modulation of human pain and suffering can lead to the progress of social humanity and civilization.

  15. Prestimulus functional connectivity determines pain perception in humans.

    PubMed

    Ploner, Markus; Lee, Michael C; Wiech, Katja; Bingel, Ulrike; Tracey, Irene

    2010-01-05

    Pain is a highly subjective experience that can be substantially influenced by differences in individual susceptibility as well as personality. How susceptibility to pain and personality translate to brain activity is largely unknown. Here, we report that the functional connectivity of two key brain areas before a sensory event reflects the susceptibility to a subsequent noxious stimulus being perceived as painful. Specifically, the prestimulus connectivity among brain areas related to the subjective perception of the body and to the modulation of pain (anterior insular cortex and brainstem, respectively) determines whether a noxious event is perceived as painful. Further, these effects of prestimulus connectivity on pain perception covary with pain-relevant personality traits. More anxious and pain-attentive individuals display weaker descending connectivity to pain modulatory brain areas. We conclude that variations in functional connectivity underlie personality-related differences in individual susceptibility to pain.

  16. The role of neuroplasticity in experimental neck pain: a study of potential mechanisms impeding clinical outcomes of training.

    PubMed

    Rittig-Rasmussen, Bjarne; Kasch, Helge; Fuglsang-Frederiksen, Anders; Svensson, Peter; Jensen, Troels Staehelin

    2014-08-01

    Training is a mainstay in the clinical management of neck pain, yet, effects of various training protocols are only small to moderate and improvements are required. Previous investigations of the nervous system indicate a correlation between neuroplastic adaptation to training and functional recovery. The interaction between neck pain and training thus needs further exploration. This was a randomized experimental study of the effects of experimental neck pain and training on corticomotor excitability. Healthy volunteers were randomized to training and experimental neck pain, training and no pain, and pain and no training. Primary endpoints were corticomotor excitability assessed by transcranial magnetic stimulation and electromyography measured as changes in amplitudes and latencies of motor evoked potentials (MEPs), recorded at baseline and after 30 min, 1 h, and 1 week. Additionally, correlations between changes in MEPs and motor learning, effects of pain and concomitant neck training on pain, muscle strength, and fatigue were investigated. Data were analyzed by repeated measurement ANOVA, paired t tests, Grubbs' outlier test and correlation coefficients. Results indicated that neck pain and training significantly enhanced the inhibition of the amplitudes of the MEPs for 1 week. The results indicate that moderate neck pain and training induce long-lasting inhibition of the corticomotor pathways. This inhibition may limit the outcome of neck training in painful conditions in contrast to pain-free training conditions.

  17. Kinesthetic illusions attenuate experimental muscle pain, as do muscle and cutaneous stimulation.

    PubMed

    Gay, André; Aimonetti, Jean-Marc; Roll, Jean-Pierre; Ribot-Ciscar, Edith

    2015-07-30

    In the present study, muscle pain was induced experimentally in healthy subjects by administrating hypertonic saline injections into the tibialis anterior (TA) muscle. We first aimed at comparing the analgesic effects of mechanical vibration applied to either cutaneous or muscle receptors of the TA or to both types simultaneously. Secondly, pain alleviation was compared in subjects in whom muscle tendon vibration evoked kinesthetic illusions of the ankle joint. Muscle tendon vibration, which primarily activated muscle receptors, reduced pain intensity by 30% (p<0.01). In addition, tangential skin vibration reduced pain intensity by 33% (p<0.01), primarily by activating cutaneous receptors. Concurrently stimulating both sensory channels induced stronger analgesic effects (-51%, p<0.01), as shown by the lower levels of electrodermal activity. The strongest analgesic effects of the vibration-induced muscle inputs occurred when illusory movements were perceived (-38%, p=0.01). The results suggest that both cutaneous and muscle sensory feedback reduce muscle pain, most likely via segmental and supraspinal processes. Further clinical trials are needed to investigate these new methods of muscle pain relief.

  18. Effect of Experimental Cutaneous Hand Pain on Corticospinal Excitability and Short Afferent Inhibition

    PubMed Central

    Mercier, Catherine; Gagné, Martin; Reilly, Karen T.; Bouyer, Laurent J.

    2016-01-01

    Sensorimotor integration is altered in people with chronic pain. While there is substantial evidence that pain interferes with neural activity in primary sensory and motor cortices, much less is known about its impact on integrative sensorimotor processes. Here, the short latency afferent inhibition (SAI) paradigm was used to assess sensorimotor integration in the presence and absence of experimental cutaneous heat pain applied to the hand. Ulnar nerve stimulation was combined with transcranial magnetic stimulation to condition motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Four interstimulus intervals (ISI) were tested, based on the latency of the N20 component of the afferent sensory volley (N20−5 ms, N20+2 ms, N20+4 ms, N20+10 ms). In the PAIN condition, MEPs were smaller compared to the NEUTRAL condition (p = 0.005), and were modulated as a function of the ISI (p = 0.012). Post-hoc planned comparisons revealed that MEPs at N20+2 and N20+4 were inhibited compared to unconditioned MEPs. However, the level of inhibition (SAI) was similar in the PAIN and NEUTRAL conditions. This suggests that the interplay between pain and sensorimotor integration is not mediated through direct and rapid pathways as assessed by SAI, but rather might involve higher-order integrative areas. PMID:27690117

  19. Opioid treatment of experimental pain activates nuclear factor-κB

    PubMed Central

    Compton, Peggy; Griffis, Charles; Breen, Elizabeth Crabb; Torrington, Matthew; Sadakane, Ryan; Tefera, Eshetu; Irwin, Michael R.

    2015-01-01

    Objective To determine the independent and combined effects of pain and opioids on the activation of an early marker of inflammation, nuclear factor-κB (NF-κB). Design NF-κB activation was compared within-subjects following four randomly ordered experimental sessions of opioid-only (intravenous fentanyl 1 μg/kg), pain-only (cold-pressor), opioid + pain, and a resting condition. Setting University General Clinical Research Center. Participants Twenty-one (11 female) healthy controls. Interventions Following exposure to treatment (fentanyl administration and/or cold-pressor pain), blood samples for NF-kB analysis were obtained. Main outcome measures Intracellular levels of activated NF-κB, in unstimulated and stimulated peripheral blood mononuclear cells at 15 and 30 minutes. Results Neither pain nor opioid administration alone effected NF-κB levels in cell populations; however, the combination of treatments induced significant increases of NF-κB in stimulated peripheral blood mononuclear cell, lymphocytes, and monocytes. Conclusions The combination of acute pain with opioids, as occurs in clinical situations, activates a key transcription factor involved in proinflammatory responses. PMID:25901477

  20. Antinociceptive effect of botulinum toxin type A on experimental abdominal pain.

    PubMed

    Drinovac, Višnja; Bach-Rojecky, Lidija; Babić, Ana; Lacković, Zdravko

    2014-12-15

    Visceral pain, especially in the abdominal region, represents one of the most common types of pain. Its chronic form is usually very hard to treat by conventional analgesic agents and adjuvants. We investigated the antinociceptive effect of botulinum toxin type A (BTX-A) in male Wistar rats in two models of visceral pain: peritonitis induced by intraperitoneal injection of 1% acetic acid and colitis induced by intracolonic instillation of 0.1% capsaicin. Pain was measured as the number of abdominal writhes. Additionally, referred mechanical sensitivity in the ventral abdominal area was evaluated by von Frey test and the extent of spinal c-Fos expression was immunohistochemically examined. BTX-A significantly reduced the number of abdominal writhes in both models of visceral pain after intrathecal application in a dose of 2 U/kg. In the experimental colitis model, BTX-A (2 U/kg) reduced both referred mechanical allodynia and c-Fos expression in the dorsal horn of the spinal cord (S2/S3 segments). In contrast to intrathecal administration, BTX-A (2 U/kg) administered into the cisterna magna had no effect on pain suggesting that the primary site of its action is a spinal cord.

  1. Experimental orofacial pain and sensory deprivation lead to perceptual distortion of the face in healthy volunteers.

    PubMed

    Dagsdóttir, Lilja Kristín; Skyt, Ina; Vase, Lene; Baad-Hansen, Lene; Castrillon, Eduardo; Svensson, Peter

    2015-09-01

    Patients suffering from persistent orofacial pain may sporadically report that the painful area feels "swollen" or "differently," a phenomenon that may be conceptualized as a perceptual distortion because there are no clinical signs of swelling present. Our aim was to investigate whether standardized experimental pain and sensory deprivation of specific orofacial test sites would lead to changes in the size perception of these face areas. Twenty-four healthy participants received either 0.2 mL hypertonic saline (HS) or local anesthetics (LA) into six regions (buccal, mental, lingual, masseter muscle, infraorbital and auriculotemporal nerve regions). Participants estimated the perceived size changes in percentage (0 % = no change, -100 % = half the size or +100 % = double the size), and somatosensory function was checked with tactile stimuli. The pain intensity was rated on a 0-10 Verbal Numerical Rating Scale (VNRS), and sets of psychological questionnaires were completed. HS and LA were associated with significant self-reported perceptual distortions as indicated by consistent increases in perceived size of the adjacent face areas (P ≤ 0.050). Perceptual distortion was most pronounced in the buccal region, and the smallest increase was observed in the auriculotemporal region. HS was associated with moderate levels of pain VNRS = 7.3 ± 0.6. Weak correlations were found between HS-evoked perceptual distortion and level of dissociation in two regions (P < 0.050). Experimental pain and transient sensory deprivation evoked perceptual distortions in all face regions and overall demonstrated the importance of afferent inputs for the perception of the face. We propose that perceptual distortion may be an important phenomenon to consider in persistent orofacial pain conditions.

  2. Clara Maass, yellow fever and human experimentation.

    PubMed

    Chaves-Carballo, Enrique

    2013-05-01

    Clara Louise Maass, a 25-year-old American nurse, died of yellow fever on August 24, 1901, following experimental inoculation by infected mosquitoes in Havana, Cuba. The human yellow fever experiments were initially conducted by MAJ Walter Reed, who first used written informed consent and proved the validity of Finlay's mosquito-vector hypothesis. Despite informed consent form and an incentive of $100 in U.S. gold, human subjects were exposed to a deadly virus. The deaths of Clara Maass and two Spanish immigrants resulted in a public outcry and the immediate cessation of yellow fever human experiments in Cuba.

  3. Complex regional pain syndrome (CRPS) or continuous unilateral distal experimental pain stimulation in healthy subjects does not bias visual attention towards one hemifield.

    PubMed

    Filippopulos, Filipp M; Grafenstein, Jessica; Straube, Andreas; Eggert, Thomas

    2015-11-01

    In natural life pain automatically draws attention towards the painful body part suggesting that it interacts with different attentional mechanisms such as visual attention. Complex regional pain syndrome (CRPS) patients who typically report on chronic distally located pain of one extremity may suffer from so-called neglect-like symptoms, which have also been linked to attentional mechanisms. The purpose of the study was to further evaluate how continuous pain conditions influence visual attention. Saccade latencies were recorded in two experiments using a common visual attention paradigm whereby orientating saccades to cued or uncued lateral visual targets had to be performed. In the first experiment saccade latencies of healthy subjects were measured under two conditions: one in which continuous experimental pain stimulation was applied to the index finger to imitate a continuous pain situation, and one without pain stimulation. In the second experiment saccade latencies of patients suffering from CRPS were compared to controls. The results showed that neither the continuous experimental pain stimulation during the experiment nor the chronic pain in CRPS led to an unilateral increase of saccade latencies or to a unilateral increase of the cue effect on latency. The results show that unilateral, continuously applied pain stimuli or chronic pain have no or only very limited influence on visual attention. Differently from patients with visual neglect, patients with CRPS did not show strong side asymmetries of saccade latencies or of cue effects on saccade latencies. Thus, neglect-like clinical symptoms of CRPS patients do not involve the allocation of visual attention.

  4. Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans.

    PubMed

    Winchester, Wendy J; Gore, Katrina; Glatt, Sophie; Petit, Wendy; Gardiner, Jennifer C; Conlon, Kelly; Postlethwaite, Michael; Saintot, Pierre-Philippe; Roberts, Sonia; Gosset, James R; Matsuura, Tomomi; Andrews, Mark D; Glossop, Paul A; Palmer, Michael J; Clear, Nicola; Collins, Susie; Beaumont, Kevin; Reynolds, David S

    2014-11-01

    The transient receptor potential (subfamily M, member 8; TRPM8) is a nonselective cation channel localized in primary sensory neurons, and is a candidate for cold thermosensing, mediation of cold pain, and bladder overactivity. Studies with TRPM8 knockout mice and selective TRPM8 channel blockers demonstrate a lack of cold sensitivity and reduced cold pain in various rodent models. Furthermore, TRPM8 blockers significantly lower body temperature. We have identified a moderately potent (IC50 = 103 nM), selective TRPM8 antagonist, PF-05105679 [(R)-3-[(1-(4-fluorophenyl)ethyl)(quinolin-3-ylcarbonyl)amino]methylbenzoic acid]. It demonstrated activity in vivo in the guinea pig bladder ice water and menthol challenge tests with an IC50 of 200 nM and reduced core body temperature in the rat (at concentrations >1219 nM). PF-05105679 was suitable for acute administration to humans and was evaluated for effects on core body temperature and experimentally induced cold pain, using the cold pressor test. Unbound plasma concentrations greater than the IC50 were achieved with 600- and 900-mg doses. The compound displayed a significant inhibition of pain in the cold pressor test, with efficacy equivalent to oxycodone (20 mg) at 1.5 hours postdose. No effect on core body temperature was observed. An unexpected adverse event (hot feeling) was reported, predominantly periorally, in 23 and 36% of volunteers (600- and 900-mg dose, respectively), which in two volunteers was nontolerable. In conclusion, this study supports a role for TRPM8 in acute cold pain signaling at doses that do not cause hypothermia.

  5. A rift between implicit and explicit conditioned valence in human pain relief learning

    PubMed Central

    Andreatta, Marta; Mühlberger, Andreas; Yarali, Ayse; Gerber, Bertram; Pauli, Paul

    2010-01-01

    Pain is aversive, but does the cessation of pain (‘relief’) have a reward-like effect? Indeed, fruitflies avoid an odour previously presented before a painful event, but approach an odour previously presented after a painful event. Thus, event-timing may turn punishment to reward. However, is event-timing also crucial in humans who can have explicit cognitions about associations? Here, we show that stimuli associated with pain-relief acquire positive implicit valence but are explicitly rated as aversive. Specifically, the startle response, an evolutionarily conserved defence reflex, is attenuated by stimuli that had previously followed a painful event, indicating implicit positive valence of the conditioned stimulus; nevertheless, participants explicitly evaluate these stimuli as ‘emotionally negative’. These results demonstrate a rift between the implicit and explicit conditioned valence induced by pain relief. They might explain why humans in some cases are attracted by conditioned stimuli despite explicitly judging them as negative. PMID:20356893

  6. Artificial nociception and motor responses to pain, for humans and robots.

    PubMed

    Bagnato, Carlo; Takagi, Atsushi; Burdet, Etienne

    2015-01-01

    This concept paper describes nociception and the role of pain in humans. Understanding the mechanisms of pain can give insight into the implementation of artificial pain for robots. Identification of noxious contacts could help robots to elicit reactions in order to avoid or minimize damage to the robot and the environment. The information processing of artificial pain can also be used to optimally regulate incoming sensory information and prevent accidents or real pain to the users of robotic systems and prostheses, improving the performance of robots and their interaction with human users. Besides the applications of artificial nociception for robotic manipulation and intelligent prostheses, the development of computational models of pain mechanisms for the discrimination of noxious stimuli from innocuous touch can find crucial clinical applications, addressing the vulnerable non-verbal population who are unable to report pain.

  7. The effect of cognitive bias modification for interpretation on avoidance of pain during an acute experimental pain task.

    PubMed

    Jones, Emma Blaisdale; Sharpe, Louise

    2014-08-01

    Research confirms that patients with chronic pain show a tendency to interpret ambiguous stimuli as pain related. However, whether modifying these interpretive pain biases impacts pain outcomes is unknown. This study aimed to demonstrate that interpretation biases towards pain can be modified, and that changing these biases influences pain outcomes in the cold pressor task. One hundred and six undergraduate students were randomly allocated to receive either threatening or reassuring information regarding the cold pressor. They also were randomly allocated to 1 of 2 conditions in the Ambiguous Scenarios Task, in which they were trained to have either a threatening interpretation of pain (pain bias condition) or a nonthreatening interpretation of pain (no pain bias condition). Therefore, the study had a 2 (threat/reassuring)×2 (pain bias/no pain bias) design. Analyses showed that a bias was induced contingent on condition, and that the threat manipulation was effective. Participants in the pain bias condition hesitated more before doing the cold pressor task than those in the no pain bias condition, as did those in the threat compared with the reassurance condition. The major finding was that interpretive bias mediated the relationship between bias condition and hesitance time, supporting the causal role of interpretive biases for avoidance behaviors in current chronic pain models. No differences were found on other pain outcomes regarding bias or threat, and the efficacy of the bias modification was not impacted by different levels of threat. These results suggest that cognitive bias modification should be further explored as a potential intervention in pain.

  8. The impact of neurodynamic testing on the perception of experimentally induced muscle pain.

    PubMed

    Coppieters, Michel W; Kurz, Kimberly; Mortensen, Thor Einar; Richards, Nicola L; Skaret, Ingrid A; McLaughlin, Laurie M; Hodges, Paul W

    2005-02-01

    Neurodynamic tests such as the straight leg raising (SLR) and slump test are frequently used for assessment of mechanosensitivity of neural tissues. However, there is ongoing debate in the literature regarding the contributions of neural and non-neural tissues to the elicited symptoms because many structures are affected by these tests. Sensitizing manoeuvres are limb or spinal movements added to neurodynamic tests, which aim to identify the origin of the symptoms by preferentially loading or unloading neural structures. A prerequisite for the use of sensitizing manoeuvres to identify neural involvement is that the addition of sensitizing manoeuvres has no impact on pain perception when the origin of the pain is non-neural. In this study, experimental muscle pain was induced by injection of hypertonic saline in tibialis anterior or soleus in 25 asymptomatic, naive volunteers. A first experiment investigated the impact of hip adduction, abduction, medial and lateral rotation in the SLR position. In a second experiment, the different stages of the slump test were examined. The intensity and area of experimentally induced muscle pain did not increase when sensitizing manoeuvres were added to the SLR or throughout the successive stages of the slump test. The findings of this study lend support to the validity of the use of sensitizing manoeuvres during neurodynamic testing.

  9. [Experimental models of human skin aging].

    PubMed

    Nikolakis, G; Zoschke, C; Makrantonaki, E; Hausmann, C; Schäfer-Korting, M; Zouboulis, C C

    2016-02-01

    The skin is a representative model for the study of human aging. Despite the high regenerative capacity of the skin, skin physiology changes over the course of life. Medical and cosmetic research is trying to prevent aging, to slow, to stop, or to reverse it. Effects of age-related DNA damage and of changing skin structure on pharmacological parameters are largely unknown. This review article summarizes the state of scientific knowledge in the field of experimental models of human skin aging and shows approaches to improve organotypic skin models, to develop predictive models of aging, and improve aging research.

  10. The Haglund painful heel syndrome. Experimental investigation of cause and therapeutic implications.

    PubMed

    Heneghan, M A; Pavlov, H

    1984-01-01

    Haglund syndrome, a common cause of pain in the posterior heel, consists of a painful swelling of the local soft tissues (the so-called pump bump) and prominence of the calcaneal bursal projection. The condition is caused by compression of the distal Achilles tendon and surrounding soft tissue between the os calcis and the posterior shoe counter. Osseous plantar projections appear to be a critical etiologic factor in Haglund syndrome. With an experimental model, it has been demonstrated that osseous projections on the plantar surface of the calcaneus adversely influence the bone-soft tissue relation of the posterior heel. Shoe heel elevation has been shown to be clinically effective in alleviating symptoms. It is demonstrated with an experimental model that elevation of the shoe heel decreases the pitch angle. This diminishes the prominence of the bursal projection and allows the foot to slip forward, displacing the posterior calcaneus away from the shoe counter.

  11. Experimental tooth clenching. A model for studying mechanisms of muscle pain.

    PubMed

    Dawson, Andreas

    2013-01-01

    The overall goal of this thesis was to broaden knowledge of pain mechanisms in myofascial temporomandibular disorders (M-TMD). The specific aims were to: Develop a quality assessment tool for experimental bruxism studies (study I). Investigate proprioceptive allodynia after experimental tooth clenching exercises (study II). Evaluate the release of serotonin (5-HT), glutamate, pyruvate, and lactate in healthy subjects (study III) and in patients with M-TMD (study IV), after experimental tooth clenching exercises. In (I), tool development comprised 5 steps: (i) preliminary decisions, (ii) item generation, (iii) face-validity assessment, (iv) reliability and discriminative validity testing, and (v) instrument refinement. After preliminary decisions and a literature review, a list of 52 items to be considered for inclusion in the tool was generated. Eleven experts were invited to participate on the Delphi panel, of which 10 agreed. After four Delphi rounds, 8 items remained and were included in the Quality Assessment Tool for Experimental Bruxism Studies (Qu-ATEBS). Inter-observer reliability was acceptable (k = 0.77), and discriminative validity high (phi coefficient 0.79; P < 0.01). During refinement, 1 item was removed; the final tool comprised 7 items. In (II), 16 healthy females participated in three 60-min sessions, each with 24- and 48-h follow-ups. Participants were randomly assigned to a repetitive experimental tooth clenching task with a clenching level of 10%, 20%, or 40% of maximal voluntary clenching force (MVCF). Pain intensity, fatigue, perceived intensity of vibration (PIV), perceived discomfort (PD), and pressure pain threshold (PPT) were measured throughout. A significant increase in pain intensity and fatigue but not in PD was observed over time. A significant increase in PIV was only observed at 40 min, and PPT decreased significantly over time at 50 and 60 min compared to baseline. In (III), 30 healthy subjects (16 females, and 14 males

  12. Cholestasis: human disease and experimental animal models.

    PubMed

    Rodríguez-Garay, Emilio Alberto

    2003-01-01

    Cholestasis may result from a failure in bile secretion in hepatocytes or ductular cells, or from a blockade to the free bile flow. Human cholestasis may be induced by many drugs, being antibiotics the more common. Other types of cholestasis seen in humans are a group of familial cholestatic disorders, obstructive cholestasis, primary biliary cirrhosis, extrahepatic biliary atresia, primary sclerosing cholangitis, cholestasis of pregnancy, oral contraceptive-induced cholestasis, and sepsis-induced cholestasis. Experimental animal models allow the understanding of pathophysiological mechanisms involved and their clinical correlates. The most common experimental models of intrahepatic cholestasis are estrogen-induced, endotoxin-induced and drug-induced cholestasis. A well known model of extrahepatic biliary obstruction is common bile duct ligation. Drug-induced cholestasis were described using different drugs. On this regard, alpha naphthylisothiocyanate treatment has been extensively used, permitting to describe not only cholestatic alterations but also compensatory mechanisms. Congenital defficiency of transport proteins also were studied in natural rat models of cholestasis. The experimental animal models allow to define down-regulated alterations of hepatocyte transport proteins, and up-regulated ones acting as compensatory mechanisms. In conclusion, animal model and transport protein studies are necessary for the progressive understanding of congenital and acquired human cholestasis, and regulatory mechanisms that operate on liver cells.

  13. Pain in experimental autoimmune encephalitis: a comparative study between different mouse models

    PubMed Central

    2012-01-01

    Background Pain can be one of the most severe symptoms associated with multiple sclerosis (MS) and develops with varying levels and time courses. MS-related pain is difficult to treat, since very little is known about the mechanisms underlying its development. Animal models of experimental autoimmune encephalomyelitis (EAE) mimic many aspects of MS and are well-suited to study underlying pathophysiological mechanisms. Yet, to date very little is known about the sensory abnormalities in different EAE models. We therefore aimed to thoroughly characterize pain behavior of the hindpaw in SJL and C57BL/6 mice immunized with PLP139-151 peptide or MOG35-55 peptide respectively. Moreover, we studied the activity of pain-related molecules and plasticity-related genes in the spinal cord and investigated functional changes in the peripheral nerves using electrophysiology. Methods We analyzed thermal and mechanical sensitivity of the hindpaw in both EAE models during the whole disease course. Qualitative and quantitative immunohistochemical analysis of pain-related molecules and plasticity-related genes was performed on spinal cord sections at different timepoints during the disease course. Moreover, we investigated functional changes in the peripheral nerves using electrophysiology. Results Mice in both EAE models developed thermal hyperalgesia during the chronic phase of the disease. However, whereas SJL mice developed marked mechanical allodynia over the chronic phase of the disease, C57BL/6 mice developed only minor mechanical allodynia over the onset and peak phase of the disease. Interestingly, the magnitude of glial changes in the spinal cord was stronger in SJL mice than in C57BL/6 mice and their time course matched the temporal profile of mechanical hypersensitivity. Conclusions Diverse EAE models bearing genetic, clinical and histopathological heterogeneity, show different profiles of sensory and pathological changes and thereby enable studying the mechanistic basis

  14. Gp120 in the pathogenesis of human HIV-associated pain

    PubMed Central

    Yuan, Subo; Shi, Yuqiang; Chen, Jinghong; Zhou, Xiangfu; Li, Guangyu; Gelman, Benjamin B.; Lisinicchia, Joshua G.; Carlton, Susan M.; Ferguson, Monique R.; MD, Alai Tan.; Sarna, Sushil K.; Tang, Shao-Jun

    2014-01-01

    Objective Chronic pain is a common neurological comorbidity of HIV-1 infection, but the etiological cause remains elusive. The objective of this study was to identify the HIV-1 causal factor that critically contributes to the pathogenesis of HIV-associated pain. Methods We first compared the levels of HIV-1 proteins in postmortem tissues of the spinal cord dorsal horn (SDH) from HIV-1/AIDS patients who developed chronic pain (‘pain-positive’ HIV-1 patients) and HIV-1 patients who did not develop chronic pain (‘pain-negative’ HIV-1 patients). Then, we used the HIV-1 protein that was specifically increased in the ‘pain-positive’ patients to generate mouse models. Finally, we performed comparative analyses on the pathological changes in the models and the HIV-1 patients. Results We found that HIV-1 gp120 was significantly higher in ‘pain-positive’ HIV-1 patients (vs. ‘pain-negative’ HIV-1 patients). This finding suggested that gp120 was a potential causal factor of the HIV-associated pain. To test this hypothesis, we used a mouse model generated by intrathecal injection (i.t.) of gp120 and compared the pathologies of the model and the ‘pain-positive’ human HIV-1 patients. The results showed that the mouse model and ‘pain-positive’ human HIV-1 patients developed extensive similarities in their pathological phenotypes, including pain behaviors, peripheral neuropathy, glial reactivation, synapse degeneration and aberrant activation of pain-related signaling pathways in the SDH. Interpretation Our findings suggest that gp120 may critically contribute to the pathogenesis of HIV-associated pain. PMID:24633867

  15. Structural Health Monitoring: Leveraging Pain in the Human Body

    NASA Astrophysics Data System (ADS)

    Nayak, Subhadarshi

    2012-07-01

    Tissue damage, or the perception thereof, is managed through pain experience. The neurobiological process of pain triggers most effective defense mechanisms for our safety. Structural health monitoring (SHM) is also a very similar function, albeit in engineering systems. SHM technology can leverage many aspects of pain mechanisms to progress in several critical areas. Discrimination between features from the undamaged and damaged structures can follow the threshold gate mechanism of the pain perception. Furthermore, the sensing mechanisms can be adaptive to changes by adjusting the threshold as does the pain perception. A distributed sensor network, often advanced by SHM, can be made fault-tolerant and robust by following the perception way of self-organization and redundancy. Data handling in real life is a huge challenge for large-scale SHM. As sensory data of pain is first cleaned, the threshold is then processed through experiential information gathering and use.

  16. Manipulating the Placebo Response in Experimental Pain by Altering Doctor’s Performance Style

    PubMed Central

    Czerniak, Efrat; Biegon, Anat; Ziv, Amitai; Karnieli-Miller, Orit; Weiser, Mark; Alon, Uri; Citron, Atay

    2016-01-01

    Background: Performance is paramount in traditional healing rituals. From a Western perspective, such performative behavior can be understood principally as inducing patients’ faith in the performer’s supernatural healing powers and effecting positive changes through the same mechanisms attributed to the placebo response, which is defined as improvement of clinical outcome in individuals receiving inactive treatment. Here we examined the possibility of using theatrical performance tools, including stage directions and scripting, to reproducibly manipulate the style and content of a simulated doctor–patient encounter and influence the placebo response in experimental pain. Methods: A total of 122 healthy volunteers (18–45 years, 76 men) exposed to experimental pain (the cold pressor test) were assessed for pain threshold and tolerance before and after receiving a placebo cream from a “doctor” impersonated by a trained actor. The actor alternated between two distinct scripts and stage directions, i.e., performance styles created by a theater director/playwright, one emulating a standard doctor–patient encounter (scenario A) and the other emphasizing attentiveness and strong suggestion, elements also present in ritual healing (scenario B). The placebo response size was calculated as the %difference in pain threshold and tolerance after exposure relative to baseline. In addition, subjects demonstrating a ≥30% increase in pain threshold or tolerance relative to baseline were defined as responders. Each encounter was videotaped in its entirety. Results: Inspection of the videotapes confirmed the reproducibility and consistency of the distinct scenarios enacted by the “doctor”-performer. Furthermore, scenario B resulted in a significant increase in pain threshold relative to scenario A. Interestingly, this increase derived from the placebo responder subgroup; as shown by two-way analysis of variance (performance style, F = 4.30; p = 0.040; η2 = 0

  17. Diffuse noxious inhibitory control evoked by tonic craniofacial pain in humans.

    PubMed

    Sowman, P F; Wang, K; Svensson, P; Arendt-Nielsen, L

    2011-02-01

    Tonic pain in one body segment can inhibit the perception of pain in another body segment. This phenomenon is mediated by diffuse noxious inhibitory controls (DNIC), and its efficacy in craniofacial regions is investigated in this study. A compressive device that evoked a tonic, moderate/severe, headache-like, conditioning pain (∼8/10 on a visual analogue scale) was applied for 15min. Eleven males participated in the study. Pressure pain threshold (PPT) and pressure pain tolerance (PPTol) at multiple heterosegmental body sites (right masseter, splenius capitis, second intermediate phalange, brachioradialis and tibialis anterior) were measured before, during and at multiple time points (5, 20 and 35min) after the termination of the conditioning pain. PPTs and PPTols were compared within participants across two experimental sessions; one that included painful conditioning stimulation, and a separate control session on a different day. Painful conditioning increased PPT significantly during pain over the masseter (p<0.05) and over the tibialis anterior (p<0.01). PPTol was unchanged. In the period after the painful conditioning stimulation PPT was depressed compared to control. This study shows that pain evoked from the craniofacial region evokes DNIC-like mechanisms on segmental as well as heterosegmental sites.

  18. Quality Improvement Project to Improve Patient Satisfaction With Pain Management: Using Human-Centered Design.

    PubMed

    Trail-Mahan, Tracy; Heisler, Scott; Katica, Mary

    2016-01-01

    In this quality improvement project, our health system developed a comprehensive, patient-centered approach to improving inpatient pain management and assessed its impact on patient satisfaction across 21 medical centers. Using human-centered design principles, a bundle of 6 individual and team nursing practices was developed. Patient satisfaction with pain management, as measured by the Hospital Consumer Assessment of Healthcare Providers and Systems pain composite score, increased from the 25th to just under the 75th national percentile.

  19. Concept priming and pain: an experimental approach to understanding gender roles in sex-related pain differences.

    PubMed

    Fowler, Stephanie L; Rasinski, Heather M; Geers, Andrew L; Helfer, Suzanne G; France, Christopher R

    2011-04-01

    Prior research has found that sex differences in pain are partially due to individual variations in gender roles. In a laboratory study, we tested the hypothesis that the presence of covert gender role cues can also moderate the extent to which women and men experience pain. Specifically, we varied gender role cues by asking male and female participants to write about instances in which they behaved in a stereotypically feminine, masculine, or neutral manner. Pain and cardiovascular reactivity to the cold pressor task were then assessed. Results revealed that, when primed with femininity, men reported less pain and anxiety from the cold pressor task than women. However, no differences existed between the sexes in the masculine or neutral prime conditions. The results indicate that covert gender cues can alter pain reports. Further, at least in some situations, feminine role cues may be more influential on pain reports than masculine role cues.

  20. Human shank experimental investigation and computer simulation

    NASA Astrophysics Data System (ADS)

    Krasnoschekov, Viktor V.; Maslov, Leonid B.

    2000-01-01

    A new combined approach to analyze a physiological state of the human shank is developed. Investigated vibration research complex records resonance curve of the shank tissues automatically for different kinds of vibration excitation and for various positions of the foot. A special computer model is implemented for the estimation of the experimental data, for a priori prognosis of the bio-object behavior and its dynamic characteristics in the case of various kinds and of different degrees of injury. The method is described by the viscous-elasticity non-homogeneous 1D continuum equation. It is solved by finite element method. The problem in shank cross-section is solved by boundary element method. The analysis of computer simulated resonance curves makes it possible to understand the experimental data correctly and to check the diagnostic criteria of the injury.

  1. Subcutaneous Botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin.

    PubMed

    Gazerani, Parisa; Pedersen, Natalia Spicina; Staahl, Camilla; Drewes, Asbjørn Mohr; Arendt-Nielsen, Lars

    2009-01-01

    The present human study aimed at investigating the effect of subcutaneous administration of Botulinum toxin type A (BoNT/A) on capsaicin-induced trigeminal pain, neurogenic inflammation and experimentally induced cutaneous pain modalities. Fourteen healthy males (26.3+/-2.6 years) were included in this double-blind and placebo-controlled trial. The subjects received subcutaneous BoNT/A (22.5U) and isotonic saline in the mirror sides of their forehead. Pain and neurogenic inflammation was induced by four intradermal injections of capsaicin (100mug/muL) (before, and days 1, 3 and 7 after treatments). The capsaicin-induced pain intensity, pain area, the area of secondary hyperalgesia, the area of visible flare and vasomotor reactions were recorded together with cutaneous heat, electrical and pressure pain thresholds. BoNT/A reduced the capsaicin-induced trigeminal pain intensity compared to saline (F=37.9, P<0.001). The perceived pain area was smaller for the BoNT/A-treated side compared to saline (F=7.8, P<0.05). BoNT/A reduced the capsaicin-induced secondary hyperalgesia (F=5.3, P<0.05) and flare area (F=10.3, P<0.01) compared to saline. BoNT/A reduced blood flow (F(1,26)=109.5, P<0.001) and skin temperature (F(1,26)=63.1, P<0.001) at the capsaicin injection sites compared to saline and its suppressive effect was maximal at days 3 and 7 (P<0.05, post hoc test). BoNT/A elevated cutaneous heat pain thresholds (F=17.1, P<0.001) compared to saline; however, no alteration was recorded for electrical or pressure pain thresholds (P>0.05). Findings from the present study suggest that BoNT/A appears to preferentially target Cfibers and probably TRPV1-receptors, block neurotransmitter release and subsequently reduce pain, neurogenic inflammation and cutaneous heat pain threshold.

  2. Human Factors Experimental Design and Analysis Reference

    DTIC Science & Technology

    2007-07-01

    and R2Adj – PRESS Statistic – Mallows C(p) A linear regression model that includes all predictors investigated may not be the best model in terms of...as the Adjusted Coefficient of Determination, R2Adj, the PRESS statistic, and Mallows C(p) value. Human Factors Experimental Design and Analysis...equations with highest R2 using R2Adj, PRESS, and Mallows C(p) • Evaluation – Cumbersome as number of X’s increase 10 X’s = (210-1) = 1,023 Regression

  3. Recombinant human growth hormone improves cognitive capacity in a pain patient exposed to chronic opioids.

    PubMed

    Rhodin, A; von Ehren, M; Skottheim, B; Grönbladh, A; Ortiz-Nieto, F; Raininko, R; Gordh, T; Nyberg, F

    2014-07-01

    During recent decades, the increasing use of opioids for chronic non-cancer pain has raised concerns regarding tolerance, addiction, and importantly cognitive dysfunction. Current research suggests that the somatotrophic axis could play an important role in cognitive function. Administration of growth hormone (GH) to GH-deficient humans and experimental animals has been shown to result in significant improvements in cognitive capacity. In this report, a patient with cognitive disabilities resulting from chronic treatment with opioids for neuropathic pain received recombinant human growth hormone (rhGH) replacement therapy. A 61-year-old man presented with severe cognitive dysfunction after long-term methadone treatment for intercostal neuralgia and was diagnosed with GH insufficiency by GH releasing hormone-arginine testing. The effect of rhGH replacement therapy on his cognitive capacity and quality of life was investigated. The hippocampal volume was measured using magnetic resonance imaging, and the ratios of the major metabolites were calculated using proton magnetic resonance spectroscopy. Cognitive testing revealed significant improvements in visuospatial cognitive function after rhGH. The hippocampal volume remained unchanged. In the right hippocampus, the N-acetylaspartate/creatine ratio (reflecting nerve cell function) was initially low but increased significantly during rhGH treatment, as did subjective cognitive, physical and emotional functioning. This case report indicates that rhGH replacement therapy could improve cognitive behaviour and well-being, as well as hippocampal metabolism and functioning in opioid-treated patients with chronic pain. The idea that GH could affect brain function and repair disabilities induced by long-term exposure to opioid analgesia is supported.

  4. Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans.

    PubMed

    Ceko, Marta; Milenkovic, Nevena; le Coutre, Philipp; Westermann, Jörg; Lewin, Gary R

    2014-07-01

    The tyrosine kinase receptor c-Kit is critically involved in the modulation of nociceptive sensitivity in mice. Ablation of the c-Kit gene results in hyposensitivity to thermal pain, whereas activation of c-Kit produces hypersensitivity to noxious heat, without altering sensitivity to innocuous mechanical stimuli. In this study, we investigated the role of c-Kit signaling in human pain perception. We hypothesized that subjects treated with Imatinib or Nilotinib, potent inhibitors of tyrosine kinases including c-Kit but also Abl1, PDFGFRα, and PDFGFRβ, that are used to treat chronic myeloid leukemia (CML), would experience changes in thermal pain sensitivity. We examined 31 asymptomatic CML patients (14 male and 17 female) receiving Imatinib/Nilotinib treatment and compared them to 39 age- and sex-matched healthy controls (12 male and 27 female). We used cutaneous heat and cold stimulation to test normal and noxious thermal sensitivity, and a grating orientation task to assess tactile acuity. Thermal pain thresholds were significantly increased in the Imatinib/Nilotinib-treated group, whereas innocuous thermal and tactile thresholds were unchanged compared to those in the control group. In conclusion, our findings suggest that the biological effects of c-Kit inhibition are comparable in mice and humans in that c-Kit activity is required to regulate thermal pain sensitivity but does not affect innocuous thermal and mechanical sensation. The effect on experimental heat pain observed in our study is comparable to those of several common analgesics; thus modulation of the c-Kit pathway can be used to specifically modulate noxious heat and cold sensitivity in humans.

  5. IL-17 is not essential for inflammation and chronic pelvic pain development in an experimental model of chronic prostatitis/chronic pelvic pain syndrome.

    PubMed

    Motrich, Ruben D; Breser, María L; Sánchez, Leonardo R; Godoy, Gloria J; Prinz, Immo; Rivero, Virginia E

    2016-03-01

    Pain and inflammation in the absence of infection are hallmarks in chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) patients. The etiology of CP/CPPS is unclear, and autoimmunity has been proposed as a cause. Experimental autoimmune prostatitis (EAP) models have long been used for studying CP/CPPS. Herein, we studied prostate inflammation induction and chronic pelvic pain development in EAP using IL-12p40-KO, IL-4-KO, IL-17-KO, and wild-type (C57BL/6) mice. Prostate antigen (PAg) immunization in C57BL/6 mice induced specific Th1 and Th17 immune responses and severe prostate inflammation and cell infiltration, mainly composed of CD4 T cells and macrophages. Moreover, chronic pelvic pain was evidenced by increased allodynia responses. In immunized IL-17-KO mice, the presence of a prominent PAg-specific Th1 immune response caused similar prostate inflammation and chronic pelvic pain. Furthermore, markedly high PAg-specific Th1 immune responses, exacerbated prostate inflammation, and chronic pelvic pain were detected in immunized IL-4-KO mice. Conversely, immunized IL-12p40-KO mice developed PAg-specific Th2 immune responses, characterized by high IL-4 secretion and neither infiltration nor damage in the prostate. As observed in wild-type control animals, IL12p40-KO mice did not evidence tactile allodynia responses. Our results suggest that, as in patients, chronic pelvic pain is a consequence of prostate inflammation. After PAg immunization, a Th1-associated immune response develops and induces prostate inflammation and chronic pelvic pain. The absence of Th1 or Th2 cytokines, respectively, diminishes or enhances EAP susceptibility. In addition, IL-17 showed not to be essential for pathology induction and chronic pelvic pain development.

  6. Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer.

    PubMed

    Cajanus, Kristiina; Holmström, Emil J; Wessman, Maija; Anttila, Verneri; Kaunisto, Mari A; Kalso, Eija

    2016-02-01

    Fatty acid amide hydrolase (FAAH) metabolizes the endocannabinoid anandamide, which has an important role in nociception. We investigated the role of common FAAH single-nucleotide polymorphisms (SNPs) in experimentally induced and postoperative pain. One thousand women undergoing surgery for breast cancer participated in the study. They were tested for cold (n = 900) and heat pain (n = 1000) sensitivity. After surgery, their pain intensities and analgesic consumption were carefully registered. FAAH genotyping was performed using MassARRAY platform and genome-wide chip (n = 926). Association between 8 FAAH SNPs and 9 pain phenotypes was analyzed using linear regression models. The results showed that carrying 2 copies of a missense variant converting proline at position 129 to threonine (rs324420) resulted in significantly lower cold pain sensitivity and less need for postoperative analgesia. More specifically, rs324420 and another highly correlated SNP, rs1571138, associated significantly with cold pain intensity (corrected P value, 0.0014; recessive model). Patients homozygous for the minor allele (AA genotype) were less sensitive to cold pain (β = -1.48; 95% CI, -2.14 to -0.8). Two other SNPs (rs3766246 and rs4660928) showed nominal association with cold pain, and SNPs rs4141964, rs3766246, rs324420, and rs1571138 nominal association with oxycodone consumption. In conclusion, FAAH gene variation was shown to associate with cold pain sensitivity with P129T/rs324420 being the most likely causal variant as it is known to reduce the FAAH enzyme activity. The same variant showed nominal association with postoperative oxycodone consumption. Our conclusions are, however, limited by the lack of replication and the results should be replicated in an independent cohort.

  7. Pharmacological pain control for human immunodeficiency virus—infected adults with a history of drug dependence

    PubMed Central

    Basu, Sanjay; Bruce, R. Douglas; Barry, Declan T.; Altice, Frederick L.

    2007-01-01

    Clinicians treating human immunodeficiency virus (HIV)-infected patients with substance use disorders often face the challenge of managing patients' acute or chronic pain conditions while keeping in mind the potential dangers of prescription opiate dependence. In this clinical review, we critically appraise the existing data concerning barriers to appropriate treatment of pain among HIV-infected patients with substance use disorders. We then analyze published studies concerning the choice of pharmacological pain control regimens for acute and chronic pain conditions in HIV-infected patients, keeping in mind HIV-specific issues related to drug interactions and substance use disorders. We summarize this information in the form of flowcharts for physicians approaching HIV-infected patients who present with complaints of pain, providing evidence-based guidance for the structuring of pain management services and for addressing aberrant drug-taking behaviors. PMID:17481463

  8. Can personality traits and gender predict the response to morphine? An experimental cold pain study.

    PubMed

    Pud, Dorit; Yarnitsky, David; Sprecher, Elliot; Rogowski, Zeev; Adler, Rivka; Eisenberg, Elon

    2006-02-01

    The aim of the present study was to examine the possible role of personality traits, in accordance with Cloninger's theory, and gender, in the variability of responsiveness to opioids. Specifically, it was intended to test whether or not the three personality dimensions - harm avoidance (HA), reward dependence (RD) and novelty seeking (NS) - as suggested by Cloninger, can predict inter-personal differences in responsiveness to morphine after exposure to experimental cold pain. Thirty-four healthy volunteers (15 females, 19 males) were given the cold pressor test (CPT). Pain threshold, tolerance, and magnitude (VAS) were measured before and after (six measures, 30 min apart) the administration of either 0.5 mg/kg oral morphine sulphate (n=21) or 0.33 mg/kg oral active placebo (diphenhydramine) (n=13) in a randomized, double blind design. Assessment of the three personality traits, according to Cloninger's Tridimensional Personality Questionnaire, was performed before the CPT. A high HA score (but not RD, NS, or baseline values of the three pain parameters) predicted a significantly larger pain relief following the administration of morphine sulphate (but not of the placebo). Women exhibited a larger response in response to both treatments, as indicated by a significantly increased threshold and tolerance following morphine sulphate as well as significantly increased tolerance and decreased magnitude following placebo administration. The present study confirms the existence of individual differences in response to analgesic treatment. It suggests that high HA personality trait is associated with better responsiveness to morphine treatment, and that females respond better than men to both morphine and placebo.

  9. Human brain mapping: Experimental and computational approaches

    SciTech Connect

    Wood, C.C.; George, J.S.; Schmidt, D.M.; Aine, C.J.; Sanders, J.; Belliveau, J.

    1998-11-01

    This is the final report of a three-year, Laboratory-Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). This program developed project combined Los Alamos' and collaborators' strengths in noninvasive brain imaging and high performance computing to develop potential contributions to the multi-agency Human Brain Project led by the National Institute of Mental Health. The experimental component of the project emphasized the optimization of spatial and temporal resolution of functional brain imaging by combining: (a) structural MRI measurements of brain anatomy; (b) functional MRI measurements of blood flow and oxygenation; and (c) MEG measurements of time-resolved neuronal population currents. The computational component of the project emphasized development of a high-resolution 3-D volumetric model of the brain based on anatomical MRI, in which structural and functional information from multiple imaging modalities can be integrated into a single computational framework for modeling, visualization, and database representation.

  10. Experimental hypoglycemia is a human model of stress-induced hyperalgesia.

    PubMed

    Gibbons, Christopher H; Adler, Gail K; Bonyhay, Istvan; Freeman, Roy

    2012-11-01

    Hypoglycemia is a physiological stress that leads to the release of stress hormones, such as catecholamines and glucocorticoids, and proinflammatory cytokines. These factors, in euglycemic animal models, are associated with stress-induced hyperalgesia. The primary aim of this study was to determine whether experimental hypoglycemia in humans would lead to a hyperalgesic state. In 2 separate 3-day admissions separated by 1 to 3 months, healthy study participants were exposed to two 2-hour euglycemic hyperinsulinemic clamps or two 2-hour hypoglycemic hyperinsulinemic clamps. Thermal quantitative sensory testing and thermal pain assessments were measured the day before and the day after euglycemia or hypoglycemia. In contrast to prior euglycemia exposure, prior hypoglycemia exposure resulted in enhanced pain sensitivity to hot and cold stimuli as well as enhanced temporal summation to repeated heat-pain stimuli. These findings suggest that prior exposure to hypoglycemia causes a state of enhanced pain sensitivity that is consistent with stress-induced hyperalgesia. This human model may provide a framework for hypothesis testing and targeted, mechanism-based pharmacological interventions to delineate the molecular basis of hyperalgesia and pain susceptibility.

  11. Intrinsic variability in the human response to pain is assembled from multiple, dynamic brain processes.

    PubMed

    Mayhew, Stephen D; Hylands-White, Nicholas; Porcaro, Camillo; Derbyshire, Stuart W G; Bagshaw, Andrew P

    2013-07-15

    The stimulus-evoked response is the principle measure used to elucidate the timing and spatial location of human brain activity. Brain and behavioural responses to pain are influenced by multiple intrinsic and extrinsic factors and display considerable, natural trial-by-trial variability. However, because the neuronal sources of this variability are poorly understood the functional information it contains is under-exploited for understanding the relationship between brain function and behaviour. We recorded simultaneous EEG-fMRI during rest and noxious thermal stimulation to characterise the relationship between natural fluctuations in behavioural pain-ratings, the spatiotemporal dynamics of brain network responses and intrinsic connectivity. We demonstrate that fMRI response variability in the pain network is: dependent upon its resting-state functional connectivity; modulated by behaviour; and correlated with EEG evoked-potential amplitude. The pre-stimulus default-mode network (DMN) fMRI signal predicts the subsequent magnitude of pain ratings, evoked-potentials and pain network BOLD responses. Additionally, the power of the ongoing EEG alpha oscillation, an index of cortical excitability, modulates the DMN fMRI response to pain. The complex interaction between alpha-power, DMN activity and both the behavioural report of pain and the brain's response to pain demonstrates the neurobiological significance of trial-by-trial variability. Furthermore, we show that multiple, interconnected factors contribute to both the brain's response to stimulation and the psychophysiological emergence of the subjective experience of pain.

  12. Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.

    PubMed

    Goldberg, Y P; Pimstone, S N; Namdari, R; Price, N; Cohen, C; Sherrington, R P; Hayden, M R

    2012-10-01

    We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain-of-function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage-dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.

  13. Human embryonic stem cell lines model experimental human cytomegalovirus latency.

    PubMed

    Penkert, Rhiannon R; Kalejta, Robert F

    2013-05-28

    Herpesviruses are highly successful pathogens that persist for the lifetime of their hosts primarily because of their ability to establish and maintain latent infections from which the virus is capable of productively reactivating. Human cytomegalovirus (HCMV), a betaherpesvirus, establishes latency in CD34(+) hematopoietic progenitor cells during natural infections in the body. Experimental infection of CD34(+) cells ex vivo has demonstrated that expression of the viral gene products that drive productive infection is silenced by an intrinsic immune defense mediated by Daxx and histone deacetylases through heterochromatinization of the viral genome during the establishment of latency. Additional mechanistic details about the establishment, let alone maintenance and reactivation, of HCMV latency remain scarce. This is partly due to the technical challenges of CD34(+) cell culture, most notably, the difficulty in preventing spontaneous differentiation that drives reactivation and renders them permissive for productive infection. Here we demonstrate that HCMV can establish, maintain, and reactivate in vitro from experimental latency in cultures of human embryonic stem cells (ESCs), for which spurious differentiation can be prevented or controlled. Furthermore, we show that known molecular aspects of HCMV latency are faithfully recapitulated in these cells. In total, we present ESCs as a novel, tractable model for studies of HCMV latency.

  14. Unraveling dynamics of human physical activity patterns in chronic pain conditions

    NASA Astrophysics Data System (ADS)

    Paraschiv-Ionescu, Anisoara; Buchser, Eric; Aminian, Kamiar

    2013-06-01

    Chronic pain is a complex disabling experience that negatively affects the cognitive, affective and physical functions as well as behavior. Although the interaction between chronic pain and physical functioning is a well-accepted paradigm in clinical research, the understanding of how pain affects individuals' daily life behavior remains a challenging task. Here we develop a methodological framework allowing to objectively document disruptive pain related interferences on real-life physical activity. The results reveal that meaningful information is contained in the temporal dynamics of activity patterns and an analytical model based on the theory of bivariate point processes can be used to describe physical activity behavior. The model parameters capture the dynamic interdependence between periods and events and determine a `signature' of activity pattern. The study is likely to contribute to the clinical understanding of complex pain/disease-related behaviors and establish a unified mathematical framework to quantify the complex dynamics of various human activities.

  15. Preventing Chronic Pain: A Human Systems Approach-Results From a Massive Open Online Course.

    PubMed

    Fricton, James; Anderson, Kathleen; Clavel, Alfred; Fricton, Regina; Hathaway, Kate; Kang, Wenjun; Jaeger, Bernadette; Maixner, William; Pesut, Daniel; Russell, Jon; Weisberg, Mark B; Whitebird, Robin

    2015-09-01

    Chronic pain conditions are the top reason patients seek care, the most common reason for disability and addiction, and the biggest driver of healthcare costs; their treatment costs more than cancer, heart disease, dementia, and diabetes care. The personal impact in terms of suffering, disability, depression, suicide, and other problems is incalculable. There has been much effort to prevent many medical and dental conditions, but little effort has been directed toward preventing chronic pain. To address this deficit, a massive open online course (MOOC) was developed for students and healthcare professionals. "Preventing Chronic Pain: A Human Systems Approach" was offered by the University of Minnesota through the online platform Coursera. The first offering of this free open course was in the spring of 2014 and had 23 650 participants; 53% were patients or consumers interested in pain. This article describes the course concepts in preventing chronic pain, the analytic data from course participants, and postcourse evaluation forms.

  16. Preventing Chronic Pain: A Human Systems Approach—Results From a Massive Open Online Course

    PubMed Central

    Anderson, Kathleen; Clavel, Alfred; Fricton, Regina; Hathaway, Kate; Kang, Wenjun; Jaeger, Bernadette; Maixner, William; Pesut, Daniel; Russell, Jon; Weisberg, Mark B.; Whitebird, Robin

    2015-01-01

    Chronic pain conditions are the top reason patients seek care, the most common reason for disability and addiction, and the biggest driver of healthcare costs; their treatment costs more than cancer, heart disease, dementia, and diabetes care. The personal impact in terms of suffering, disability, depression, suicide, and other problems is incalculable. There has been much effort to prevent many medical and dental conditions, but little effort has been directed toward preventing chronic pain. To address this deficit, a massive open online course (MOOC) was developed for students and healthcare professionals. “Preventing Chronic Pain: A Human Systems Approach” was offered by the University of Minnesota through the online platform Coursera. The first offering of this free open course was in the spring of 2014 and had 23 650 participants; 53% were patients or consumers interested in pain. This article describes the course concepts in preventing chronic pain, the analytic data from course participants, and postcourse evaluation forms. PMID:26421231

  17. Modality-specific facilitation and adaptation to painful tonic stimulation in humans.

    PubMed

    Polianskis, Romanas; Graven-Nielsen, Thomas; Arendt-Nielsen, Lars

    2002-01-01

    The study assessed the influence of stimulus modality on adaptation or facilitation of pain during tonic cold and tourniquet pressure stimulation. Experimental set-up for the cold stimulation consisted of a thermo-tank with water, cooled to 3 degrees C, circulation pump, electronic thermometer and an electronic 10 cm visual analogue scale (VAS). Experimental set-up for the tonic pressure stimulation consisted of a pneumatic tourniquet cuff, a computer-controlled air compressor, and an electronic VAS. The first experiment assessed temporal profiles of pain intensity and skin temperature during immersion of the non-dominant hand and lower arm into cold water for 3 min or until the pain tolerance limit was reached. The second experiment assessed temporal profile of cuff pain intensity during constant compressions for 10 min beginning at pain intensities of 2, 4, and 6 cm on the VAS ("VAS 2", "VAS 4" and "VAS 6" sessions). Subjects enduring cold stimulation for less than 3 min were defined as non-adapting to cold and vice versa. The intensity of cold pain in non-adapting subjects increased significantly faster than in adapting subjects and reached significantly higher magnitude. The course of pain intensity during constant compression, estimated by a linear regression line, was increasing or decreasing, representing facilitation or adaptation of pain, respectively. The typical profile of adaptation consisted of an "overshoot" in pain intensity, followed by a decrease in pain intensity. There was significant correlation in VAS slopes between sessions separated by 2-5 days, suggesting consistent pattern in pain responses to tonic pressure stimulation. Adaptation or facilitation rates and the overshoot magnitude were dependent on the initial pain intensity (2, 4, or 6 cm on the VAS). The facilitation rate was highest and the adaptation rate was lowest during the "VAS 2" session, while the facilitation rate was lowest and the adaptation rate was highest during the "VAS 6

  18. Voluntary and reflex control of human back muscles during induced pain

    PubMed Central

    Zedka, Milan; Prochazka, Arthur; Knight, Brian; Gillard, Debby; Gauthier, Michel

    1999-01-01

    inhibition exists between the right and left human ES. It is concluded that deep back pain does not influence the stretch reflexes in the back muscles but modulates the voluntary activation of these muscles. PMID:10523425

  19. The acquisition of fear of movement-related pain and associative learning: a novel pain-relevant human fear conditioning paradigm.

    PubMed

    Meulders, Ann; Vansteenwegen, Debora; Vlaeyen, Johan W S

    2011-11-01

    Current fear-avoidance models consider fear of pain as a key factor in the development of chronic musculoskeletal pain. Generally, the idea is that by virtue of the formation of associations or acquired propositional knowledge about the relation between neutral movements and pain, these movements may signal pain, and hence start to elicit defensive fear responses (eg, avoidance behavior). This assumption has never been investigated experimentally. Therefore, we developed a pain-relevant fear conditioning paradigm using a movement as a conditioned stimulus (CS) and a painful electrocutaneous stimulus as an unconditioned stimulus (US) to examine the acquisition of fear of movement-related pain in healthy subjects. In a within-subjects design, participants manipulated a joystick to the left/right in the experimental (predictable) condition, and upward/downward in the control (unpredictable) condition or vice versa. In the predictable condition, one movement direction (CS+), and not the other (CS-), was followed by painful stimuli. In the unpredictable condition, painful stimuli were always delivered during the intertrial interval. Both fear of movement-related pain ratings and eyeblink startle measures were more elevated in response to the CS+ than to the CS-, whereas no differences occurred between both unreinforced CSs in the control condition. Participants were slower initiating a CS+ movement than a CS- movement, while response latencies to CSs in the control condition did not differ. These data support the acquisition of fear of movement-related pain by associative learning. Results are discussed in the broader context of the acquisition of pain-related fear in patients with musculoskeletal pain.

  20. Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human

    PubMed Central

    Dahl, Jørgen B.; Werner, Marianne; Taylor, Bradley K.; Werner, Mads U.

    2015-01-01

    Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3–10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain. Trial Registration EudraCT 2012-005663-27 PMID:26305798

  1. Effect of experimental low back pain on neuromuscular control of the trunk in healthy volunteers and patients with chronic low back pain.

    PubMed

    Dubois, Jean-Daniel; Piché, Mathieu; Cantin, Vincent; Descarreaux, Martin

    2011-10-01

    Studies of electromyographic (EMG) activity and lumbopelvic rhythm have led to a better understanding of neuromuscular alterations in chronic low back pain (cLBP) patients. Whether these changes reflect adaptations to chronic pain or are induced by acute pain is still unclear. This work aimed to assess the effects of experimental LBP on lumbar erector spinae (LES) EMG activity and lumbopelvic kinematics during a trunk flexion-extension task in healthy volunteers and LBP patients. The contribution of disability to these effects was also examined. Twelve healthy participants and 14 cLBP patients performed flexion-extension tasks in three conditions; control, innocuous heat and noxious heat, applied on the skin over L5 or T7. The results indicated that noxious heat at L5 evoked specific increases in LES activity during static full trunk flexion and extension, irrespective of participants' group. Kinematic data suggested that LBP patients adopted a different movement strategy than controls when noxious heat was applied at the L5 level. Besides, high disability was associated with less kinematic changes when approaching and leaving full flexion. These results indicate that experimental pain can induce neuromechanical alterations in cLBP patients and healthy volunteers, and that higher disability in patients is associated with decreased movement pattern changes.

  2. Changes in sensory hand representation and pain thresholds induced by motor cortex stimulation in humans.

    PubMed

    Houzé, Bérengère; Bradley, Claire; Magnin, Michel; Garcia-Larrea, Luis

    2013-11-01

    Shrinking of deafferented somatosensory regions after neural damage is thought to participate to the emergence of neuropathic pain, and pain-relieving procedures have been reported to induce the normalization of altered cortical maps. While repetitive magnetic stimulation (rTMS) of the motor cortex can lessen neuropathic pain, no evidence has been provided that this is concomitant to changes in sensory maps. Here, we assessed in healthy volunteers the ability of 2 modes of motor cortex rTMS commonly used in pain patients to induce changes in pain thresholds and plastic phenomena in the S1 cortex. Twenty minutes of high-frequency (20 Hz) rTMS significantly increased pain thresholds in the contralateral hand, and this was associated with the expansion of the cortical representation of the hand on high-density electroencephalogram source analysis. Neither of these effects were observed after sham rTMS, nor following intermittent theta-burst stimulation (iTBS). The superiority of 20-Hz rTMS over iTBS to induce sensory plasticity may reflect its better match with intrinsic cortical motor frequencies, which oscillate at around 20 Hz. rTMS-induced changes might partly counterbalance the plasticity induced by a nerve lesion, and thus substantiate the use of rTMS to treat human pain. However, a mechanistic relation between S1 plasticity and pain-relieving effects is far from being established.

  3. Experimentally induced masseter-pain changes masseter but not sternocleidomastoid muscle-related activity during mastication.

    PubMed

    Pasinato, Fernanda; Santos-Couto-Paz, Clarissa C; Zeredo, Jorge Luis Lopes; Macedo, Sergio Bruzadelli; Corrêa, Eliane C R

    2016-12-01

    The aim of this study was to verify the effects of induced masseter-muscle pain on the amplitude of muscle activation, symmetry and coactivation of jaw- and neck-muscles during mastication. Twenty-eight male volunteers, mean age±SD 20.6±2.0years, participated in this study. Surface electromyography of the masseter and sternocleidomastoid (SCM) muscles was performed bilaterally during mastication of a gummy candy before and after injections of monosodium glutamate solution and isotonic saline solution. As a result, we observed a decrease in the amplitude of activation of the masseter muscle on the working side (p=0.009; d=0.34) and a reduction in the asymmetry between the working and the balancing side during mastication (p=0.007; d=0.38). No changes were observed either on the craniocervical electromyographic variables. In conclusion, experimentally induced pain reduced the masseter muscle activation on the working side, thereby reducing the physiological masseters' recruitment asymmetry between the two sides during mastication. No effects on SCM activity were detected. These results may partly explain the initial maladaptative changes underlying TMD conditions.

  4. HDAC inhibitors restore C-fibre sensitivity in experimental neuropathic pain model

    PubMed Central

    Matsushita, Yosuke; Araki, Kohei; Omotuyi, Olaposi idowu; Mukae, Takehiro; Ueda, Hiroshi

    2013-01-01

    Background and Purpose Hypoesthesia is a clinical feature of neuropathic pain. The feature is partly explained by the evidence of epigenetic repression of Nav1.8 sodium channel in the dorsal root ganglion (DRG). Experimental Approach We investigated the possibility of trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to reverse the unique C-fibre sensitivity observed following partial ligation of sciatic nerve in mice. Key Results Nerve injury-induced down-regulation of DRG Nav1.8 sodium channel and C-fibre-related hypoesthesia were reversed by TSA, VPA and SAHA treatments, which inhibit histone deacetylase (HDAC), and increase histone acetylation at the regulatory sequence of Nav1.8. Conclusions and Implications Taken together, these studies provide the evidence that hypoesthesia and underlying down-regulation of Nav1.8, negative symptoms observed in nerve injury-induced neuropathic pain models are regulated by an epigenetic chromatin remodelling through HDAC-related machineries. PMID:24032674

  5. Pain-Related Brain Activity Evoked by Active and Dynamic Arm Movement: Delayed-Onset Muscle Soreness as a Promising Model for Studying Movement-Related Pain in Humans

    PubMed Central

    Matsuda, Yoichi; Kan, Shigeyuki; Uematsu, Hironobu; Shibata, Masahiko; Fujino, Yuji

    2015-01-01

    Objective To demonstrate delayed-onset muscle soreness (DOMS) is a suitable model for the study of movement-evoked pain, we attempted to identify brain regions specifically involved in pain evoked by active and dynamic movement under DOMS condition. Subject Twelve healthy volunteers Methods DOMS was induced in the left upper-arm flexor muscles by an eccentric elbow contraction exercise. Movement-evoked pain in the affected muscles was evaluated just before (day 0) and after (days 1–7 and 30) the exercise using a visual analog scale. Subjects underwent functional magnetic resonance imaging scans while performing repeated elbow flexion on day 2 (DOMS condition) and day 30 (painless condition). We compared brain activity between the DOMS and painless conditions. Results Movement-evoked pain reached peak intensity on day 2 and disappeared by day 30 in all subjects. No subject felt pain at rest on either of these days. Contralateral primary motor cortex (M1), parietal operculum and bilateral presupplementary motor area (pre-SMA) showed greater activity during active and dynamic arm movement with DOMS than during the same movement without pain. There was no difference in activation of brain regions known collectively as the “pain matrix,” except for the parietal operculum, between the two conditions. Conclusion Active and dynamic movement with pain selectively evoked activation of M1, pre-SMA, and parietal operculum, as assessed using DOMS. Our results demonstrate that DOMS is a promising experimental model for the study of movement-evoked pain in humans. PMID:25929675

  6. The flaws and human harms of animal experimentation.

    PubMed

    Akhtar, Aysha

    2015-10-01

    Nonhuman animal ("animal") experimentation is typically defended by arguments that it is reliable, that animals provide sufficiently good models of human biology and diseases to yield relevant information, and that, consequently, its use provides major human health benefits. I demonstrate that a growing body of scientific literature critically assessing the validity of animal experimentation generally (and animal modeling specifically) raises important concerns about its reliability and predictive value for human outcomes and for understanding human physiology. The unreliability of animal experimentation across a wide range of areas undermines scientific arguments in favor of the practice. Additionally, I show how animal experimentation often significantly harms humans through misleading safety studies, potential abandonment of effective therapeutics, and direction of resources away from more effective testing methods. The resulting evidence suggests that the collective harms and costs to humans from animal experimentation outweigh potential benefits and that resources would be better invested in developing human-based testing methods.

  7. An experimental characterization of human torso motion

    NASA Astrophysics Data System (ADS)

    Cafolla, Daniele; Chen, I.-Ming; Ceccarelli, Marco

    2015-12-01

    The torso plays an important role in the human-like operation of humanoids. In this paper, a method is proposed to analyze the behavior of the human torso by using inertial and magnetic sensing tools. Experiments are conducted to characterize the motion performance of the human torso during daily routine operations. Furthermore, the forces acting on the human body during these operations are evaluated to design and validate the performance of a humanoid robot.

  8. Effects of human contact and vagal regulation on pain reactivity and visual attention in newborns.

    PubMed

    Arditi, Hadar; Feldman, Ruth; Eidelman, Arthur I

    2006-11-01

    In two experiments we examined the effects of human contact and vagal regulation on newborns' pain reactivity and visual attention. Baseline cardiac vagal tone was measured during quiet sleep and during the experiment, and vagal withdrawal was indexed as change in vagal tone from baseline to pain (study 1) or attention (study 2). In study 1, 62 healthy newborns were videotaped during a heel-prick procedure and pain reactivity was assessed from micro-level coding of facial expressions, cry behavior, and body movements. Infants were randomly assigned to a contact condition, held by a female assistant, or a no contact condition, on an infant-seat in a similar angle. In study 2, 62 additional healthy newborns, randomly assigned to contact and noncontact conditions, were presented with 2 visual stimuli for a 60 s familiarization period, which were then paired with a novel stimulus. Visual interest, alertness, and novelty preference were coded. Human contact had no effect on the newborns' pain response. Visual attention increased with human contact and newborns in the contact condition looked at the stimuli more frequently, with higher alertness, for longer durations, and had a higher novelty preference. Autonomic reactivity-as indexed by vagal withdrawal-differentiated newborns with intense and mild pain response. Discussion focused on proximity to conspecifics as a contributor to emerging regulatory and adaptive functioning in the human infant.

  9. Experimental muscle pain increases variability of neural drive to muscle and decreases motor unit coherence in tremor frequency band

    PubMed Central

    Yavuz, Utku Ş.; Negro, Francesco; Falla, Deborah

    2015-01-01

    It has been observed that muscle pain influences force variability and low-frequency (<3 Hz) oscillations in the neural drive to muscle. In this study, we aimed to investigate the effect of experimental muscle pain on the neural control of muscle force at higher frequency bands, associated with afferent feedback (alpha band, 5–13 Hz) and with descending cortical input (beta band, 15–30 Hz). Single-motor unit activity was recorded, in two separate experimental sessions, from the abductor digiti minimi (ADM) and tibialis anterior (TA) muscles with intramuscular wire electrodes, during isometric abductions of the fifth finger at 10% of maximal force [maximum voluntary contraction (MVC)] and ankle dorsiflexions at 25% MVC. The contractions were repeated under three conditions: no pain (baseline) and after intramuscular injection of isotonic (0.9%, control) and hypertonic (5.8%, painful) saline. The results showed an increase of the relative power of both the force signal and the neural drive at the tremor frequency band (alpha, 5–13 Hz) between the baseline and hypertonic (painful) conditions for both muscles (P < 0.05) but no effect on the beta band. Additionally, the strength of motor unit coherence was lower (P < 0.05) in the hypertonic condition in the alpha band for both muscles and in the beta band for the ADM. These results indicate that experimental muscle pain increases the amplitude of the tremor oscillations because of an increased variability of the neural control (common synaptic input) in the tremor band. Moreover, the concomitant decrease in coherence suggests an increase in independent input in the tremor band due to pain. PMID:26019314

  10. Reduced habituation to experimental pain in migraine patients: a CO(2) laser evoked potential study.

    PubMed

    Valeriani, M; de Tommaso, M; Restuccia, D; Le Pera, D; Guido, M; Iannetti, G D; Libro, G; Truini, A; Di Trapani, G; Puca, F; Tonali, P; Cruccu, G

    2003-09-01

    The habituation to sensory stimuli of different modalities is reduced in migraine patients. However, the habituation to pain has never been evaluated. Our aim was to assess the nociceptive pathway function and the habituation to experimental pain in patients with migraine. Scalp potentials were evoked by CO(2) laser stimulation (laser evoked potentials, LEPs) of the hand and facial skin in 24 patients with migraine without aura (MO), 19 patients with chronic tension-type headache (CTTH), and 28 control subjects (CS). The habituation was studied by measuring the changes of LEP amplitudes across three consecutive repetitions of 30 trials each (the repetitions lasted 5 min and were separated by 5-min intervals). The slope of the regression line between LEP amplitude and number of repetitions was taken as an index of habituation. The LEPs consisted of middle-latency, low-amplitude responses (N1, contralateral temporal region, and P1, frontal region) followed by a late, high-amplitude, negative-positive complex (N2/P2, vertex). The latency and amplitude of these responses were similar in both patients and controls. While CS and CTTH patients showed a significant habituation of the N2/P2 response, in MO patients this LEP component did not develop any habituation at all after face stimulation and showed a significantly lower habituation than in CS after hand stimulation. The habituation index of the vertex N2/P2 complex exceeded the normal limits in 13 out of the 24 MO patients and in none of the 19 CTTH patients (P<0.0001; Fisher's exact test). Moreover, while the N1-P1 amplitude showed a significant habituation in CS after hand stimulation, it did not change across repetitions in MO patients. In conclusion, no functional impairment of the nociceptive pathways, including the trigeminal pathways, was found in either MO or CTTH patients. But patients with migraine had a reduced habituation, which probably reflects an abnormal excitability of the cortical areas involved in

  11. Chenopodium ambrosioides L. Reduces Synovial Inflammation and Pain in Experimental Osteoarthritis

    PubMed Central

    Calado, Gustavo P.; Lopes, Alberto Jorge O.; Costa Junior, Livio M.; Lima, Francisco das Chagas A.; Silva, Lucilene A.; Pereira, Wanderson S.; do Amaral, Flávia M. M.; Garcia, João Batista S.; Cartágenes, Maria do Socorro de S.; Nascimento, Flávia R. F.

    2015-01-01

    The chronicity of osteoarthritis (OA), characterized by pain and inflammation in the joints, is linked to a glutamate receptor, N-methyl-D-aspartate (NMDA). The use of plant species such as Chenopodium ambrosioides L. (Amaranthaceae) as NMDA antagonists offers a promising perspective. This work aims to analyze the antinociceptive and anti-inflammatory responses of the crude hydroalcoholic extract (HCE) of C. ambrosioides leaves in an experimental OA model. Wistar rats were separated into six groups (n = 24): clean (C), negative control (CTL-), positive control (CTL+), HCE0.5, HCE5 and HCE50. The first group received no intervention. The other groups received an intra-articular injection of sodium monoiodoacetate (MIA) (8 mg/kg) on day 0. After six hours, they were orally treated with saline, Maxicam plus (meloxicam + chondroitin sulfate) and HCE at doses of 0.5 mg/kg, 5 mg/kg and 50 mg/kg, respectively. After three, seven and ten days, clinical evaluations were performed (knee diameter, mechanical allodynia, mechanical hyperalgesia and motor activity). On the tenth day, after euthanasia, synovial fluid and draining lymph node were collected for cellular quantification, and cartilage was collected for histopathological analysis. Finally, molecular docking was performed to evaluate the compatibility of ascaridole, a monoterpene found in HCE, with the NMDA receptor. After the third day, HCE reduced knee edema. HCE5 showed less cellular infiltrate in the cartilage and synovium and lower intensities of allodynia from the third day and of hyperalgesia from the seventh day up to the last treatment day. The HCE5 and HCE50 groups improved in forced walking. In relation to molecular docking, ascaridole showed NMDA receptor binding affinity. C. ambrosioides HCE was effective in the treatment of OA because it reduced synovial inflammation and behavioral changes due to pain. This effect may be related to the antagonistic effect of ascaridole on the NMDA receptor. PMID:26524084

  12. Chenopodium ambrosioides L. Reduces Synovial Inflammation and Pain in Experimental Osteoarthritis.

    PubMed

    Calado, Gustavo P; Lopes, Alberto Jorge O; Costa Junior, Livio M; Lima, Francisco das Chagas A; Silva, Lucilene A; Pereira, Wanderson S; Amaral, Flávia M M do; Garcia, João Batista S; Cartágenes, Maria do Socorro de S; Nascimento, Flávia R F

    2015-01-01

    The chronicity of osteoarthritis (OA), characterized by pain and inflammation in the joints, is linked to a glutamate receptor, N-methyl-D-aspartate (NMDA). The use of plant species such as Chenopodium ambrosioides L. (Amaranthaceae) as NMDA antagonists offers a promising perspective. This work aims to analyze the antinociceptive and anti-inflammatory responses of the crude hydroalcoholic extract (HCE) of C. ambrosioides leaves in an experimental OA model. Wistar rats were separated into six groups (n = 24): clean (C), negative control (CTL-), positive control (CTL+), HCE0.5, HCE5 and HCE50. The first group received no intervention. The other groups received an intra-articular injection of sodium monoiodoacetate (MIA) (8 mg/kg) on day 0. After six hours, they were orally treated with saline, Maxicam plus (meloxicam + chondroitin sulfate) and HCE at doses of 0.5 mg/kg, 5 mg/kg and 50 mg/kg, respectively. After three, seven and ten days, clinical evaluations were performed (knee diameter, mechanical allodynia, mechanical hyperalgesia and motor activity). On the tenth day, after euthanasia, synovial fluid and draining lymph node were collected for cellular quantification, and cartilage was collected for histopathological analysis. Finally, molecular docking was performed to evaluate the compatibility of ascaridole, a monoterpene found in HCE, with the NMDA receptor. After the third day, HCE reduced knee edema. HCE5 showed less cellular infiltrate in the cartilage and synovium and lower intensities of allodynia from the third day and of hyperalgesia from the seventh day up to the last treatment day. The HCE5 and HCE50 groups improved in forced walking. In relation to molecular docking, ascaridole showed NMDA receptor binding affinity. C. ambrosioides HCE was effective in the treatment of OA because it reduced synovial inflammation and behavioral changes due to pain. This effect may be related to the antagonistic effect of ascaridole on the NMDA receptor.

  13. Effectiveness of Self-Hypnosis on the Relief of Experimental Dental Pain: A Randomized Trial.

    PubMed

    Wolf, Thomas Gerhard; Wolf, Dominik; Below, Dagna; d'Hoedt, Bernd; Willershausen, Brita; Daubländer, Monika

    2016-01-01

    This randomized, controlled clinical trial evaluates the effectiveness of self-hypnosis on pain perception. Pain thresholds were measured, and a targeted, standardized pain stimulus was created by electrical stimulation of the dental pulp of an upper anterior tooth. Pain stimulus was rated by a visual analogue scale (VAS). The pain threshold under self-hypnosis was higher (57.1 ± 17.1) than without hypnotic intervention (39.5 ± 11.8) (p < .001). Pain was rated lower on the VAS with self-hypnosis (4.0 ± 3.8) than in the basal condition without self-hypnosis (7.1 ± 2.7) (p < .001). Self-hypnosis can be used in clinical practice as an adjunct to the gold standard of local anesthesia for pain management, as well as an alternative in individual cases.

  14. The effect of Reiki on pain and anxiety in women with abdominal hysterectomies: a quasi-experimental pilot study.

    PubMed

    Vitale, Anne T; O'Connor, Priscilla C

    2006-01-01

    The purpose of this pilot study was to compare reports of pain and levels of state anxiety in 2 groups of women after abdominal hysterectomy. A quasi-experimental design was used in which the experimental group (n = 10) received traditional nursing care plus three 30-minute sessions of Reiki, while the control group (n = 12) received traditional nursing care. The results indicated that the experimental group reported less pain and requested fewer analgesics than the control group. Also, the experimental group reported less state anxiety than the control group on discharge at 72 hours postoperation. The authors recommend replication of this study with a similar population, such as women who require nonemergency cesarian section deliveries.

  15. A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development.

    PubMed

    Nahorski, Michael S; Al-Gazali, Lihadh; Hertecant, Jozef; Owen, David J; Borner, Georg H H; Chen, Ya-Chun; Benn, Caroline L; Carvalho, Ofélia P; Shaikh, Samiha S; Phelan, Anne; Robinson, Margaret S; Royle, Stephen J; Woods, C Geoffrey

    2015-08-01

    Congenital inability to feel pain is very rare but the identification of causative genes has yielded significant insights into pain pathways and also novel targets for pain treatment. We report a novel recessive disorder characterized by congenital insensitivity to pain, inability to feel touch, and cognitive delay. Affected individuals harboured a homozygous missense mutation in CLTCL1 encoding the CHC22 clathrin heavy chain, p.E330K, which we demonstrate to have a functional effect on the protein. We found that CLTCL1 is significantly upregulated in the developing human brain, displaying an expression pattern suggestive of an early neurodevelopmental role. Guided by the disease phenotype, we investigated the role of CHC22 in two human neural crest differentiation systems; human induced pluripotent stem cell-derived nociceptors and TRKB-dependant SH-SY5Y cells. In both there was a significant downregulation of CHC22 upon the onset of neural differentiation. Furthermore, knockdown of CHC22 induced neurite outgrowth in neural precursor cells, which was rescued by stable overexpression of small interfering RNA-resistant CHC22, but not by mutant CHC22. Similarly, overexpression of wild-type, but not mutant, CHC22 blocked neurite outgrowth in cells treated with retinoic acid. These results reveal an essential and non-redundant role for CHC22 in neural crest development and in the genesis of pain and touch sensing neurons.

  16. Brain Network Response to Acupuncture Stimuli in Experimental Acute Low Back Pain: An fMRI Study.

    PubMed

    Shi, Yu; Liu, Ziping; Zhang, Shanshan; Li, Qiang; Guo, Shigui; Yang, Jiangming; Wu, Wen

    2015-01-01

    Most neuroimaging studies have demonstrated that acupuncture can significantly modulate brain activation patterns in healthy subjects, while only a few studies have examined clinical pain. In the current study, we combined an experimental acute low back pain (ALBP) model and functional magnetic resonance imaging (fMRI) to explore the neural mechanisms of acupuncture analgesia. All ALBP subjects first underwent two resting state fMRI scans at baseline and during a painful episode and then underwent two additional fMRI scans, once during acupuncture stimulation (ACUP) and once during tactile stimulation (SHAM) pseudorandomly, at the BL40 acupoint. Our results showed that, compared with the baseline, the pain state had higher regional homogeneity (ReHo) values in the pain matrix, limbic system, and default mode network (DMN) and lower ReHo values in frontal gyrus and temporal gyrus; compared with the OFF status, ACUP yielded broad deactivation in subjects, including nearly all of the limbic system, pain status, and DMN, and also evoked numerous activations in the attentional and somatosensory systems; compared with SHAM, we found that ACUP induced more deactivations and fewer activations in the subjects. Multiple brain networks play crucial roles in acupuncture analgesia, suggesting that ACUP exceeds a somatosensory-guided mind-body therapy for ALBP.

  17. Botulinum toxin A does not alter capsaicin-induced pain perception in human skin.

    PubMed

    Schulte-Mattler, Wilhelm J; Opatz, Oliver; Blersch, Wendelin; May, Arne; Bigalke, Hans; Wohlfahrt, Kai

    2007-09-15

    A genuine peripheral antinociceptive and anti-inflammatory effect of Botulinum neurotoxin type A (BoNT/A) has been proposed but could not be demonstrated in humans so far. Therefore, 100 mouse units of Botulinum toxin A (Dysport) and placebo were injected in a double blind paradigm in defined skin areas of 50 subjects. At baseline and after 4 and 8 weeks allodynia was induced in the skin areas with capsaicin ointment. Heat and cold pain threshold temperatures were measured with quantitative sensory testing, and threshold intensities upon electrical stimulation with a pain specific surface electrode were determined. No BoNT/A related differences in pain perception were found at any quality. There is neither a direct peripheral antinociceptive effect nor a significant effect against neurogenic inflammation of BoNT/A in humans.

  18. High- and low-frequency transcutaneous electrical nerve stimulation does not reduce experimental pain in elderly individuals

    PubMed Central

    Bergeron-Vézina, Kayla; Corriveau, Hélène; Martel, Marylie; Harvey, Marie-Philippe; Léonard, Guillaume

    2015-01-01

    Abstract Despite its widespread clinical use, the efficacy of transcutaneous electrical nerve stimulation (TENS) remains poorly documented in elderly individuals. In this randomized, double-blind crossover study, we compared the efficacy of high-frequency (HF), low-frequency (LF), and placebo (P) TENS in a group of 15 elderly adults (mean age: 67 ± 5 years). The effect of HF-, LF-, and P-TENS was also evaluated in a group of 15 young individuals (26 ± 5 years; same study design) to validate the effectiveness of the TENS protocols that were used in the elderly group. Each participant came to the laboratory on 3 separate occasions to receive, in random order, HF-, LF-, and P-TENS. Pain intensity and pain perception thresholds were assessed before, during, and after TENS, using an experimental heat pain paradigm. For the young group, there was a significant decrease in pain intensity during and after HF- and LF-TENS when compared with baseline, with both HF- and LF-TENS being superior to P-TENS. In the older group, HF- and LF-TENS did not reduce pain when compared with baseline and no difference was observed between the 2 active TENS sessions and P-TENS. High-frequency, LF-, and P-TENS all increased pain thresholds in young individuals, whereas in older individuals, only LF-TENS increased pain thresholds. Taken together, these results suggest that TENS is effective in young, but not in older, individuals. Future studies should be conducted to confirm these results in pain populations and to identify strategies that could enhance the effect of TENS in the elderly. PMID:26101836

  19. High- and low-frequency transcutaneous electrical nerve stimulation does not reduce experimental pain in elderly individuals.

    PubMed

    Bergeron-Vézina, Kayla; Corriveau, Hélène; Martel, Marylie; Harvey, Marie-Philippe; Léonard, Guillaume

    2015-10-01

    Despite its widespread clinical use, the efficacy of transcutaneous electrical nerve stimulation (TENS) remains poorly documented in elderly individuals. In this randomized, double-blind crossover study, we compared the efficacy of high-frequency (HF), low-frequency (LF), and placebo (P) TENS in a group of 15 elderly adults (mean age: 67 ± 5 years). The effect of HF-, LF-, and P-TENS was also evaluated in a group of 15 young individuals (26 ± 5 years; same study design) to validate the effectiveness of the TENS protocols that were used in the elderly group. Each participant came to the laboratory on 3 separate occasions to receive, in random order, HF-, LF-, and P-TENS. Pain intensity and pain perception thresholds were assessed before, during, and after TENS, using an experimental heat pain paradigm. For the young group, there was a significant decrease in pain intensity during and after HF- and LF-TENS when compared with baseline, with both HF- and LF-TENS being superior to P-TENS. In the older group, HF- and LF-TENS did not reduce pain when compared with baseline and no difference was observed between the 2 active TENS sessions and P-TENS. High-frequency, LF-, and P-TENS all increased pain thresholds in young individuals, whereas in older individuals, only LF-TENS increased pain thresholds. Taken together, these results suggest that TENS is effective in young, but not in older, individuals. Future studies should be conducted to confirm these results in pain populations and to identify strategies that could enhance the effect of TENS in the elderly.

  20. TOLUENE EXPERIMENTAL EXPOSURES IN HUMANS: PHARMACOKINETICS AND BEHAVIOR

    EPA Science Inventory

    Toluene Experimental Exposures in Humans:
    Pharmacokinetics and Behavioral Effects
    (Ongoing Research)

    Vernon A. Benignus1, Philip J. Bushnell2 and William K. Boyes2

    Human subjects will be exposed to 250 and 500 ppm toluene for one hour in the Human St...

  1. Effect of Experimental Hand Pain on Training-Induced Changes in Motor Performance and Corticospinal Excitability

    PubMed Central

    Mavromatis, Nicolas; Neige, Cécilia; Gagné, Martin; Reilly, Karen T.; Mercier, Catherine

    2017-01-01

    Pain influences plasticity within the sensorimotor system and the aim of this study was to assess the effect of pain on changes in motor performance and corticospinal excitability during training for a novel motor task. A total of 30 subjects were allocated to one of two groups (Pain, NoPain) and performed ten training blocks of a visually-guided isometric pinch task. Each block consisted of 15 force sequences, and subjects modulated the force applied to a transducer in order to reach one of five target forces. Pain was induced by applying capsaicin cream to the thumb. Motor performance was assessed by a skill index that measured shifts in the speed–accuracy trade-off function. Neurophysiological measures were taken from the first dorsal interosseous using transcranial magnetic stimulation. Overall, the Pain group performed better throughout the training (p = 0.03), but both groups showed similar improvements across training blocks (p < 0.001), and there was no significant interaction. Corticospinal excitability in the NoPain group increased halfway through the training, but this was not observed in the Pain group (Time × Group interaction; p = 0.01). These results suggest that, even when pain does not negatively impact on the acquisition of a novel motor task, it can affect training-related changes in corticospinal excitability. PMID:28165363

  2. Botulinum toxin type A reduces capsaicin-evoked pain and neurogenic vasodilatation in human skin.

    PubMed

    Tugnoli, Valeria; Capone, Jay Guido; Eleopra, Roberto; Quatrale, Rocco; Sensi, Mariachiara; Gastaldo, Ernesto; Tola, Maria Rosaria; Geppetti, Pierangelo

    2007-07-01

    The effect of Botulinum Toxin type A (BoNT/A) on pain and neurogenic vasodilatation induced by application to the human skin of thermal stimuli and capsaicin was evaluated in a double blind study. A capsaicin cream (0.5 ml of a 0.075%) was applied to the skin of both forearms of eighteen subjects randomly pretreated with either BoNT/A (Botox) or 0.9% saline (NS). Capsaicin was applied to a skin area either inside (protocol A) or adjacent to the BoNT/A treated area (protocol B). Pre-treatment with BoNT/A did not affect thermal-specific and thermal-pain thresholds (by quantitative sensory testing). However, capsaicin-induced pain sensation (by a visual analogue scale), flare area (by acetate sheet) and changes in cutaneous blood flow (CBF, by laser Doppler flowmetry) were reduced when capsaicin was administered inside (protocol A) the BoNT/A treated area. In Protocol B, capsaicin-induced pain was unchanged, and capsaicin-induced flare/increase in CBF were reduced only in the area treated with BoNT/A, but not in the BoNT/A untreated area. Results indicate that (i) BoNT/A reduces capsaicin-induced pain and neurogenic vasodilatation without affecting the transmission of thermal and thermal-pain modalities; (ii) reduction in capsaicin-induced pain occurs only if capsaicin is administered into the BoNT/A pretreated area; (iii) reduction in neurogenic vasodilatation by BoNT/A does not contribute to its analgesic action. BoNT/A could be tested for the treatment of conditions characterised by neurogenic inflammation and inflammatory pain.

  3. Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain.

    PubMed

    Gingras, Jacinthe; Smith, Sarah; Matson, David J; Johnson, Danielle; Nye, Kim; Couture, Lauren; Feric, Elma; Yin, Ruoyuan; Moyer, Bryan D; Peterson, Matthew L; Rottman, James B; Beiler, Rudolph J; Malmberg, Annika B; McDonough, Stefan I

    2014-01-01

    Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.

  4. Global Nav1.7 Knockout Mice Recapitulate the Phenotype of Human Congenital Indifference to Pain

    PubMed Central

    Gingras, Jacinthe; Smith, Sarah; Matson, David J.; Johnson, Danielle; Nye, Kim; Couture, Lauren; Feric, Elma; Yin, Ruoyuan; Moyer, Bryan D.; Peterson, Matthew L.; Rottman, James B.; Beiler, Rudolph J.; Malmberg, Annika B.; McDonough, Stefan I.

    2014-01-01

    Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund’s adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain. PMID:25188265

  5. How humans integrate the prospects of pain and reward during choice

    PubMed Central

    Talmi, Deborah; Dayan, Peter; Kiebel, Stefan J.; Frith, Chris D.; Dolan, Raymond J.

    2010-01-01

    The maxim “no pain, no gain” summarises scenarios where an action leading to reward also entails a cost. Although we know a substantial amount about how the brain represents pain and reward separately, we know little about how they are integrated during goal directed behaviour. Two theoretical models might account for the integration of reward and pain. An additive model specifies that the disutility of costs is summed linearly with the utility of benefits, while an interactive model suggests that cost and benefit utilities interact so that the sensitivity to benefits is attenuated as costs become increasingly aversive. Using a novel task that required integration of physical pain and monetary reward, we examined the mechanism underlying cost-benefit integration in humans. We provide evidence in support of an interactive model in behavioural choice. Using functional neuroimaging we identify a neural signature for this interaction such that when the consequences of actions embody a mixture of reward and pain, there is an attenuation of a predictive reward-signal in both ventral anterior cingulate cortex and ventral striatum. We conclude that these regions subserve integration of action costs and benefits in humans, a finding that suggests a cross-species similarity in neural substrates that implement this function and illuminates mechanisms that underlie altered decision making under aversive conditions. PMID:19923294

  6. Comparative Analysis of Pain Behaviours in Humanized Mouse Models of Sickle Cell Anemia

    PubMed Central

    Lei, Jianxun; Benson, Barbara; Tran, Huy; Ofori-Acquah, Solomon F.; Gupta, Kalpna

    2016-01-01

    Pain is a hallmark feature of sickle cell anemia (SCA) but management of chronic as well as acute pain remains a major challenge. Mouse models of SCA are essential to examine the mechanisms of pain and develop novel therapeutics. To facilitate this effort, we compared humanized homozygous BERK and Townes sickle mice for the effect of gender and age on pain behaviors. Similar to previously characterized BERK sickle mice, Townes sickle mice show more mechanical, thermal, and deep tissue hyperalgesia with increasing age. Female Townes sickle mice demonstrate more hyperalgesia compared to males similar to that reported for BERK mice and patients with SCA. Mechanical, thermal and deep tissue hyperalgesia increased further after hypoxia/reoxygenation (H/R) treatment in Townes sickle mice. Together, these data show BERK sickle mice exhibit a significantly greater degree of hyperalgesia for all behavioral measures as compared to gender- and age-matched Townes sickle mice. However, the genetically distinct “knock-in” strategy of human α and β transgene insertion in Townes mice as compared to BERK mice, may provide relative advantage for further genetic manipulations to examine specific mechanisms of pain. PMID:27494522

  7. Effects of perceived and exerted pain control on neural activity during pain relief in experimental heat hyperalgesia: a fMRI study.

    PubMed

    Mohr, C; Leyendecker, S; Petersen, D; Helmchen, C

    2012-04-01

    Perceived control over pain can attenuate pain perception by mechanisms of endogenous pain control and emotional reappraisal irrespective of whether this control is exerted or only perceived. Self-initiated termination of pain elicits different expectations of subsequent pain relief as compared to perceived pain control. It is unknown whether and how this perceived vs. exerted control on pain differs and affects subsequent pain relief. Using fMRI, we studied two factors of pain control on pain relief: the (i) sense of control (perceived control but no execution) and (ii) the execution of control (exerted control). To account for the impact of factual execution of pain control on pain relief we applied bearable short and hardly bearable long contact-heat stimuli which were applied either controllable or not. Using controllability as factor, there was dissociable neural activity during pain relief: following the perceived control condition neural activity was found in the orbitofrontal and mediofrontal cortex and, following the exerted control condition, in the anterolateral and dorsolateral prefrontal cortex and posterior parietal cortex. We conclude that (i) pain controllability has an impact on pain relief and (ii) the prefrontal cortex shows dissociable neural activity during pain relief following exerted vs. perceived pain control. This might reflect the higher grade of uncertainty during pain relief following perceived pain control mediated by the orbitofrontal and medial prefrontal cortex and processes of working memory and updating expectations during pain relief following exerted control mediated by the lateral prefrontal cortex.

  8. Racial bias in pain perception and response: experimental examination of automatic and deliberate processes

    PubMed Central

    Mathur, Vani A.; Richeson, Jennifer A.; Paice, Judith A.; Muzyka, Michael; Chiao, Joan Y.

    2014-01-01

    Racial disparities in pain treatment pose a significant public health and scientific problem. Prior studies demonstrate clinicians and non-clinicians are less perceptive, and suggest less treatment for, the pain of African Americans, relative to European Americans. Here we investigate the effects of explicit/implicit patient race presentation, patient race, and perceiver race on pain perception and response. African American and European American participants rated pain perception, empathy, helping motivation, and treatment suggestion in response to vignettes about patients’ pain. Vignettes were accompanied by a rapid (implicit), or static (explicit) presentation of an African or European American patient’s face. Participants perceived and responded more to European American patients in the implicit prime condition, when the effect of patient race was below the level of conscious regulation. This effect was reversed when patient race was presented explicitly. Additionally, female participants perceived and responded more to the pain of all patients, relative to male participants, and in the implicit prime condition, African American participants were more perceptive and responsive than European Americans to the pain of all patients. Taken together, these results suggest that known disparities in pain treatment may be largely due to automatic (below the level of conscious regulation), rather than deliberate (subject to conscious regulation) biases. These biases were not associated with traditional implicit measures of racial attitudes, suggesting that biases in pain perception and response may be independent of general prejudice. Perspective Results suggest racial biases in pain perception and treatment are at least partially due to automatic processes. When the relevance of patient race is made explicit, however, biases are attenuated and even reversed. We also find preliminary evidence that African Americans may be more sensitive to the pain of others than

  9. Human Experimentation: Impact on Health Education Research.

    ERIC Educational Resources Information Center

    Vacalis, T. Demetri; Griffis, Kathleen

    1980-01-01

    The problems of the use of humans as subjects of medical research and the protection of their rights are discussed. Issues include the use of informed consent, the evaluation of risks and benefits, and the review of research plans by a committee. (JD)

  10. Effect of adenoviral delivery of prodynorphin gene on experimental inflammatory pain induced by formalin in rats

    PubMed Central

    Chen, Xionggang; Wang, Tingting; Lin, Caizhu; Chen, Baihong

    2014-01-01

    Circumstantial evidences suggest that dynorphins and their common precursor prodynorphin (PDYN) are involved in antinociception and neuroendocrine signaling. DREAM knockout mice had increased levels of PDYN and dynorphin expression, and reduced sensitivity to painful stimuli. However, some data support the notion that the up-regulation of spinal dynorphin expression is a common critical feature in neuropathic pain. It is not clear whether the production of dynorphin A can be increased when more PDYN is present. In this study we investigated the changes in pain behaviors, spinal PDYN mRNA expression and dynorphin A production on formalin-induced pain in rats receiving the pretreatment of adenoviral delivery of PDYN. Our results showed that the adenoviral transfer of PDYN gene was sufficient to reduce pain behaviors resulting from formalin injection, and the antinociceptive effect after receiving the pretreatment of adenoviral delivery of PDYN was mediated at the level of the spinal cord via KOR. PMID:25663984

  11. Reducing social stress elicits emotional contagion of pain in mouse and human strangers.

    PubMed

    Martin, Loren J; Hathaway, Georgia; Isbester, Kelsey; Mirali, Sara; Acland, Erinn L; Niederstrasser, Nils; Slepian, Peter M; Trost, Zina; Bartz, Jennifer A; Sapolsky, Robert M; Sternberg, Wendy F; Levitin, Daniel J; Mogil, Jeffrey S

    2015-02-02

    Empathy for another's physical pain has been demonstrated in humans [1] and mice [2]; in both species, empathy is stronger between familiars. Stress levels in stranger dyads are higher than in cagemate dyads or isolated mice [2, 3], suggesting that stress might be responsible for the absence of empathy for the pain of strangers. We show here that blockade of glucocorticoid synthesis or receptors for adrenal stress hormones elicits the expression of emotional contagion (a form of empathy) in strangers of both species. Mice and undergraduates were tested for sensitivity to noxious stimulation alone and/or together (dyads). In familiar, but not stranger, pairs, dyadic testing was associated with increased pain behaviors or ratings compared to isolated testing. Pharmacological blockade of glucocorticoid synthesis or glucocorticoid and mineralocorticoid receptors enabled the expression of emotional contagion of pain in mouse and human stranger dyads, as did a shared gaming experience (the video game Rock Band) in human strangers. Our results demonstrate that emotional contagion is prevented, in an evolutionarily conserved manner, by the stress of a social interaction with an unfamiliar conspecific and can be evoked by blocking the endocrine stress response.

  12. Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing.

    PubMed

    King, Christopher D; Goodin, Burel; Kindler, Lindsay L; Caudle, Robert M; Edwards, Robert R; Gravenstein, Nikolaus; Riley, Joseph L; Fillingim, Roger B

    2013-06-01

    The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter-balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain.

  13. Pain relief by various kinds of interference stimulation applied to the peripheral skin in humans: pain-related brain potentials following CO2 laser stimulation.

    PubMed

    Kakigi, R; Watanabe, S

    1996-01-01

    Pain perception is changed by various kinds of interference stimulation applied to the peripheral skin in humans. We investigated pain-related somatosensory evoked brain potentials (pain SEPs) following CO2 laser stimulation applied to the hand or foot in normal subjects, to elucidate the underlying mechanisms. A pain visual analogue scale (VAS) was also scored to determine the degree of subjective feeling of painful sensation. The following stimulations were applied as the interference: (1) vibration, (2) active and passive movements of the hand or foot, (3) noxious warming by hot water (46 degrees C) and (4) noxious cooling by ice water (0 degrees C). These interference stimulations were applied not only to the same hand or foot as the laser stimuli but also to the contralateral hand or foot. Significant changes in the amplitude of pain SEPs and VAS score were observed to some degree for each type of interference, and we concluded that gate control theory and diffuse noxious inhibitory control were the most appropriate hypotheses to account for this particular phenomenon of pain relief. Some movement-related cortical activities were also considered to be an important factor. These findings could not be accounted for by simple changes in the subjects' attention. Pain relief was more prominent at the second pain ascending through C fibers than that of the first pain ascending through Adelta fibers. The responsible sites for this phenomenon are considered to be the dorsal horn of the spinal cord, the brainstem and some parts of the brain such as the second sensory cortex and the cingulate cortex.

  14. Experimental Muscle Pain Impairs the Synergistic Modular Control of Neck Muscles.

    PubMed

    Gizzi, Leonardo; Muceli, Silvia; Petzke, Frank; Falla, Deborah

    2015-01-01

    A motor task can be performed via different patterns of muscle activation that show regularities that can be factorized in combinations of a reduced number of muscle groupings (also referred to as motor modules, or muscle synergies). In this study we evaluate whether an acute noxious stimulus induces a change in the way motor modules are combined to generate movement by neck muscles. The neck region was selected as it is a region with potentially high muscular redundancy. We used the motor modules framework to assess the redistribution of muscular activity of 12 muscles (6 per side) in the neck region of 8 healthy individuals engaged in a head and neck aiming task, in non-painful conditions (baseline, isotonic saline injection, post pain) and after the injection of hypertonic saline into the right splenius capitis muscle. The kinematics of the task was similar in the painful and control conditions. A general decrease of activity was noted for the injected muscle during the painful condition together with an increase or decrease of the activity of the other muscles. Subjects did not adopt shared control strategies (motor modules inter subject similarity at baseline 0.73±0.14); the motor modules recorded during the painful condition could not be used to reconstruct the activation patterns of the control conditions, and the painful stimulus triggered a subject-specific redistribution of muscular activation (i.e., in some subjects the activity of a given muscle increased, whereas in other subjects it decreased with pain). Alterations of afferent input (i.e., painful stimulus) influenced motor control at a multi muscular level, but not kinematic output. These findings provide new insights into the motor adaptation to pain.

  15. 16 CFR 1702.10 - Human experimental data involving the testing of human subjects.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Human experimental data involving the testing of human subjects. 1702.10 Section 1702.10 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION... PACKAGING ACT REQUIREMENTS; PETITION PROCEDURES AND REQUIREMENTS § 1702.10 Human experimental data...

  16. 16 CFR 1702.10 - Human experimental data involving the testing of human subjects.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Human experimental data involving the testing of human subjects. 1702.10 Section 1702.10 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION... PACKAGING ACT REQUIREMENTS; PETITION PROCEDURES AND REQUIREMENTS § 1702.10 Human experimental data...

  17. Effects of experimental craniofacial pain on fine jaw motor control: a placebo-controlled double-blinded study.

    PubMed

    Kumar, Abhishek; Castrillon, Eduardo; Svensson, Krister G; Baad-Hansen, Lene; Trulsson, Mats; Svensson, Peter

    2015-06-01

    The aim of the experiment was to test the hypothesis that experimental pain in the masseter muscle or temporomandibular joint (TMJ) would perturb the oral fine motor control, reflected in bigger variability of bite force values and jaw muscle activity, during repeated splitting of food morsels. Twenty healthy volunteers participated in four sessions. An intervention was made by injection of either 0.2 ml of monosodium glutamate/isotonic saline (MSG/IS) (randomized) in either the masseter or TMJ (randomized). The participants were asked to hold and split a flat-faced placebo tablet with their anterior teeth, thirty times each at baseline, during intervention and post-intervention. Pain was measured using a 0-10 visual analog scale. The force applied by the teeth to "hold" and "split" the tablet along with the corresponding electromyographic (EMG) activity of the jaw muscles and subject-based reports on perception of pain was recorded. The data analysis included a three-way analysis of variance model. The peak pain intensity was significantly higher during the painful MSG injections in the TMJ (6.1 ± 0.4) than the injections in masseter muscle (5.5 ± 0.5) (P = 0.037). Variability of hold force was significantly smaller during the MSG injection than IS injection in the masseter (P = 0.024). However, there was no significant effect of intervention on the variability of split force during the masseter injections (P = 0.769) and variability of hold and split force during the TMJ injections (P = 0.481, P = 0.545). The variability of the EMG activity of the jaw muscles did not show significant effects of intervention. Subject-based reports revealed that pain did not interfere in the ability to hold the tablet in 57.9 and 78.9 %, and the ability to split the tablet in 78.9 and 68.4 %, of the participants, respectively, during painful masseter and TMJ injections. Hence, experimental pain in the masseter muscle or TMJ did not have any robust effect in terms of bigger

  18. Simultaneous fMRI-PET of the opioidergic pain system in human brain.

    PubMed

    Wey, Hsiao-Ying; Catana, Ciprian; Hooker, Jacob M; Dougherty, Darin D; Knudsen, Gitte M; Wang, Danny J J; Chonde, Daniel B; Rosen, Bruce R; Gollub, Randy L; Kong, Jian

    2014-11-15

    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, [(11)C]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.

  19. An experimental study of human birth models

    NASA Astrophysics Data System (ADS)

    Baumer, Alexa; Gossmann, Roseanna; Fauci, Lisa J.; Leftwich, Megan C.

    2016-11-01

    The laboring uterus is a complex and dynamic fluid system. Relatively little is known about the fluid properties in this system. However, the two primary fluids of interest, amniotic fluid and vernix caseosa, likely play integral roles in the force transferred to the fetus during the final stages of parturition. This investigation probes the role of fluid in the force transfer during delivery by considering physical models that determine the role of various components of the full system. The first experimental model represents the fetus passing through the birth canal as concentric cylinders with a fluid filled gap. The rigid, inner cylinder moves through the highly flexible outer cylinder at a prescribed velocity. The geometry of the inner cylinder is varied by aspect ratio and length. A total of five different inner geometries are used to fully investigate the parameter space. As the inner cylinder moves through the outer cylinder, strain measurements are taken. These measurements are converted to force measurements as a function of time and position in the outer cylinder. The results of these experiments are compared with numerical results to form a more complete picture of force transfer. This model can be used as the foundation for predicting the force needed to deliver a fetus in the final stages of parturition. Additionally, more complex models, that incorporate uterine contraction forces, are being developed.

  20. Acute effect of Aloe vera gel extract on experimental models of pain.

    PubMed

    Rathor, Naveen; Mehta, Ashish K; Sharma, Amit K; Mediratta, Pramod K; Sharma, Krishna K

    2012-12-01

    The present study was performed to explore the effect of aqueous extract of Aloe vera on behavioural parameters of pain. Pain assessment was performed by the tail-flick and formalin tests. A. vera (100 mg/kg, per oral (p.o.)) produced an insignificant decrease in the pain response in the tail-flick and formalin tests. Moreover, A. vera (200 and 400 mg/kg, p.o.) did not have significant effect on the tail-flick test. However, A. vera (200 and 400 mg/kg, p.o.) significantly decreased the second phase of the formalin-induced pain. Thus, these findings suggest that A. vera exerts its effect by a peripheral mechanism of action rather than central.

  1. Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus

    PubMed Central

    Liu, C.C.; Shi, C-Q; Franaszczuk, P.J.; Crone, N.E.; Schretlen, D.; Ohara, S.; Lenz, F.A.

    2011-01-01

    The pathways by which painful stimuli are signaled within the human medial temporal lobe are unknown. Rodent studies have shown that nociceptive inputs are transmitted from the brainstem or thalamus through one of two pathways to the central nucleus of the amygdala. The indirect pathway projects from the basal and lateral nuclei of the amygdala to the central nucleus, while the direct pathway projects directly to the central nucleus. We now test the hypothesis that the human ventral amygdala (putative basal and lateral nuclei) exerts a causal influence upon the dorsal amygdala (putative central nucleus), during the application of a painful laser stimulus. Local field potentials (LFPs) were recorded from depth electrode contacts implanted in the medial temporal lobe for the treatment of epilepsy, and causal influences were analyzed by Granger causality (GRC). This analysis indicates that the dorsal amygdala exerts a pre-stimulus causal influence upon the hippocampus, consistent with an attention-related response to the painful laser. Within the amygdala, the analysis indicates that the ventral contacts exert a causal influence upon dorsal contacts, consistent with the human (putative) indirect pathway. Potentials evoked by the laser (LEPs) were not recorded in the ventral nuclei, but were recorded at dorsal amygdala contacts which were not preferentially those receiving causal influences from the ventral contacts. Therefore, it seems likely that the putative indirect pathway is associated with causal influences from the ventral to the dorsal amygdala, and is distinct from the human (putative) indirect pathway which mediates LEPs in the dorsal amygdala. PMID:21256929

  2. Hypnosis and Local Anesthesia for Dental Pain Relief-Alternative or Adjunct Therapy?-A Randomized, Clinical-Experimental Crossover Study.

    PubMed

    Wolf, Thomas Gerhard; Wolf, Dominik; Callaway, Angelika; Below, Dagna; d'Hoedt, Bernd; Willershausen, Brita; Daubländer, Monika

    2016-01-01

    This prospective randomized clinical crossover trial was designed to compare hypnosis and local anesthesia for experimental dental pain relief. Pain thresholds of the dental pulp were determined. A targeted standardized pain stimulus was applied and rated on the Visual Analogue Scale (0-10). The pain threshold was lower under hypnosis (58.3 ± 17.3, p < .001), maximal (80.0) under local anesthesia. The pain stimulus was scored higher under hypnosis (3.9 ± 3.8) than with local anesthesia (0.0, p < .001). Local anesthesia was superior to hypnosis and is a safe and effective method for pain relief in dentistry. Hypnosis seems to produce similar effects observed under sedation. It can be used in addition to local anesthesia and in individual cases as an alternative for pain control in dentistry.

  3. Influence of topical capsaicin on facial sensitivity in response to experimental pain.

    PubMed

    Lee, Y-S; Kho, H-S; Kim, Y-K; Chung, S-C

    2007-01-01

    Capsaicin, the pungent component of the red pepper, has been used as an analgesic in a variety of pain conditions, but sensory impairment after long-term treatment has been concerned. This study investigated the influence of topical capsaicin on various types of sensations including pain in the facial areas innervated by the mental nerve, and also evaluated whether the measurement of cutaneous current perception threshold (CPT) is reliable for the quantification of sensory change following capsaicin application. Twenty healthy subjects were given topical capsaicin cream (0.075%), which was applied to the mental area unilaterally, four times daily for 2 weeks. Burning sensation after capsaicin application gradually decreased with repeated applications. Repeated topical capsaicin resulted in reduced sensation to mechanical, heat and cold pain without changing non-painful tactile sensation. It also resulted in increased CPTs at 5 Hz and 250 Hz stimuli but no change in the CPTs at 2000 Hz from the first evaluation after capsaicin treatment and throughout the treatment period. This study demonstrated that topical capsaicin treatment for the management of chronic localized pain can be safely applied to the face without affecting non-painful normal sensations, and that CPT testing is a clinically useful tool for the quantification of sensory changes following capsaicin application.

  4. Neuroplastic changes related to pain occur at multiple levels of the human somatosensory system: A somatosensory-evoked potentials study in patients with cervical radicular pain.

    PubMed

    Tinazzi, M; Fiaschi, A; Rosso, T; Faccioli, F; Grosslercher, J; Aglioti, S M

    2000-12-15

    Studies suggest that pain may play a major role in determining cortical rearrangements in the adult human somatosensory system. Most studies, however, have been performed under conditions whereby pain coexists with massive deafferentation (e.g., amputations). Moreover, no information is available on whether spinal and brainstem changes contribute to pain-related reorganizational processes in humans. Here we assess the relationships between pain and plasticity by recording somatosensory-evoked potentials (SEPs) in patients who complained of pain to the right thumb after a right cervical monoradiculopathy caused by compression of the sixth cervical root, but did not present with clinical or neurophysiological signs of deafferentation. Subcortical and cortical potentials evoked by stimulation of digital nerves of the right thumb and middle finger were compared with those obtained after stimulation of the left thumb and middle finger and with those obtained in a control group tested in comparable conditions. Amplitudes of spinal N13, brainstem P14, parietal N20 and P27, and frontal N30 potentials after stimulation of the painful right thumb were greater than those of the nonpainful left thumb and showed a positive correlation with magnitude of pain. This right-left asymmetry was absent after stimulation of the patients' middle fingers and in control subjects. Results suggest that chronic cervical radicular pain is associated with changes in neural activity at multiple levels of the somatosensory system. The absence of correlation between the amplitude of spinal, brainstem, and cortical components of SEPs suggests that enhancement of cortical activity is not a simple amplification of subcortical enhancement.

  5. Human-Robot Emergency Response - Experimental Platform and Preliminary Dataset

    DTIC Science & Technology

    2014-07-28

    Human -Robot Emergency Response - Experimental Platform and Preliminary Dataset Technical Report #UM-CS-2014-006 Hee-Tae Jung, Takeshi Takahashi,and...2014 Abstract This paper presents progress towards a research infrastructure for studying human -robot performance in laboratory emergency response...scenarios and a preliminary dataset. It incorporates an emergency response team that is composed of a human participant, n ≤ 4 vision sensors in a

  6. Chemicals and cancer in humans: first evidence in experimental animals.

    PubMed Central

    Huff, J

    1993-01-01

    Certain human diseases have been traced to exposure to environmental and occupational chemicals. In many instances the first evidence of potential adverse effects came from experimental studies and were subsequently discovered in humans. Associations of human cancers, as a diverse group of diseases, and chemicals have been made since the middle 1700s. Since then, nearly 100 chemicals, mixtures of chemicals, or exposure circumstances are now recognized as being or strongly implicated as being carcinogenic to humans. Of the less than 1000 agents evaluated adequately for carcinogenicity in laboratory animals, a varying spectrum of data from studies on humans are available for only about 20-25%. So far, more than 60 agents are linked unequivocally as causing cancer in humans, and another 50 or so are strongly suspected of being carcinogenic to humans. Not all of these have been or can be evaluated in animals because some are industrial processes or "occupations," some are environmental and cultural risk factors, and some are mixtures of agents. For those that can be studied experimentally, the qualitative concordance between humans and animals approaches unity, and in every case there is at least one common organ site of cancer in both species. The evidence of carcinogenicity in experimental animals preceded that observed in humans for nearly 30 agents and is the subject of this paper. PMID:8354167

  7. Development Of an Experimental Animal Model For Lower Back Pain By Percutaneous Injury-Induced Lumbar Facet Joint Osteoarthritis

    PubMed Central

    Kim, Jae-Sung; Ahmadinia, Kasra; Li, Xin; Hamilton, John L; Andrews, Steven; Haralampus, Chris A.; Xiao, Guozhi; Sohn, Hong-Moon; You, Jae-Won; Seo, Yo-Seob; Stein, Gary S.; Wijnen, Andre J Van; Kim, Su-Gwan; Im, Hee-Jeong

    2015-01-01

    We report generation and characterization of pain-related behavior in a minimally-invasive facet joint degeneration (FJD) animal model in rats. FJD was produced by a non-open percutaneous puncture-induced injury on the right lumbar FJs at three consecutive levels. Pressure hyperalgesia in the lower back was assessed by measuring the vocalization response to pressure from a force transducer. After hyperalgesia was established, pathological changes in lumbar FJs and alterations of intervertebral foramen size were assessed by histological and imaging analyses. To investigate treatment options for lumber FJ osteoarthritis-induced pain, animals with established hyperalgesia were administered with analgesic drugs, such as morphine, a selective COX-2 inhibitor, a non-steroidal anti-inflammatory drug (NSAID) (ketorolac), or pregabalin. Effects were assessed by behavioral pain responses. One week after percutaneous puncture-induced injury of the lumbar FJs, ipsilateral primary pressure hyperalgesia developed and was maintained for at least 12 weeks without foraminal stenosis. Animals showed decreased spontaneous activity, but no secondary hyperalgesia in the hind paws. Histopathological and microfocus X-ray computed tomography analyses demonstrated that the percutaneous puncture injury resulted in osteoarthritis-like structural changes in the FJs cartilage and subchondral bone. Pressure hyperalgesia was completely reversed by morphine. The administration of celecoxib produced moderate pain reduction with no statistical significance while the administration of ketorolac and pregabalin produced no analgesic effect on FJ osteoarthritis-induced back pain. Our animal model of non-open percutanous puncture-induced injury of the lumbar FJs in rats shows similar characteristics of low back pain produced by human facet arthropathy. PMID:25858171

  8. Immunology of experimental and natural human hookworm infection.

    PubMed

    Gaze, S; Bethony, J M; Periago, M V

    2014-08-01

    Human hookworm infection is one amongst the most prevalent of the neglected tropical diseases. An informative experimental animal model, that is, one that parallels a human infection, is not available for the study of human hookworm infection. Much of our current understanding of the human immune response during hookworm infection relies on the studies from experimental infection of hookworm-naïve individuals or the natural infections from individuals residing in hookworm-endemic areas. The experimental human infections tend to be acute, dose-controlled infections, often with a low larval inoculum so that they are well tolerated by human volunteers. Natural hookworm infections usually occur in areas where hookworm transmission is constant and infection is chronic. In cases where there has been drug administration in an endemic area, re-infection often occurs quickly even amongst those who were treated. Hence, although many of the characteristics of experimental and natural hookworm infection differ, both models have elements in common: mainly an intense Th2 response with the production of total and specific IgE as well as elevated levels of eosinophilia, IL-5, IL-10 and TNF. While hookworm infection affects millions of individuals worldwide, much of the human immunology of this infection still needs to be studied and understood.

  9. The lidocaine metabolite N-ethylglycine has antinociceptive effects in experimental inflammatory and neuropathic pain

    PubMed Central

    Werdehausen, Robert; Mittnacht, Sebastian; Bee, Lucy A.; Minett, Michael S.; Armbruster, Anja; Bauer, Inge; Wood, John N.; Hermanns, Henning; Eulenburg, Volker

    2015-01-01

    Abstract Glycine transporter 1 (GlyT1) plays a crucial role in regulating extracellular glycine concentrations and might thereby constitute a new drug target for the modulation of glycinergic inhibition in pain signaling. Consistent with this view, inhibition of GlyT1 has been found to induce antinociceptive effects in various animal pain models. We have shown previously that the lidocaine metabolite N-ethylglycine (EG) reduces GlyT1-dependent glycine uptake by functioning as an artificial substrate for this transporter. Here, we show that EG is specific for GlyT1 and that in rodent models of inflammatory and neuropathic pain, systemic treatment with EG results in an efficient amelioration of hyperalgesia and allodynia without affecting acute pain. There was no effect on motor coordination or the development of inflammatory edema. No adverse neurological effects were observed after repeated high-dose application of EG. EG concentrations both in blood and spinal fluid correlated with an increase of glycine concentration in spinal fluid. The time courses of the EG and glycine concentrations corresponded well with the antinociceptive effect. Additionally, we found that EG reduced the increase in neuronal firing of wide-dynamic-range neurons caused by inflammatory pain induction. These findings suggest that systemically applied lidocaine exerts antihyperalgesic effects through its metabolite EG in vivo, by enhancing spinal inhibition of pain processing through GlyT1 modulation and subsequent increase of glycine concentrations at glycinergic inhibitory synapses. EG and other substrates of GlyT1, therefore, may be a useful therapeutic agent in chronic pain states involving spinal disinhibition. PMID:25932687

  10. Concepts of pain mechanisms: the contribution of functional imaging of the human brain.

    PubMed

    Casey, K L

    2000-01-01

    Functional imaging of the conscious human brain has a solid physiological basis in synaptically induced rCBF responses. We still do not know how these responses are generated, but recent studies have shown that the rCBF response is parametrically positively correlated with functional measures of neuronal activity. Technical advances in both fMRI and PET imaging have improved the spatial and temporal resolution of imaging methods. Further advances may be expected in the near future. Consequently, we now have an important tool to apply to the study of normal and, most importantly, pathological pain. There is a tendency to expect too much of this exciting technique, but the problems we wish to address are complex and will require considerable time, effort, and patience. We now know that the CNS adapts to both peripheral and central nervous system injury, sometimes in beneficial ways, but sometimes with reorganization that is maladaptive. An understanding of the pathophysiology of neuropathic pain is further complicated by the new knowledge, emphasized by functional brain imaging, that pain and pain modulation is mediated, not by a simple pathway with one or a few central targets, but by a network of multiple interacting modules of neuronal activity. Simplified phrenological thinking, with complete psychological functions separate and localized, is appealing, but wildly misleading. It is far more realistic and productive to apply qualitative and quantitative spatial and temporal analyses to the distributed activity of the conscious, communicating human brain. This will not be quick and easy, but there is every reason for optimism in our search for a thorough and useful understanding of both normal and pathological pain.

  11. A Clinical Experimental Model to Evaluate Analgesic Effect of Remote Ischemic Preconditioning in Acute Postoperative Pain

    PubMed Central

    Pereira, Francisco Elano Carvalho; Mello, Irene Lopes; Pimenta, Fernando Heladio de Oliveira Medeiros; Costa, Debora Maia; Wong, Deysi Viviana Tenazoa; Fernandes, Claudia Regina; Lima Junior, Roberto César; Gomes, Josenília M. Alves

    2016-01-01

    This study aims to evaluate the viability of a clinical model of remote ischemic preconditioning (RIPC) and its analgesic effects. It is a prospective study with twenty (20) patients randomly divided into two groups: control group and RIPC group. The opioid analgesics consumption in the postoperative period, the presence of secondary mechanical hyperalgesia, the scores of postoperative pain by visual analog scale, and the plasma levels interleukins (IL-6) were evaluated. The tourniquet applying after spinal anesthetic block was safe, producing no pain for all patients in the tourniquet group. The total dose of morphine consumption in 24 hours was significantly lower in RIPC group than in the control group (p = 0.0156). The intensity analysis of rest pain, pain during coughing and pain in deep breathing, showed that visual analogue scale (VAS) scores were significantly lower in RIPC group compared to the control group: p = 0.0087, 0.0119, and 0.0015, respectively. There were no differences between groups in the analysis of presence or absence of mechanical hyperalgesia (p = 0.0704) and in the serum levels of IL-6 dosage over time (p < 0.0001). This clinical model of remote ischemic preconditioning promoted satisfactory analgesia in patients undergoing conventional cholecystectomy, without changing serum levels of IL-6. PMID:27446611

  12. Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models.

    PubMed

    Kinchington, Paul R; Goins, William F

    2011-12-01

    Pain and post-herpetic neuralgia (PHN) are common and highly distressing complications of herpes zoster that remain a significant public health concern and in need of improved therapies. Zoster results from reactivation of the herpesvirus varicella zoster virus (VZV) from a neuronal latent state established at the primary infection (varicella). PHN occurs in some one fifth to one third of zoster cases with severity, incidence, and duration of pain increasing with rising patient age. While VZV reactivation and the ensuing ganglionic damage trigger the pain response, the mechanisms underlying protracted PHN are not understood, and the lack of an animal model of herpes zoster (reactivation) makes this issue more challenging. A recent preclinical rodent model has developed that opens up the potential to allow the exploration of the underlying mechanisms and treatments for VZV-induced pain. Rats inoculated with live cell-associated human VZV into the hind paw reliably demonstrate thermal hyperalgesia and mechanical allodynia for extended periods and then spontaneously recover. Dorsal root ganglia express a limited VZV gene subset, including the IE62 regulatory protein, and upregulate expression of markers suggesting a neuropathic pain state. The model has been used to investigate treatment modalities and aspects of pain signaling and is under investigation by the authors to delineate VZV genetics involved in the induction of pain. This article compares human zoster-associated pain and PHN to the pain indicators in the rat and poses important questions that, if answered, could be the basis for new treatments.

  13. The experimental analysis of human sexual arousal: Some recent developments

    PubMed Central

    Roche, Bryan; Barnes, Dermot

    1998-01-01

    Experimental analyses of human sexual arousal have been decidedly sparse. Recent developments in the analysis of derived relational responding, however, have opened the way for a modern behavior-analytic treatment of complex or “novel” human behavior, including specific instances of human sexual arousal. The current article examines some of these developments and their relevance to the analysis of emotional behavior, with a focus on sexual arousal. Recent research that has examined the acquisition of sexual stimulus functions within a relational frame paradigm is then outlined. Finally, a series of relational frame interpretations of a variety of human sexual arousal phenomena is offered. PMID:22478296

  14. Experimental chemotherapy of human tumors heterotransplanted in nude mice.

    PubMed

    Giovanella, B C

    1980-01-01

    Human tumors heterotransplanted in nude mice offer the most realistic model for experimental chemotherapy of human neoplasms. Almost all the known human malignancies have been successfully transplanted in the nudes, although the rate of takes varies considerably between different tumor types. So far, a good correlation has been observed between the results obtained treating with the same drug the same tumor in the patient and in the nude mouse. Our experience in this field is, however, still too limited for the direct extrapolation of chemotherapeutic results obtained in the nudes to human tumors.

  15. Toward an integrative view of human pain and suffering. Reply to comments on “Facing the experience of pain: A neuropsychological perspective”

    NASA Astrophysics Data System (ADS)

    Fabbro, Franco; Crescentini, Cristiano

    2014-09-01

    We would like to begin this response by recognizing the important contribution made by Grant [1], Pagnoni and Porro [2], Avenanti, Vicario and Borgomaneri [3], Masataka [4], Gard [5], and De Anna [6] to our review [7]. Through their thought-provoking and insightful commentaries, and with their diverse expertise, all commentators have contributed to enrich the discussion on human pain and suffering.

  16. Efficacy and safety of PPC-5650 on experimental rectal pain in patients with irritable bowel syndrome.

    PubMed

    Nielsen, Lecia Møller; Olesen, Anne Estrup; Andresen, Trine; Simrén, Magnus; Törnblom, Hans; Drewes, Asbjørn Mohr

    2015-02-01

    PPC-5650 is a new pharmacological agent that can modulate acid-sensing ion channel activity, leading to a reduction in the pain signal under up-regulated conditions. The non-clinical programme for PPC-5650 supported a role for this novel agent in the treatment of pain in patients with irritable bowel syndrome (IBS). In patients with IBS, the aims of the study were: (1) to assess the efficacy of a single bolus of PPC-5650 locally applied in the rectum using multi-modal stimulations of the recto sigmoid and (2) to assess the safety profile of PPC-5650. The study was a randomized, double-blind, placebo-controlled, cross-over trial in patients with IBS, excluding females of child-bearing potential. The study consisted of a training visit, study visit 1 and 2 and a follow-up visit. Rectosigmoid electrical, thermal and mechanical stimulations were performed, pain perception was rated on a pain intensity scale and referred pain areas were assessed. All adverse events were registered. Twenty-five patients with IBS were enrolled and completed the study (9 women and 16 men; mean age 50.4 ± 12.7 years). No effects of the study drug were found on any of the rectal stimulations or for referred pain areas (all p > 0.05). No significant or clinically relevant treatment-related differences were seen for the laboratory safety variables or any other reported adverse event. In conclusion, in patients with IBS on rectal sensitivity to multi-modal stimulations, PPC-5650 did not produce efficacy relative to placebo. The overall safety and tolerability of PPC-5650 was acceptable.

  17. Effects of acupressure on menstrual distress and low back pain in dysmenorrheic young adult women: an experimental study.

    PubMed

    Chen, Huei-Mein; Wang, Hsiu-Hung; Chiu, Min-Huei; Hu, Hsou-Mei

    2015-06-01

    The purpose of this study was to examine the effects of acupressure on menstrual distress and low back pain (LBP) in dysmenorrheic young adult women. In all, 129 female students, who had been experiencing dysmenorrhea with LBP during menstruation and who scored more than 4 points on the visual analog scale for pain, were randomly assigned to an experimental group and a control group. The experimental group (n = 65) received acupressure massage three times a week for 30 minutes on the sanyinjiao (SP6), ciliao (BL32), and taichong (Liver 3) acupoints. The control group (n = 64) received only a manual of menstrual health education without acupressure intervention. Data were collected at five time points: at baseline, 30 minutes, and 4, 8, and 12 months after the intervention. During the 12-month follow-up, the experimental group had significantly lower menstrual distress and LBP scores than the control group. Among 65 participants in the experimental group, 53 (82%) reported a moderate to high levels of menstrual distress, 51 (78%) reported moderate to high levels of LBP relief, and 49 (75%) reported moderate to high levels of satisfaction with acupressure. Our findings may serve as a reference for health care professionals and young women to improve self-care during menstruation and help further understand the therapeutic effects of acupressure on menstrual distress and LBP.

  18. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders.

    PubMed

    Drenth, Joost P H; Waxman, Stephen G

    2007-12-01

    The voltage-gated sodium-channel type IX alpha subunit, known as Na(v)1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Na(v)1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Na(v)1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Na(v)1.7 result in loss of Na(v)1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Na(v)1.7 in pain sensation in humans.

  19. Combined neuromodulatory interventions in acute experimental pain: assessment of melatonin and non-invasive brain stimulation

    PubMed Central

    da Silva, Nádia Regina Jardim; Laste, Gabriela; Deitos, Alícia; Stefani, Luciana Cadore; Cambraia-Canto, Gustavo; Torres, Iraci L. S.; Brunoni, Andre R.; Fregni, Felipe; Caumo, Wolnei

    2015-01-01

    Transcranial direct current stimulation (tDCS) and melatonin can effectively treat pain. Given their potentially complementary mechanisms of action, their combination could have a synergistic effect. Thus, we tested the hypothesis that compared to the control condition and melatonin alone, tDCS combined with melatonin would have a greater effect on pain modulatory effect, as assessed by quantitative sensory testing (QST) and by the pain level during the Conditioned Pain Modulation (CPM)-task. Furthermore, the combined treatment would have a greater cortical excitability effect as indicated by the transcranial magnetic stimulation (TMS) and on the serum BDNF level. Healthy males (n = 20), (aged 18–40 years), in a blinded, placebo-controlled, crossover, clinical trial, were randomized into three groups: sublingual melatonin (0.25 mg/kg) + a-tDCS, melatonin (0.25 mg/kg) + sham-(s)-tDCS, or sublingual placebo+sham-(s)-tDCS. Anodal stimulation (2 mA, 20 min) was applied over the primary motor cortex. There was a significant difference in the heat pain threshold (°C) for melatonin+a-tDCS vs. placebo+s-tDCS (mean difference: 4.86, 95% confidence interval [CI]: 0.9 to 8.63) and melatonin+s-tDCS vs. placebo+s-tDCS (mean: 5.16, 95% CI: 0.84 to 8.36). There was no difference between melatonin+s-tDCS and melatonin+a-tDCS (mean difference: 0.29, 95% CI: −3.72 to 4.23). The mean change from the baseline on amplitude of motor evocate potential (MEP) was significantly higher in the melatonin+a-tDCS (−19.96% ± 5.2) compared with melatonin+s-tDCS group (−1.36% ± 5.35) and with placebo+s-tDCS group (3.61% ± 10.48), respectively (p < 0.05 for both comparisons). While melatonin alone or combined with a-tDCS did not significantly affect CPM task result, and serum BDNF level. The melatonin effectively reduced pain; however, its association with a-tDCS did not present an additional modulatory effect on acute induced pain. PMID:25873871

  20. The effect of repeated intramuscular alfentanil injections on experimental pain and abuse liability indices in healthy males

    PubMed Central

    Tompkins, D. Andrew; Smith, Michael T.; Bigelow, George E.; Moaddel, Ruin; Venkata, S.L. Vatem; Strain, Eric C.

    2013-01-01

    Objective Opioid-induced hyperalgesia (OIH), increased sensitivity to noxious stimuli following repeated opioid exposures, has been demonstrated in pre-clinical studies. However, there is no accepted, prospective model of OIH following repeated opioid exposures currently available in humans. This study assessed a potential prospective OIH model. Methods Double-blind intramuscular (IM) injections of a short-acting opioid, (alfentanil 15 mcg/kg; N=8) were compared to active placebo (diphenhydramine 25 mg; N=3) on cold and pressure pain testing and standard abuse liability measures in eight 10-hour sessions (1 injection/session) over 4–5 weeks in healthy pain-free males. Decreases from session baseline pain threshold (PThr) and tolerance (PTol) were calculated to represent hyperalgesia, and were assessed both within and across sessions. Results Mean decreases in cold PTol were seen in the alfentanil group at 180 minutes (−3.8 seconds, +/−26.5) and 480 minutes (−1.63 seconds, +/−31.5) after drug administration. There was a trend for differences between conditions on cold PThr hyperalgesia but not for pressure PThr. Alfentanil participants had greater mean ratings on LIKING and HIGH visual analog scales at peak effects (30 minutes), but these scores did not change across sessions. Discussion Repeated alfentanil exposures over 4–5 weeks resulted in within session decreases in cold pain tolerance from baseline but these differences were not substantially different from diphenhydramine controls. The results did not support the phenomenon of OIH in this model, although definitive conclusions regarding the existence of OIH in humans likely requires a larger sample size or an alternative model. PMID:23446076

  1. Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant

    PubMed Central

    Leipold, Enrico; Hanson-Kahn, Andrea; Frick, Miya; Gong, Ping; Bernstein, Jonathan A.; Voigt, Martin; Katona, Istvan; Oliver Goral, R.; Altmüller, Janine; Nürnberg, Peter; Weis, Joachim; Hübner, Christian A.; Heinemann, Stefan H.; Kurth, Ingo

    2015-01-01

    Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na+ channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to NaV1.9. Mutated channels diminish the resting membrane potential of mouse primary sensory neurons and cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype. On the basis of direct comparison of the mutations linked to either cold-aggravated pain or pain insensitivity, we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of NaV1.9 hyperactivity. PMID:26645915

  2. Nocardia brasiliensis: from microbe to human and experimental infections.

    PubMed

    Salinas-Carmona, M C

    2000-09-01

    Nocardia brasiliensis is a Gram-positive bacterium that lives as a saprophyte in soil. In this article the physical properties, chemical composition and taxonomic position of this species is reviewed. Human infections and an experimental model of actinomycetoma in BALB/c mice as well as the host-immune response is described.

  3. Ethics in human experimentation: examples in aeromedical research.

    PubMed

    Popper, S E; McCloskey, K

    1995-01-01

    The existence of ethical standards directing how humans are utilized in clinical and human-use research have a significant impact on the conduct and outcome of aeromedical research. The validity of the data generated by human research is a direct result of the application of these ethical guidelines. The risk/benefit ratio evaluation can terminate a project even before its initiation. New technology, individual beliefs, and a changing society will continue to guarantee controversy over how human subjects should be screened and evaluated as well as how research should utilize them. Ethical guidelines are not cast in stone. Their interpretation is influenced by new experimental results, the individual researcher, the intended subject, the composition of human use committees, and the social environment. How we address new and old concerns alike will dictate the research environment of the future.

  4. Influence of Polymorphisms in the HTR3A and HTR3B Genes on Experimental Pain and the Effect of the 5-HT3 Antagonist Granisetron

    PubMed Central

    Hedenberg-Magnusson, Britt; List, Thomas; Svensson, Peter; Schalling, Martin

    2016-01-01

    The aim of this study was to investigate experimentally if 5-HT3 single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT3-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding HTR3A (rs1062613) and HTR3B (rs1176744). First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn. PMID:28002447

  5. Association between sensitisation and pain-related behaviours in an experimental canine model of osteoarthritis.

    PubMed

    Rialland, Pascale; Otis, Colombe; Moreau, Maxim; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne; Beaudry, Francis; Del Castillo, Jerome R E; Bertaim, Thierry; Gauvin, Dominique; Troncy, Eric

    2014-10-01

    Evaluation of nociceptive sensitisation in canine osteoarthritis studies has been poorly reported, or even related to other clinical symptoms. In 16 dogs, peak vertical force (PVF), subjective pain assessment using 3 scales, sympathetic stress response with electrodermal activity (EDA) measurement, and behavioural changes with video analysis and telemetered motor activity were quantified at baseline (D-7), and 28 and 56 days post transection of the cranial cruciate ligament. As markers of central sensitisation, selected spinal cord biomarkers (substance P and transthyretin) were quantified at D56. Electrical withdrawal thresholds on the stifle and the tail were measured as indicative of peripheral and central quantitative sensory testing (QST) sensitisation, respectively. The effects of vehicle administration (n=8) were compared with tiludronate (2mg/kg subcutaneously, q2 week, starting at D0) administration. Generalized estimated equations tested the association between the behavioural and physiological methods and QST sensitisation, and therefore the sensitivity of the methods for detecting treatment efficacy. Compared to tiludronate, at D56, vehicle-treated dogs had increased spinal substance P (P=0.01), concomitant decreased transthyretin (P=0.02), and (compared to baseline) demonstrated peripheral and central QST sensitisation, which was not present for tiludronate. Only PVF, the spontaneous behaviour "walking with full weight-bearing," and EDA were associated with occurrence of QST sensitisation and indicated significant tiludronate analgesic efficacy after inclusion of central QST sensitisation as a predictor variable in the statistical model. This study establishes the strong interest to implement QST as a predictor of canine osteoarthritis pain symptoms explained by pain sensitisation.

  6. Effect of muscle relaxants on experimental jaw-muscle pain and jaw-stretch reflexes: a double-blind and placebo-controlled trial.

    PubMed

    Svensson, Peter; Wang, Kelun; Arendt-Nielsen, Lars

    2003-01-01

    A randomised, double-blind, placebo-controlled three-way cross-over study was performed to investigate the effect of two muscle relaxants (tolperisone hydrochloride and pridinol mesilate) on experimental jaw-muscle pain and jaw-stretch reflexes. Fifteen healthy men participated in three randomised sessions separated by at least 1 week. In each session 300 mg tolperisone, 8 mg pridinol mesilate or placebo was administered orally as a single dose. One hour after drug administration 0.3 ml hypertonic saline (5.8%) was injected into the right masseter to produce muscle pain. Subjects continuously rated their perceived pain intensity on an electronic 10-cm visual analogue scale (VAS). The pressure pain threshold (PPT) was measured and short-latency reflex responses were evoked in the pre-contracted (15% maximal voluntary contraction) masseter and temporalis muscles by a standardised stretch device (1 mm displacement, 10 ms ramp time) before (baseline), 1 h after medication (post-drug), during ongoing experimental muscle pain (pain-post-drug), and 15 min after pain had vanished (post-pain). Analysis of variance demonstrated significantly lower VAS peak pain scores (5.9 +/- 0.4 cm) after administration of tolperisone hydrochloride compared with pridinol mesilate (6.8 +/- 0.4 cm) and placebo (6.6 +/- 0.4 cm) (P=0.020). Administration of pridinol mesilate was associated with a significant decrease in PPTs compared with tolperisone hydrochloride and placebo (P=0.002) after medication, but not after experimental jaw-muscle pain. The normalised peak-to-peak amplitude of the stretch reflexes were not significantly influenced by the test medication (P=0.762), but were in all sessions significantly facilitated during ongoing experimental jaw-muscle pain (P=0.034). In conclusion, tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jaw-muscle pain whereas the present dose had no effect on the short-latency jaw

  7. Use of localized human growth hormone and testosterone injections in addition to manual therapy and exercise for lower back pain: a case series with 12-month follow-up

    PubMed Central

    Dubick, Marc N; Ravin, Thomas H; Michel, Yvonne; Morrisette, David C

    2015-01-01

    Objective The objective of this case series was to investigate the feasibility and safety of a novel method for the management of chronic lower back pain. Injections of recombinant human growth hormone and testosterone to the painful and dysfunctional areas in individuals with chronic lower back pain were used. In addition, the participants received manual therapies and exercise addressing physical impairments such as motor control, strength, endurance, pain, and loss of movement. Pain ratings and self-rated functional outcomes were assessed. Study design This is a case series involving consecutive patients with chronic lower back pain who received the intervention of injections of recombinant human growth hormone and testosterone, and attended chiropractic and/or physical therapy. Outcomes were measured at 12 months from the time of injection. Setting A community based hospital affiliated office, and a private practice block suite. Participants A total of 60 consecutive patients attending a pain management practice for chronic lower back pain were recruited for the experimental treatment. Most participants were private pay. Interventions Participants who provided informed consent and were determined not to have radicular pain received diagnostic blocks. Those who responded favorably to the diagnostic blocks received injections of recombinant human growth hormone and testosterone in the areas treated with the blocks. Participants also received manipulation- and impairment-based exercises. Outcome measures Outcomes were assessed at 12 months through pain ratings with the Mankowski Pain Scale and the Oswestry Disability Index. Results Of the 60 patients recruited, 49 provided informed consent, and 39 completed all aspects of the study. Those patients receiving the intervention reported a significant decrease in pain ratings (P<0.01) and a significant improvement in self-rated Oswestry Disability Index scores (P<0.01). In addition, in the Oswestry Disability Index

  8. Capsaicin-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans.

    PubMed

    Henrich, Florian; Magerl, Walter; Klein, Thomas; Greffrath, Wolfgang; Treede, Rolf-Detlef

    2015-09-01

    Long-term potentiation in the spinal dorsal horn requires peptidergic C-fibre activation in animals. Perceptual correlates of long-term potentiation following high-frequency electrical stimulation in humans include increased sensitivity to electrical stimuli at the high frequency stimulation site (homotopic pain-long-term potentiation) and increased sensitivity to pinprick surrounding the high frequency stimulation site (heterotopic pain-long-term potentiation, equivalent to secondary hyperalgaesia). To characterize the peripheral fibre populations involved in induction of pain-long-term potentiation, we performed two selective nerve block experiments in 30 healthy male volunteers. Functional blockade of TRPV1-positive nociceptors by high-concentration capsaicin (verified by loss of heat pain) significantly reduced pain ratings to high frequency stimulation by 47% (P < 0.001), homotopic pain-long-term potentiation by 71% (P < 0.01), heterotopic pain-long-term potentiation by 92% (P < 0.001) and the area of secondary hyperalgesia by 76% (P < 0.001). The selective blockade of A-fibre conduction by nerve compression (verified by loss of first pain to pinprick) significantly reduced pain ratings to high frequency stimulation by 37% (P < 0.01), but not homotopic pain-long-term potentiation (-5%). It had a marginal effect on heterotopic pain-long-term potentiation (-35%, P = 0.059), while the area of secondary hyperalgesia remained unchanged (-2%, P = 0.88). In conclusion, all nociceptor subclasses contribute to high frequency stimulation-induced pain (with a relative contribution of C > Aδ fibres, and an equal contribution of TRPV1-positive and TRPV1-negative fibres). TRPV1-positive C-fibres are the main inducers of both homotopic and heterotopic pain-long-term potentiation. TRPV1-positive A-fibres contribute substantially to the induction of heterotopic pain-long-term potentiation. TRPV1-negative C-fibres induce a component of homotopic self-facilitation but not

  9. Antihyperalgesic Effect of Hesperidin Improves with Diosmin in Experimental Neuropathic Pain.

    PubMed

    Carballo-Villalobos, Azucena I; González-Trujano, María-Eva; Pellicer, Francisco; López-Muñoz, Francisco J

    Neuropathic pain is caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system. In this study, we investigated the hesperidin antihyperalgesic effects alone or combined with diosmin in a model of neuropathic pain to corroborate a possible synergistic antinociceptive activity. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, after chronic constriction injury (CCI) model in rats receiving hesperidin (HS, 5 doses from 10 to 1000 mg/kg) alone or combined with diosmin (DS, 10 and 100 mg/kg) in comparison to gabapentin (31.6 mg/kg). UHPLC-MS analysis of cerebral samples was used to recognize the central concentrations of these flavonoids. Participation of different receptors was also investigated in the presence of haloperidol, bicuculline, and naloxone antagonists. Acute hesperidin administration significantly decreased mechanical and thermal hyperalgesia in CCI rats. Antihyperalgesic response of hesperidin, improved by a combination with diosmin (DS10/HS100) in both stimuli, was blockaded by haloperidol, bicuculline, and naloxone, but not WAY100635, antagonists. Both flavonoids were detected in brain samples. In conclusion, hesperidin alone and combined with diosmin produces antihyperalgesic response in the CCI model in rats. Antihyperalgesic effect of DS10/HS100 combination involves central activity partially modulated by D2, GABAA, and opioids, but not by 5-HT1A, receptors.

  10. Antihyperalgesic Effect of Hesperidin Improves with Diosmin in Experimental Neuropathic Pain

    PubMed Central

    Pellicer, Francisco; López-Muñoz, Francisco J.

    2016-01-01

    Neuropathic pain is caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system. In this study, we investigated the hesperidin antihyperalgesic effects alone or combined with diosmin in a model of neuropathic pain to corroborate a possible synergistic antinociceptive activity. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, after chronic constriction injury (CCI) model in rats receiving hesperidin (HS, 5 doses from 10 to 1000 mg/kg) alone or combined with diosmin (DS, 10 and 100 mg/kg) in comparison to gabapentin (31.6 mg/kg). UHPLC-MS analysis of cerebral samples was used to recognize the central concentrations of these flavonoids. Participation of different receptors was also investigated in the presence of haloperidol, bicuculline, and naloxone antagonists. Acute hesperidin administration significantly decreased mechanical and thermal hyperalgesia in CCI rats. Antihyperalgesic response of hesperidin, improved by a combination with diosmin (DS10/HS100) in both stimuli, was blockaded by haloperidol, bicuculline, and naloxone, but not WAY100635, antagonists. Both flavonoids were detected in brain samples. In conclusion, hesperidin alone and combined with diosmin produces antihyperalgesic response in the CCI model in rats. Antihyperalgesic effect of DS10/HS100 combination involves central activity partially modulated by D2, GABAA, and opioids, but not by 5-HT1A, receptors. PMID:27672659

  11. Literary works as case studies for teaching human experimentation ethics.

    PubMed

    Cassidy, V R

    1996-03-01

    Case studies are widely used as a teaching strategy for a variety of topics in various disciplines. They are particularly valued as a teaching strategy in the teaching of ethics because they provide a context for understanding the complexities of situations involving ethical dilemmas. This article describes the successful use of two literary works as case studies in teaching master's students about the ethical issues in human experimentation. Pygmalion and Flowers for Algernon were selected to exemplify the ethical considerations important in the conduct of research with human subjects. Students found the assignment both personally and professionally stimulating and recommended continued use of the assignment in the course.

  12. Human fetal chromaffin cells: a potential tool for cell pain therapy.

    PubMed

    Jozan, Suzanne; Aziza, Jacqueline; Châtelin, Sophie; Evra, Corinne; Courtade-Saïdi, Monique; Parant, Olivier; Sol, Jean Christophe; Zhou, Huafang; Lazorthes, Yves

    2007-06-01

    Transplantation of adrenal medulla cells has been proposed in the treatment of various conditions. Indeed, these cells possess a bipotentiality: neural and neuroendocrine, which could be exploited for brain repair or pain therapy. In a previous study, we characterized these human cells in vitro over 7-10 gestational weeks (GW) [Zhou, H., Aziza, J., Sol, J.C., Courtade-Saidi, M., Chatelin, S., Evra, C., Parant, O., Lazorthes, Y., and Jozan, S., 2006. Cell therapy of pain: Characterization of human fetal chromaffin cells at early adrenal medulla development. Exp. Neurol. 198, 370-381]. We report here our results on the extension to 23 GW. This developmental period can be split into three stages. During the first stage (7-10 GW), we observed in situ that extra-adrenal surrounding cells display the same morphology and phenotype as the intra-adrenal chromaffin cells. We also found that the intra-adrenal chromaffin cells could be committed in vitro towards an adrenergic phenotype using differentiating agents. During the second stage (11 to 15-16 GW), two types of cells (Type 1 and Type 2 cells) were identified morphologically both inside and outside the gland. Interestingly, we noted that the Type 2 cells stem from the Type 1 cells. However, during this developmental period only the intra-adrenal Type 2 cells will evolve towards an adrenergic phenotype. In the third stage (17-23 GW), we observed the ultimate location of the medulla gland. Both the in situ results and the in vitro experiments indicate that particular procedures need to be implemented prior transplantation of chromaffin cells. First, in order to obtain a large number of immature chromaffin cells, they must be isolated from the intra and extra-adrenal gland and should then be committed towards an adrenergic phenotype in vitro for subsequent use in pain therapy. This strategy is under investigation in our laboratory.

  13. Tamoxifen experimental carcinogenicity studies: Implications for human effects

    SciTech Connect

    Williams, G.M.

    1995-02-01

    Tamoxifen is an effective antiestrogen in the treatment of breast cancer and is considered highly safe. In recent years, several trials have been initiated in women to evaluate its potential for the prevention of breast cancer. Such long-term administration of a medication to healthy people requires a substantial degree of safety. This review examines experimental carcinogenicity and mechanistic studies on tamoxifen and the implications for human effects. 25 refs.

  14. Informed consent in human experimentation before the Nuremberg code.

    PubMed

    Vollmann, J; Winau, R

    1996-12-07

    The issue of ethics with respect to medical experimentation in Germany during the 1930s and 1940s was crucial at the Nuremberg trials and related trials of doctors and public health officials. Those involved in horrible crimes attempted to excuse themselves by arguing that there were no explicit rules governing medical research on human beings in Germany during the period and that research practices in Germany were not different from those in allied countries. In this context the Nuremberg code of 1947 is generally regarded as the first document to set out ethical regulations in human experimentation based on informed consent. New research, however, indicates that ethical issues of informed consent in guidelines for human experimentation were recognised as early as the nineteenth century. These guidelines shed light on the still contentious issue of when the concepts of autonomy, informed consent, and therapeutic and non-therapeutic research first emerged. This issue assumes renewed importance in the context of current attempts to assess liability and responsibility for the abuse of people in various experiments conducted since the second world war in the United States, Canada, Russia, and other nations.

  15. Informed consent in human experimentation before the Nuremberg code.

    PubMed Central

    Vollmann, J.; Winau, R.

    1996-01-01

    The issue of ethics with respect to medical experimentation in Germany during the 1930s and 1940s was crucial at the Nuremberg trials and related trials of doctors and public health officials. Those involved in horrible crimes attempted to excuse themselves by arguing that there were no explicit rules governing medical research on human beings in Germany during the period and that research practices in Germany were not different from those in allied countries. In this context the Nuremberg code of 1947 is generally regarded as the first document to set out ethical regulations in human experimentation based on informed consent. New research, however, indicates that ethical issues of informed consent in guidelines for human experimentation were recognised as early as the nineteenth century. These guidelines shed light on the still contentious issue of when the concepts of autonomy, informed consent, and therapeutic and non-therapeutic research first emerged. This issue assumes renewed importance in the context of current attempts to assess liability and responsibility for the abuse of people in various experiments conducted since the second world war in the United States, Canada, Russia, and other nations. Images p1445-a p1446-a PMID:8973233

  16. Transcranial direct current stimulation over the opercular somatosensory region does not influence experimentally induced pain: a triple blind, sham-controlled study

    PubMed Central

    Koyama, Soichiro; Nakagawa, Kei

    2017-01-01

    Transcranial magnetic stimulation (TMS) over the opercular somatosensory region (OP), which includes the secondary somatosensory cortex and the insular cortex, suppresses pain sensation. However, whether transcranial direct current stimulation (tDCS) over the OP has a similar effect on pain sensation remains unknown. We examined whether pain sensation would be suppressed by tDCS over the OP. Our experiment with a triple-blind, sham-controlled, crossover design involved 12 healthy participants. Participants were asked to rate their subjective pain intensity during and after three types of bihemispheric tDCS: right anodal/left cathodal OP tDCS, left anodal/right cathodal OP tDCS (2 mA, 12 min), and sham tDCS (15 s). Pain stimuli were alternately applied to the dorsum of each index finger using intraepidermal electrical stimulation. We observed no significant effect of tDCS over the OP on the perception of experimentally induced pain. Subjective pain intensity did not differ significantly between the three tDCS conditions. The present null results have crucial implications for the selection of optimal stimulation regions and parameters for clinical pain treatment. PMID:27984542

  17. 16 CFR 1702.10 - Human experimental data involving the testing of human subjects.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 2 2014-01-01 2014-01-01 false Human experimental data involving the testing of human subjects. 1702.10 Section 1702.10 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION POISON PREVENTION PACKAGING ACT OF 1970 REGULATIONS PETITIONS FOR EXEMPTIONS FROM POISON...

  18. 16 CFR 1702.10 - Human experimental data involving the testing of human subjects.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 2 2012-01-01 2012-01-01 false Human experimental data involving the testing of human subjects. 1702.10 Section 1702.10 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION POISON PREVENTION PACKAGING ACT OF 1970 REGULATIONS PETITIONS FOR EXEMPTIONS FROM POISON...

  19. 16 CFR 1702.10 - Human experimental data involving the testing of human subjects.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Human experimental data involving the testing of human subjects. 1702.10 Section 1702.10 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION POISON PREVENTION PACKAGING ACT OF 1970 REGULATIONS PETITIONS FOR EXEMPTIONS FROM POISON...

  20. Participation of neuronal nitric oxide synthase in experimental neuropathic pain induced by sciatic nerve transection.

    PubMed

    Chacur, M; Matos, R J B; Alves, A S; Rodrigues, A C; Gutierrez, V; Cury, Y; Britto, L R G

    2010-04-01

    Nerve injury leads to a neuropathic pain state that results from central sensitization. This phenomenom is mediated by NMDA receptors and may involve the production of nitric oxide (NO). In this study, we investigated the expression of the neuronal isoform of NO synthase (nNOS) in the spinal cord of 3-month-old male, Wistar rats after sciatic nerve transection (SNT). Our attention was focused on the dorsal part of L3-L5 segments receiving sensory inputs from the sciatic nerve. SNT resulted in the development of neuropathic pain symptoms confirmed by evaluating mechanical hyperalgesia (Randall and Selitto test) and allodynia (von Frey hair test). Control animals did not present any alteration (sham-animals). The selective inhibitor of nNOS, 7-nitroindazole (0.2 and 2 microg in 50 microL), blocked hyperalgesia and allodynia induced by SNT. Immunohistochemical analysis showed that nNOS was increased (48% by day 30) in the lumbar spinal cord after SNT. This increase was observed near the central canal (Rexed's lamina X) and also in lamina I-IV of the dorsal horn. Real-time PCR results indicated an increase of nNOS mRNA detected from 1 to 30 days after SNT, with the highest increase observed 1 day after injury (1469%). Immunoblotting confirmed the increase of nNOS in the spinal cord between 1 and 15 days post-lesion (20%), reaching the greatest increase (60%) 30 days after surgery. The present findings demonstrate an increase of nNOS after peripheral nerve injury that may contribute to the increase of NO production observed after peripheral neuropathy.

  1. Effects of analgesia of the distal interphalangeal joint and navicular bursa on experimental lameness caused by solar pain in horses.

    PubMed

    Sardari, K; Kazemi, H; Mohri, M

    2002-11-01

    It has been hypothesized that pain originating from the dorsal margin of the sole of the hoof in horses can be attenuated by analgesia of either the distal interphalangeal (DIP) joint, or of the navicular bursa (NB). To test this hypothesis, an experimental lameness was induced in the toe region of the left forelimb in six adult horses. After this, both synovial structures were blocked and the effects on the lameness were semi-quantitatively scored. Lameness was induced by creating pressure on the dorsal margin of the sole with the help of set-screws that were screwed into a nut, welded to the inside of each branch of the shoe. Gaits were recorded on a videotape before and after application of the screws, and after application of either a local anaesthetic or saline into the DIP joint or NB. The gaits were independently evaluated by two blinded clinicians and scored. Lameness scores were high after application of the screws and remained high after the administration of saline, but decreased significantly (P < 0.05) after administration of the local anaesthetic. Analgesia of the DIP joint as well as the NB appeared to be able to desensitize a portion of the sole. It was concluded that pain arising from the toe region of the sole should not be excluded as a cause of lameness when lameness is attenuated by analgesia of the DIP joint, or of the NB.

  2. Effect of subcutaneous treatment with human umbilical cord blood-derived multipotent stem cells on peripheral neuropathic pain in rats

    PubMed Central

    Lee, Min Ju; Yoon, Tae Gyoon; Kang, Moonkyu

    2017-01-01

    In this study, we aim to determine the in vivo effect of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) on neuropathic pain, using three, principal peripheral neuropathic pain models. Four weeks after hUCB-MSC transplantation, we observed significant antinociceptive effect in hUCB-MSC–transplanted rats compared to that in the vehicle-treated control. Spinal cord cells positive for c-fos, CGRP, p-ERK, p-p 38, MMP-9 and MMP 2 were significantly decreased in only CCI model of hUCB-MSCs-grafted rats, while spinal cord cells positive for CGRP, p-ERK and MMP-2 significantly decreased in SNL model of hUCB-MSCs-grafted rats and spinal cord cells positive for CGRP and MMP-2 significantly decreased in SNI model of hUCB-MSCs-grafted rats, compared to the control 4 weeks or 8weeks after transplantation (p<0.05). However, cells positive for TIMP-2, an endogenous tissue inhibitor of MMP-2, were significantly increased in SNL and SNI models of hUCB-MSCs-grafted rats. Taken together, subcutaneous injection of hUCB-MSCs may have an antinociceptive effect via modulation of pain signaling during pain signal processing within the nervous system, especially for CCI model. Thus, subcutaneous administration of hUCB-MSCs might be beneficial for improving those patients suffering from neuropathic pain by decreasing neuropathic pain activation factors, while increasing neuropathic pain inhibition factor. PMID:28280408

  3. Much Pain, Little Gain? Paradigm-Specific Models and Methods in Experimental Psychology.

    PubMed

    Meiser, Thorsten

    2011-03-01

    Paradigm-oriented research strategies in experimental psychology have strengths and limitations. On the one hand, experimental paradigms play a crucial epistemic and heuristic role in basic psychological research. On the other hand, empirical research is often limited to the observed effects in a certain paradigm, and theoretical models are frequently tied to the particular features of the given paradigm. A paradigm-driven research strategy therefore jeopardizes the pursuit of research questions and theoretical models that go beyond a specific paradigm. As one example of a more integrative approach, recent research on illusory and spurious correlations has attempted to overcome the limitations of paradigm-specific models in the context of biased contingency perception and social stereotyping. Last but not least, the use of statistical models for the analysis of elementary cognitive functions is a means toward a more integrative terminology and theoretical perspective across different experimental paradigms and research domains.

  4. What experimental experience affects dogs' comprehension of human communicative actions?

    PubMed

    Hauser, Marc D; Comins, Jordan A; Pytka, Lisa M; Cahill, Donal P; Velez-Calderon, Sofia

    2011-01-01

    Studies of dogs report that individuals reliably respond to the goal-directed communicative actions (e.g., pointing) of human experimenters. All of these studies use some version of a multi-trial approach, thereby allowing for the possibility of rapid learning within an experimental session. The experiments reported here ask whether dogs can respond correctly to a communicative action based on only a single presentation, thereby eliminating the possibility of learning within the experimental context. We tested 173 dogs. For each dog reaching our test criteria, we used a single presentation of six different goal-directed actions within a session, asking whether they correctly follow to a target goal (container with concealed food) a (1) distal hand point, (2) step toward one container, (3) hand point to one container followed by step toward the other, (4) step toward one container and point to the other, (5) distal foot point with the experimenter's hands free, and (6) distal foot point with the experimenter's hands occupied. Given only a single presentation, dogs selected the correct container when the experimenter hand pointed, foot pointed with hands occupied, or stepped closer to the target container, but failed on the other actions, despite using the same method. The fact that dogs correctly followed foot pointing with hands occupied, but not hands free, suggests that they are sensitive to environmental constraints, and use this information to infer rational, goal-directed action. We discuss these results in light of the role of experience in recognizing communicative gestures, as well as the significance of coding criteria for studies of canine competence.

  5. Chronic Neuropathic Pain: It's about the Rhythm.

    PubMed

    Alshelh, Zeynab; Di Pietro, Flavia; Youssef, Andrew M; Reeves, Jenna M; Macey, Paul M; Vickers, E Russell; Peck, Christopher C; Murray, Greg M; Henderson, Luke A

    2016-01-20

    The neural mechanisms underlying the development and maintenance of chronic neuropathic pain remain unclear. Evidence from human investigations suggests that neuropathic pain is associated with altered thalamic burst firing and thalamocortical dysrhythmia. Additionally, experimental animal investigations show that neuropathic pain is associated with altered infra-slow (<0.1 Hz) frequency oscillations within the dorsal horn and somatosensory thalamus. The aim of this investigation was to determine whether, in humans, neuropathic pain was also associated with altered infra-slow oscillations within the ascending "pain" pathway. Using resting-state functional magnetic resonance imaging, we found that individuals with orofacial neuropathic pain have increased infra-slow oscillatory activity throughout the ascending pain pathway, including within the spinal trigeminal nucleus, somatosensory thalamus, thalamic reticular nucleus, and primary somatosensory cortex. Furthermore, these infra-slow oscillations were temporally coupled across these multiple sites and occurred at frequencies similar to calcium waves in activated astrocytes. The region encompassing the spinal trigeminal nucleus also displayed increased regional homogeneity, consistent with a local spread of neural activity by astrocyte activation. In contrast, no increase in oscillatory behavior within the ascending pain pathway occurred during acute noxious stimuli in healthy individuals. These data reveal increased oscillatory activity within the ascending pain pathway that likely underpins increased thalamocortical oscillatory activity, a self-sustaining thalamocortical dysrhythmia, and the constant perception of pain. Significance statement: Chronic neuropathic pain is associated with altered thalamic firing and thalamocortical dysrhythmia. The mechanisms responsible for these changes remain unknown. In this study, we report in individuals with neuropathic pain increased oscillatory neural activity within the

  6. Pain Intensity after an Ice Pack Application Prior to Venipuncture among School-Age Children: An Experimental Study

    ERIC Educational Resources Information Center

    Alalo, Fadeelah Mansour Ahmed; Ahmad, Awatef El Sayed; El Sayed, Hoda Mohamed Nafee

    2016-01-01

    Venipuncture and other invasive procedures as blood draws, intramuscular injections or heel pricks are the most commonly performed painful procedures in children. These can be a terrifying and painful experience for children and their families. The present study aimed to identify Pain intensity after an ice pack application prior to venipuncture…

  7. Craniofacial muscle pain: review of mechanisms and clinical manifestations.

    PubMed

    Svensson, P; Graven-Nielsen, T

    2001-01-01

    Epidemiologic surveys of temporomandibular disorders (TMD) have demonstrated that a considerable proportion of the population--up to 5% or 6%--will experience persistent pain severe enough to seek treatment. Unfortunately, the current diagnostic classification of craniofacial muscle pain is based on descriptions of signs and symptoms rather than on knowledge of pain mechanisms. Furthermore, the pathophysiology and etiology of craniofacial muscle pain are not known in sufficient detail to allow causal treatment. Many hypotheses have been proposed to explain cause-effect relationships; however, it is still uncertain what may be the cause of muscle pain and what is the effect of muscle pain. This article reviews the literature in which craniofacial muscle pain has been induced by experimental techniques in animals and human volunteers and in which the effects on somatosensory and motor function have been assessed under standardized conditions. This information is compared to the clinical correlates, which can be derived from the numerous cross-sectional studies in patients with craniofacial muscle pain. The experimental literature clearly indicates that muscle pain has significant effects on both somatosensory and craniofacial motor function. Typical somatosensory manifestations of experimental muscle pain are referred pain and increased sensitivity of homotopic areas. The craniofacial motor function is inhibited mainly during experimental muscle pain, but phase-dependent excitation is also found during mastication to reduce the amplitude and velocity of jaw movements. The underlying neurobiologic mechanisms probably involve varying combinations of sensitization of peripheral afferents, hyperexcitability of central neurons, and imbalance in descending pain modulatory systems. Reflex circuits in the brain stem seem important for the adjustment of sensorimotor function in the presence of craniofacial pain. Changes in somatosensory and motor function may therefore be

  8. Numerical and experimental investigations of human swimming motions.

    PubMed

    Takagi, Hideki; Nakashima, Motomu; Sato, Yohei; Matsuuchi, Kazuo; Sanders, Ross H

    2016-08-01

    This paper reviews unsteady flow conditions in human swimming and identifies the limitations and future potential of the current methods of analysing unsteady flow. The capability of computational fluid dynamics (CFD) has been extended from approaches assuming steady-state conditions to consideration of unsteady/transient conditions associated with the body motion of a swimmer. However, to predict hydrodynamic forces and the swimmer's potential speeds accurately, more robust and efficient numerical methods are necessary, coupled with validation procedures, requiring detailed experimental data reflecting local flow. Experimental data obtained by particle image velocimetry (PIV) in this area are limited, because at present observations are restricted to a two-dimensional 1.0 m(2) area, though this could be improved if the output range of the associated laser sheet increased. Simulations of human swimming are expected to improve competitive swimming, and our review has identified two important advances relating to understanding the flow conditions affecting performance in front crawl swimming: one is a mechanism for generating unsteady fluid forces, and the other is a theory relating to increased speed and efficiency.

  9. Numerical and experimental investigations of human swimming motions

    PubMed Central

    Takagi, Hideki; Nakashima, Motomu; Sato, Yohei; Matsuuchi, Kazuo; Sanders, Ross H.

    2016-01-01

    ABSTRACT This paper reviews unsteady flow conditions in human swimming and identifies the limitations and future potential of the current methods of analysing unsteady flow. The capability of computational fluid dynamics (CFD) has been extended from approaches assuming steady-state conditions to consideration of unsteady/transient conditions associated with the body motion of a swimmer. However, to predict hydrodynamic forces and the swimmer’s potential speeds accurately, more robust and efficient numerical methods are necessary, coupled with validation procedures, requiring detailed experimental data reflecting local flow. Experimental data obtained by particle image velocimetry (PIV) in this area are limited, because at present observations are restricted to a two-dimensional 1.0 m2 area, though this could be improved if the output range of the associated laser sheet increased. Simulations of human swimming are expected to improve competitive swimming, and our review has identified two important advances relating to understanding the flow conditions affecting performance in front crawl swimming: one is a mechanism for generating unsteady fluid forces, and the other is a theory relating to increased speed and efficiency. PMID:26699925

  10. Effect of d-fenfluramine on human experimental anxiety.

    PubMed

    Hetem, L A; de Souza, C J; Guimarães, E S; Zuardi, A W; Graeff, F G

    1996-10-01

    To investigate the role of 5-HT in human anxiety, the 5-HT releaser and uptake blocker d-fenfluramine (FEN) was administered to healthy volunteers under two models of experimental anxiety. The first was a simulated public speaking (SPS) test consisting of talking in front of a video camera, anxiety being evaluated mainly by self-rating scales. The second was a conditioned fear test, in which the changes in skin electrical conductance caused by a tone associated once with an aversive white noise were measured. The doses of 15 and 30 mg FEN, PO, decreased anxiety induced by SPS in a dose-dependent way, as indicated by the anxiety factor of Norris Visual Analogue Mood Scale. In the conditioned fear test, however, the amplitude and level of skin conductance responses to the conditioned aversive stimulus were not significantly changed by FEN. The differential effects of FEN in these human experimental models of anxiety, together with similar results reported in rats, support the view that 5-HT exerts a dual action on brain mechanisms regulating anxiety, facilitating conditioned while inhibiting unconditioned fear. The presumed reduction in unconditioned fear caused by FEN may have implications for the treatment of panic disorder.

  11. The Non-Human Primate Experimental Glaucoma Model

    PubMed Central

    Burgoyne, Claude F.

    2015-01-01

    The purpose of this report is to summarize the current strengths and weaknesses of the non-human primate (NHP) experimental glaucoma (EG) model through sections devoted to its history, methods, important findings, alternative optic neuropathy models and future directions. NHP EG has become well established for studying human glaucoma in part because the NHP optic nerve head (ONH) shares a close anatomic association with the human ONH and because it provides the only means of systematically studying the very earliest visual system responses to chronic IOP elevation, i.e. the conversion from ocular hypertension to glaucomatous damage. However, NHPs are impractical for studies that require large animal numbers, demonstrate spontaneous glaucoma only rarely, do not currently provide a model of the neuropathy at normal levels of IOP, and cannot easily be genetically manipulated, except through tissue-specific, viral vectors. The goal of this summary is to direct NHP EG and non-NHP EG investigators to the previous, current and future accomplishment of clinically relevant knowledge in this model. PMID:26070984

  12. Mechanism of inhibition by chlorpromazine of the human pain threshold sodium channel, Nav1.7.

    PubMed

    Lee, Su-Jin; Kim, Dong-Hyun; Hahn, Sang June; Waxman, Stephen G; Choi, Jin-Sung

    2017-02-03

    Chlorpromazine is a phenothiazine derivative which is primarily used for schizophrenia and occasionally for migraine. Because Nav1.7 plays an important role in pain sensation, we investigated whether chlorpromazine blocks the human Nav1.7 (hNav1.7) sodium current in HEK293 cells stably expressing hNav1.7 using the whole-cell patch-clamp technique. The peak current of hNav1.7 was reduced by chlorpromazine in a concentration-dependent manner with a half-maximal inhibitory concentration of 25.9±0.6μM and a Hill coefficient of 2.3±0.1. The calmodulin inhibitory peptide did not abolish the blockade of hNav1.7 currents by chlorpromazine. The blockade of hNav1.7 currents by chlorpromazine was completely and repeatedly reversible after washout. The half-maximal voltage of activation of hNav1.7 was not changed by chlorpromazine. However, chlorpromazine caused hyperpolarized the steady-state inactivation of hNav1.7. The recovery from inactivation in the presence of chlorpromazine was slower than in the absence of chlorpromazine. Chlorpromazine also showed strong use-dependent inhibition of the hNav1.7 current. Our results demonstrate that chlorpromazine blocks the hNav1.7 current in concentration-, state- and use-dependent manners and suggest that it merits further study for potential use in pain management.

  13. Transcranial direct current stimulation (tDCS) priming of 1Hz repetitive transcranial magnetic stimulation (rTMS) modulates experimental pain thresholds.

    PubMed

    Moloney, Tonya M; Witney, Alice G

    2013-02-08

    Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex (M1) modulate cortical excitability. Both techniques have been demonstrated to modulate chronic pain and experimental pain thresholds, but with inconsistent effects. Preconditioning M1 with weak tDCS (1mA) standardizes the effects of subsequent stimulation via rTMS on levels of cortical excitability. Here we examine whether 1Hz rTMS, primed with tDCS, could effectively standardize the modulation of pain thresholds. Thermal pain thresholds were determined using quantitative sensory testing (QST) of the palmar thenar of both hands in 12 healthy males pre and post tDCS - 1Hz rTMS over the hand area of the left M1. Cathodal tDCS preconditioning of 1Hz rTMS successfully reversed the normal suppressive effect of low frequency rTMS and effectively modulated cold and heat pain thresholds. Conversely, anodal tDCS - 1Hz rTMS led to a decrease in cold pain thresholds. Therefore, this study supports that preconditioning M1 using cathodal tDCS before subsequent stimulation via 1Hz rTMS facilitates the production of analgesia.

  14. Differences in pain-related fear acquisition and generalization: an experimental study comparing patients with fibromyalgia and healthy controls.

    PubMed

    Meulders, Ann; Jans, Anne; Vlaeyen, Johan W S

    2015-01-01

    Anomalies in fear learning, such as failure to inhibit fear to safe stimuli, lead to sustained anxiety, which in turn may augment pain. In the same vein, stimulus generalization is adaptive as it enables individuals to extrapolate the predictive value of 1 stimulus to similar stimuli. However, when fear spreads in an unbridled way to novel technically safe stimuli, stimulus generalization becomes maladaptive and may lead to dysfunctional avoidance behaviors and culminate in severe pain disability. In a voluntary movement conditioning paradigm, we compared the acquisition and generalization of pain-related fear in patients with fibromyalgia (FM) and healthy controls. During acquisition, participants received predictable pain in 1 context (ie, 1 movement predicts pain, whereas another does not), and unpredictable pain in another (ie, pain never contingent upon movement). Fear generalization to novel movements (resembling the original painful or nonpainful movement) was tested in both contexts. Results indicated that the FM group showed slower differential acquisition of pain-related fear in the predictable context, and more contextual pain-related fear in the unpredictable context. Fear of movement-related pain spreads selectively to novel movements similar to the original painful movement, and not to those resembling the nonpainful movement in the healthy controls, but nondifferential fear generalization was observed in FM. As expected, in the unpredictable context, we also observed nondifferential fear generalization; this effect was more pronounced in FM. Given the status of overgeneralization as a plausible transdiagnostic pathogenic marker, we believe that this research might increase our knowledge about pathogenesis of musculoskeletal widespread pain.

  15. Relationships between craniofacial pain and bruxism.

    PubMed

    Svensson, P; Jadidi, F; Arima, T; Baad-Hansen, L; Sessle, B J

    2008-07-01

    A still commonly held view in the literature and clinical practice is that bruxism causes pain because of overloading of the musculoskeletal tissue and craniofacial pain, on the other hand, triggers more bruxism. Furthermore, it is often believed that there is a dose-response gradient so that more bruxism (intensity, duration) leads to more overloading and pain. Provided the existence of efficient techniques to treat bruxism, it would be straightforward in such a simple system to target bruxism as the cause of pain and hence treat the pain. Of course, human biological systems are much more complex and therefore, it is no surprise that the relationship between bruxism and pain is far from being simple or even linear. Indeed, there are unexpected relationships, which complicate the establishment of adequate explanatory models. Part of the reason is the complexity of the bruxism in itself, which presents significant challenges related to operationalized criteria and diagnostic tools and underlying pathophysiology issues, which have been dealt with in other reviews in this issue. However, another important reason is the multifaceted nature of craniofacial pain. This review will address our current understanding of classification issues, epidemiology and neurobiological mechanisms of craniofacial pain. Experimental models of bruxism may help to further the understanding of the relationship between craniofacial pain and bruxism in addition to insights from intervention studies. The review will enable clinicians to understand the reasons why simple cause-effect relationships between bruxism and craniofacial pain are inadequate and the current implications for management of craniofacial pain.

  16. An experimental study of human pilot's scanning behavior

    NASA Technical Reports Server (NTRS)

    Washizu, K.; Tanaka, K.; Osawa, T.

    1982-01-01

    The scanning behavior and the control behavior of the pilot who manually controls the two-variable system, which is the most basic one of multi-variable systems are investigated. Two control tasks which simulate the actual airplane attitude and airspeed control were set up. In order to simulate the change of the situation where the pilot is placed, such as changes of flight phase, mission and others, the subject was requested to vary the weightings, as his control strategy, upon each task. Changes of human control dynamics and his canning properties caused by the modification of the situation were investigated. By making use of the experimental results, the optimal model of the control behavior and the scanning behavior of the pilot in the two-variable system is proposed from the standpoint of making the performance index minimal.

  17. Mutations that Cause Human Disease: A Computational/Experimental Approach

    SciTech Connect

    Beernink, P; Barsky, D; Pesavento, B

    2006-01-11

    International genome sequencing projects have produced billions of nucleotides (letters) of DNA sequence data, including the complete genome sequences of 74 organisms. These genome sequences have created many new scientific opportunities, including the ability to identify sequence variations among individuals within a species. These genetic differences, which are known as single nucleotide polymorphisms (SNPs), are particularly important in understanding the genetic basis for disease susceptibility. Since the report of the complete human genome sequence, over two million human SNPs have been identified, including a large-scale comparison of an entire chromosome from twenty individuals. Of the protein coding SNPs (cSNPs), approximately half leads to a single amino acid change in the encoded protein (non-synonymous coding SNPs). Most of these changes are functionally silent, while the remainder negatively impact the protein and sometimes cause human disease. To date, over 550 SNPs have been found to cause single locus (monogenic) diseases and many others have been associated with polygenic diseases. SNPs have been linked to specific human diseases, including late-onset Parkinson disease, autism, rheumatoid arthritis and cancer. The ability to predict accurately the effects of these SNPs on protein function would represent a major advance toward understanding these diseases. To date several attempts have been made toward predicting the effects of such mutations. The most successful of these is a computational approach called ''Sorting Intolerant From Tolerant'' (SIFT). This method uses sequence conservation among many similar proteins to predict which residues in a protein are functionally important. However, this method suffers from several limitations. First, a query sequence must have a sufficient number of relatives to infer sequence conservation. Second, this method does not make use of or provide any information on protein structure, which can be used to

  18. Heating and pain sensation produced in human skin by millimeter waves: comparison to a simple thermal model.

    PubMed

    Walters, T J; Blick, D W; Johnson, L R; Adair, E R; Foster, K R

    2000-03-01

    Cutaneous thresholds for thermal pain were measured in 10 human subjects during 3-s exposures at 94 GHz continuous wave microwave energy at intensities up to approximately 1.8 W cm(-2). During each exposure, the temperature increase at the skin's surface was measured by infrared thermography. The mean (+/- s.e.m.) baseline temperature of the skin was 34.0+/-0.2 degrees C. The threshold for pricking pain was 43.9+/-0.7 degrees C, which corresponded to an increase in surface temperature of approximately 9.9 degrees C (from 34.0 degrees C to 43.9 degrees C). The measured increases in surface temperature were in good agreement with a simple thermal model that accounted for heat conduction and for the penetration depth of the microwave energy into tissue. Taken together, these results support the use of the model for predicting thresholds of thermal pain at other millimeter wave (length) frequencies.

  19. A Brief History of Experimentation on Condemned and Executed Humans

    PubMed Central

    Kevorkian, Jack

    1985-01-01

    Experimentation on condemned men is assumed to have been a common practice in ancient Alexandria, but disappeared in Rome and during the Middle Ages. Sporadic cases were documented in the Renaissance and afterward, involving experiments both before and immediately after execution. The advent of the guillotine raised the question of possible persistence of consciousness after execution and that spurred much electrophysiological study of freshly decapitated heads and bodies. In 19th-century Europe, interest focused on cardiac function immediately after beheading. In the early 20th century, many condemned men in the Philippines were used by American physicians for their research on plague and beriberi. Briefly discussed is the relevance of the practice of human sacrifice in Homeric Greece and Mayan Yucatan, as well as experiments on black slaves in America. The Nazi medical crimes of World War II encompass a totally different morality, and are not really comparable to the matter at hand. They have, however, so stirred emotions as to discredit the general concept of experimentation associated with capital punishment. Even within the framework of our system of jurisprudence, the altruistic desires of many now languishing on death row are being ignored. PMID:3884824

  20. Evidence of Heterosynaptic LTD in the Human Nociceptive System: Superficial Skin Neuromodulation Using a Matrix Electrode Reduces Deep Pain Sensitivity

    PubMed Central

    Mücke, Martin; Cuhls, Henning; Radbruch, Lukas; Weigl, Tobias; Rolke, Roman

    2014-01-01

    Long term depression (LTD) is a neuronal learning mechanism after low frequency stimulation (LFS). This study compares two types of electrodes (concentric vs. matrix) and stimulation frequencies (4 and 30 Hz) to examine homo- and heterosynaptic effects indirectly depicted from the somatosensory profile of healthy subjects. Both electrodes were compared in a prospective, randomized, controlled cross-over study using 4 Hz as the conditioning LFS compared to 30 Hz (intended sham condition). Quantitative sensory testing (QST) was used to examine 13 thermal and mechanical detection and pain thresholds. Sixteen healthy volunteers (10 women, age 31.0±12.7 years) were examined. Depending on the electrodes and frequencies used a divergent pattern of sensory minus signs occurred. Using LFS the concentric electrode increased thermal thresholds, while the matrix electrode rather increased mechanical including deep pain thresholds. Findings after cutaneous neuromodulation using LFS and a matrix electrode are consistent with the concept of heterosynaptic LTD in the human nociceptive system, where deep pain sensitivity was reduced after superficial stimulation of intraepidermal nerve fibres. Cutaneous neuromodulation using LFS and a matrix electrode may be a useful tool to influence deep pain sensitivity in a variety of chronic pain syndromes. PMID:25229556

  1. Nerve compression and pain in human volunteers with narrow vs wide tourniquets

    PubMed Central

    Kovar, Florian M; Jaindl, Manuela; Oberleitner, Gerhard; Endler, Georg; Breitenseher, Julia; Prayer, Daniela; Kasprian, Gregor; Kutscha-Lissberg, Florian

    2015-01-01

    AIM: To assess the clinical effects and the morphological grade of nerve compression. METHODS: In a prospective single-center randomized, open study we assessed the clinical effects and the morphological grade of nerve compression during 20 min of either a silicon ring (group A) or pneumatic tourniquet (group B) placement variantly on the upper non-dominant limb in 14 healthy human volunteers. Before and during compression, the median and radial nerves were visualized in both groups by 3 Tesla MR imaging, using high resolutional (2.5 mm slice thickness) axial T2-weighted sequences. RESULTS: In group A, Visual analog pain scale was 5.4 ± 2.2 compared to results of group B, 2.9 ± 2.5, showing a significant difference (P = 0.028). FPS levels in group A were 2.6 ± 0.9 compared to levels in group B 1.6 ± 1, showing a significant difference (P = 0.039). Results related to measureable effect on median and radial nerve function were equal in both groups. No undue pressure signs on the skin, redness or nerve damage occurred in either group. There was no significant difference in the diameters of the nerves without and under compression in either group on T2 weighted images. CONCLUSION: Based on our results, no differences between narrow and wide tourniquets were identified. Silicon ring tourniquets can be regarded as safe for short time application. PMID:25992317

  2. A randomized, double-blind, placebo-controlled, cross-over study to evaluate analgesic activity of Terminalia chebula in healthy human volunteers using a mechanical pain model

    PubMed Central

    Pokuri, Venkata Kishan; Kumar, Chiranjeevi Uday; Pingali, Usharani

    2016-01-01

    Background and Aims: To evaluate analgesic activity and safety of single oral dose (1000 mg) of Terminalia chebula using a mechanical pain model in healthy human volunteers. Material and Methods: Twelve healthy volunteers were randomized to receive either single oral dose of 2 capsules of T. chebula 500 mg each or identical placebo capsules in a double-blinded manner. Mechanical pain was assessed using Ugo basile analgesy meter (Randall–Selitto test) before and 3 h after administration of test drug. The parameters evaluated were pain threshold force and time; pain tolerance force and time. A washout period of 1-week was given for crossover between active drug and placebo. Results: Terminalia chebula significantly increased the mean percentage change for pain threshold force and time, and pain tolerance force and time compared to placebo (P < 0.001). The mean percentage change for pain threshold force and time (20.8% and 21.0%) was increased more than that of pain tolerance force and time (13.4% and 13.4%). No adverse drug reaction was reported with either of the study medications during the study period. Conclusion: T. chebula significantly increased pain threshold and pain tolerance compared to placebo. Both the study medications were well tolerated. Further multiple dose studies may be needed to establish the analgesic efficacy of the drug in patients suffering from osteoarthritis, rheumatoid arthritis and other painful conditions. PMID:27625480

  3. Fetal pain.

    PubMed

    Rokyta, Richard

    2008-12-01

    The fetus reacts to nociceptive stimulations through different motor, autonomic, vegetative, hormonal, and metabolic changes relatively early in the gestation period. With respect to the fact that the modulatory system does not yet exist, the first reactions are purely reflexive and without connection to the type of stimulus. While the fetal nervous system is able to react through protective reflexes to potentially harmful stimuli, there is no accurate evidence concerning pain sensations in this early period. Cortical processes occur only after thalamocortical connections and pathways have been completed at the 26th gestational week. Harmful (painful) stimuli, especially in fetuses have an adverse effect on the development of humans regardless of the processes in brain. Moreover, pain activates a number of subcortical mechanisms and a wide spectrum of stress responses influence the maturation of thalamocortical pathways and other cortical activation which are very important in pain processing.

  4. Feasibility of Human Amniotic Fluid Derived Stem Cells in Alleviation of Neuropathic Pain in Chronic Constrictive Injury Nerve Model

    PubMed Central

    Chiang, Chien-Yi; Liu, Shih-An; Sheu, Meei-Ling; Chen, Fu-Chou; Chen, Chun-Jung; Su, Hong-Lin; Pan, Hung-Chuan

    2016-01-01

    Purpose The neurobehavior of neuropathic pain by chronic constriction injury (CCI) of sciatic nerve is very similar to that in humans, and it is accompanied by a profound local inflammation response. In this study, we assess the potentiality of human amniotic fluid derived mesenchymal stem cells (hAFMSCs) for alleviating the neuropathic pain in a chronic constriction nerve injury model. Methods and Methods This neuropathic pain animal model was conducted by four 3–0 chromic gut ligatures loosely ligated around the left sciatic nerve in Sprague—Dawley rats. The intravenous administration of hAFMSCs with 5x105 cells was conducted for three consecutive days. Results The expression IL-1β, TNF-α and synaptophysin in dorsal root ganglion cell culture was remarkably attenuated when co-cultured with hAFMSCs. The significant decrease of PGP 9.5 in the skin after CCI was restored by administration of hAFMSCs. Remarkably increased expression of CD 68 and TNF-α and decreased S-100 and neurofilament expression in injured nerve were rescued by hAFMSCs administration. Increases in synaptophysin and TNF-α over the dorsal root ganglion were attenuated by hAFMSCs. Significant expression of TNF-α and OX-42 over the dorsal spinal cord was substantially attenuated by hAFMSCs. The increased amplitude of sensory evoked potential as well as expression of synaptophysin and TNF-α expression was alleviated by hAFMSCs. Human AFMSCs significantly improved the threshold of mechanical allodynia and thermal hyperalgesia as well as various parameters of CatWalk XT gait analysis. Conclusion Human AFMSCs administration could alleviate the neuropathic pain demonstrated in histomorphological alteration and neurobehavior possibly through the modulation of the inflammatory response. PMID:27441756

  5. Current evidence for a modulation of low back pain by human genetic variants.

    PubMed

    Tegeder, Irmgard; Lötsch, Jörn

    2009-08-01

    The manifestation of chronic back pain depends on structural, psychosocial, occupational and genetic influences. Heritability estimates for back pain range from 30% to 45%. Genetic influences are caused by genes affecting intervertebral disc degeneration or the immune response and genes involved in pain perception, signalling and psychological processing. This inter-individual variability which is partly due to genetic differences would require an individualized pain management to prevent the transition from acute to chronic back pain or improve the outcome. The genetic profile may help to define patients at high risk for chronic pain. We summarize genetic factors that (i) impact on intervertebral disc stability, namely Collagen IX, COL9A3, COL11A1, COL11A2, COL1A1, aggrecan (AGAN), cartilage intermediate layer protein, vitamin D receptor, metalloproteinsase-3 (MMP3), MMP9, and thrombospondin-2, (ii) modify inflammation, namely interleukin-1 (IL-1) locus genes and IL-6 and (iii) and pain signalling namely guanine triphosphate (GTP) cyclohydrolase 1, catechol-O-methyltransferase, mu opioid receptor (OPMR1), melanocortin 1 receptor (MC1R), transient receptor potential channel A1 and fatty acid amide hydrolase and analgesic drug metabolism (cytochrome P450 [CYP]2D6, CYP2C9).

  6. Mast cells in human and experimental cardiometabolic diseases.

    PubMed

    Shi, Guo-Ping; Bot, Ilze; Kovanen, Petri T

    2015-11-01

    Mast cells, like many other types of inflammatory cell, perform pleiotropic roles in cardiometabolic diseases such as atherosclerosis, abdominal aortic aneurysms, obesity, and diabetes mellitus, as well as complications associated with these diseases. Low numbers of mast cells are present in the heart, aorta, and adipose tissue of healthy humans, but patients with cardiometabolic diseases and animals with experimentally-induced cardiometabolic pathologies have high numbers of mast cells with increased activity in the affected tissues. Mediators released by the activated mast cells, such as chemokines, cytokines, growth factors, heparin, histamine, and proteases, not only function as biomarkers of cardiometabolic diseases, but might also directly contribute to the pathogenesis of such diseases. Mast-cell mediators impede the functions of vascular cells, the integrity of the extracellular matrix, and the activity of other inflammatory cells, thereby contributing to the pathobiology of the conditions at multiple levels. In mouse models, mast-cell activation aggravates the progression of various cardiometabolic pathologies, whereas a genetic deficiency or pharmacological stabilization of mast cells, or depletion or inhibition of specific mast-cell mediators, tends to delay the progression of such conditions. Pharmacological inhibition of mast-cell activation or their targeted effector functions offers potential novel therapeutic strategies for patients with cardiometabolic disorders.

  7. The effect of experimental muscle pain on the amplitude and velocity sensitivity of jaw closing muscle spindle afferents.

    PubMed

    Masri, Radi; Ro, Jin Y; Capra, Norman

    2005-07-19

    The effect of experimental muscle pain on the amplitude and velocity sensitivity of muscle spindle primary afferent neurons in the trigeminal mesencephalic nucleus (Vmes) was examined. Extracellular recordings were made from 45 neurons designated as spindle primary- or secondary-like on the basis of their response to ramp-and-hold jaw movements. Velocity sensitivity was assessed in spindle primary-like afferents by calculating the mean dynamic index of each unit in response to three different velocities of jaw opening before and after intramuscular injection with hypertonic saline (HS, 5%, 100 microl). The amplitude sensitivity of all jaw muscle spindle afferents was assessed by calculating the mean firing rate of each unit in response to three different amplitudes of jaw openings during both the open and hold phases of the movement and with best-fit lines obtained, using linear regression analysis, before and after HS injection. The variance of the two regression lines obtained for each unit before and after the injection was compared using the coincidence test, and changes in intercept and slope were determined. Seventy-five percent of the primary-like units and 80% of the secondary-like units presented with changes in static behavior after HS injection. Thirty-six percent of the primary-like units showed changes in dynamic behavior. Injection of isotonic saline (control) did not alter the responses of the spindle afferent to jaw opening. Thus, our results demonstrate that the predominant effect of noxious stimulation was a shift in the amplitude sensitivity of both spindle primary-like and secondary-like afferents and, to a lesser extent, the velocity sensitivity of the spindle primary-like unit. In accordance with earlier studies in the cat hindlimb and neck muscles, these results suggest that the activation of masseter muscle nociceptor alters spindle afferent responses to stretch acting primarily through static gamma motor neurons.

  8. Method for palliation of pain in human bone cancer using therapeutic tin-117m compositions

    DOEpatents

    Srivastava, Suresh C.; Meinken, George E.; Mausner, Leonard F.; Atkins, Harold L.

    1998-12-29

    The invention provides a method for the palliation of bone pain due to cancer by the administration of a unique dosage of a tin-117m (Sn-117m) stannic chelate complex in a pharmaceutically acceptable composition. In addition, the invention provides a method for simultaneous palliation of bone pain and radiotherapy in cancer patients using compositions containing Sn-117m chelates. The invention also provides a method for palliating bone pain in cancer patients using Sn-117m-containing compositions and monitoring patient status by imaging the distribution of the Sn-117m in the patients. Also provided are pharmaceutically acceptable compositions containing Sn-117m chelate complexes for the palliation of bone pain in cancer patients.

  9. Method for palliation of pain in human bone cancer using therapeutic tin-117m compositions

    DOEpatents

    Srivastava, S.C.; Meinken, G.E.; Mausner, L.F.; Atkins, H.L.

    1998-12-29

    The invention provides a method for the palliation of bone pain due to cancer by the administration of a unique dosage of a tin-117m (Sn-117m) stannic chelate complex in a pharmaceutically acceptable composition. In addition, the invention provides a method for simultaneous palliation of bone pain and radiotherapy in cancer patients using compositions containing Sn-117m chelates. The invention also provides a method for palliating bone pain in cancer patients using Sn-117m-containing compositions and monitoring patient status by imaging the distribution of the Sn-117m in the patients. Also provided are pharmaceutically acceptable compositions containing Sn-117m chelate complexes for the palliation of bone pain in cancer patients. 5 figs.

  10. Surgical animal models of neuropathic pain: Pros and Cons.

    PubMed

    Challa, Siva Reddy

    2015-03-01

    One of the biggest challenges for discovering more efficacious drugs for the control of neuropathic pain has been the diversity of chronic pain states in humans. It is now acceptable that different mechanisms contribute to normal physiologic pain, pain arising from tissue damage and pain arising from injury to the nervous system. To study pain transmission, spot novel pain targets and characterize the potential analgesic profile of new chemical entities, numerous experimental animal pain models have been developed that attempt to simulate the many human pain conditions. Among the neuropathic pain models, surgical models have paramount importance in the induction of pain states. Many surgical animal models exist, like the chronic constriction injury (CCI) to the sciatic nerve, partial sciatic nerve ligation (pSNL), spinal nerve ligation (SNL), spared nerve injury (SNI), brachial plexus avulsion (BPA), sciatic nerve transaction (SNT) and sciatic nerve trisection. Most of these models induce responses similar to those found in causalgia, a syndrome of sustained burning pain often seen in the distal extremity after partial peripheral nerve injury in humans. Researchers most commonly use these surgical models in both rats and mice during drug discovery to screen new chemical entities for efficacy in the area of neuropathic pain. However, there is scant literature that provides a comparative discussion of all these surgical models. Each surgical model has its own benefits and limitations. It is very difficult for a researcher to choose a suitable surgical animal model to suit their experimental set-up. Therefore, particular attention has been given in this review to comparatively provide the pros and cons of each model of surgically induced neuropathic pain.

  11. Ischemic compression and joint mobilisation for the treatment of nonspecific myofascial foot pain: findings from two quasi-experimental before-and-after studies

    PubMed Central

    Hains, Guy; Boucher, Pierre B.; Lamy, Anne-Marie

    2015-01-01

    Objective: The aim of this study was to evaluate the efficacy of myofascial therapy involving ischemic compression on trigger points in combination with mobilization therapy on patients with chronic nonspecific foot pain. Study design: Two quasi-experimental before-and-after studies involving two different baseline states. Method: Foot pain patients at a private clinic were divided into two separate cohorts: A, custom orthotic users; and B, non-users. In Study A, 31 users received 15 experimental treatments consisting of ischemic compressions on trigger points and mobilization of articulations through the foot immediately after study enrollment. In study B, ten non-users were prescribed a soft prefabricated insole and were monitored for five weeks before subsequently receiving 15 experimental treatments after the initial five-week delay. Outcome measures: The Foot Function Index (FFI) and patients’ perceived improvement score (PIS) on a scale from 0% to 100%. Results: The Study A group (n=31) maintained a significant reduction in the FFI at all three follow-up evaluations. Mean improvement from baseline in FFI was 47%, 49% and 56% at 0, 1 and 6 months, respectively, post-treatment. Mean PIS was 58%, 57%, and 58%, again at 0, 1 and 6 months post-treatment. For the Study B group, mean improvement in FFI was only 19% after the monitoring period, and 64% after the experimental treatment period. Mean PIS was 31% after monitoring, and 78% after experimental treatment. In repeated measures analyses, experimental treatment was associated with a significant main effect in both of these before-and after studies (all P values<0.01). Conclusion: Combined treatment involving ischemic compression and joint mobilization for chronic foot pain is associated with significant improvements in functional and self-perceived improvement immediately and at up to six-months post-treatment. Further validation of this treatment approach within a randomized controlled trial is needed. PMID

  12. Transcranial magnetic stimulation over human secondary somatosensory cortex disrupts perception of pain intensity.

    PubMed

    Lockwood, Patricia L; Iannetti, Gian Domenico; Haggard, Patrick

    2013-09-01

    Pain is a complex sensory experience resulting from the activity of a network of brain regions. However, the functional contribution of individual regions in this network remains poorly understood. We delivered single-pulse transcranial magnetic stimulation (TMS) to the contralateral primary somatosensory cortex (S1), secondary somatosensory cortex (S2) and vertex (control site) 120 msec after selective stimulation of nociceptive afferents using neodymium:yttrium-aluminium-perovskite (Nd:YAP) laser pulses causing painful sensations. Participants were required to judge either the intensity (medium/high) or the spatial location (proximal/distal) of the stimulus in a two-alternative forced choice paradigm. When TMS pulses were delivered over S2, participants' ability to judge pain intensity was disrupted, as compared to S1 and vertex (control) stimulation. Signal-detection analysis demonstrated a loss of sensitivity to stimulation intensity, rather than a shift in perceived pain level or response bias. We did not find any effect of TMS on the ability to localise nociceptive stimuli on the skin. The novel finding that TMS over S2 can disrupt perception of pain intensity suggests a causal role for S2 in encoding of pain intensity.

  13. Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model: a study protocol

    PubMed Central

    Springborg, Anders D.; Jensen, Elisabeth K.; Taylor, Bradley K.; Werner, Mads U.

    2016-01-01

    Abstract Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion. The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose–response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization. Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm2). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days—days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2

  14. Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs.

    PubMed

    Pleticha, Josef; Heilmann, Lukas F; Evans, Christopher H; Asokan, Aravind; Samulski, Richard Jude; Beutler, Andreas S

    2014-09-02

    Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting.

  15. Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs

    PubMed Central

    2014-01-01

    Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting. PMID:25183392

  16. Antinociceptive Effect of Intrathecal Injection of Genetically Engineered Human Bone Marrow Stem Cells Expressing the Human Proenkephalin Gene in a Rat Model of Bone Cancer Pain

    PubMed Central

    Tian, Yuke; Li, Haifeng; Zhang, Dengwen; Sun, Qiang

    2017-01-01

    Background. This study aimed to investigate the use of human bone marrow mesenchymal stem cells (hBMSCs) genetically engineered with the human proenkephalin (hPPE) gene to treat bone cancer pain (BCP) in a rat model. Methods. Primary cultured hBMSCs were passaged and modified with hPPE, and the cell suspensions (6 × 106) were then intrathecally injected into a rat model of BCP. Paw mechanical withdrawal threshold (PMWT) was measured before and after BCP. The effects of hPPE gene transfer on hBMSC bioactivity were analyzed in vitro and in vivo. Results. No changes were observed in the surface phenotypes and differentiation of hBMSCs after gene transfer. The hPPE-hBMSC group showed improved PMWT values on the ipsilateral side of rats with BCP from day 12 postoperatively, and the analgesic effect was reversed by naloxone. The levels of proinflammatory cytokines such as IL-1β and IL-6 were ameliorated, and leucine-enkephalin (L-EK) secretion was augmented, in the hPPE-engineered hBMSC group. Conclusion. The intrathecal administration of BMSCs modified with the hPPE gene can effectively relieve pain caused by bone cancer in rats and might be a potentially therapeutic tool for cancer-related pain in humans. PMID:28286408

  17. Vitamin D Status Is Not Associated with Outcomes of Experimentally-Induced Muscle Weakness and Pain in Young, Healthy Volunteers

    PubMed Central

    Ring, Susan M.; Dannecker, Erin A.; Peterson, Catherine A.

    2010-01-01

    Vitamin D receptors have been identified in skeletal muscle; and symptoms of vitamin D deficiency include muscle weakness and pain. Moreover, increased serum 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with improved muscle function. To further clarify the importance of vitamin D to muscle, we examined the association between vitamin D status and exercise-induced muscle pain and weakness in healthy people. Muscle damage to the elbow flexors was induced with eccentric exercise (EE) in 48 individuals (22.5 ± 3.2 yrs). Muscle pain ratings following unloaded movement and peak isometric force (IF) were collected before EE and for 4 days post-EE. Linear regression was used to determine if serum 25(OH)D was a predictor of any outcome. In males, R2-values from 0.48 to 1.00. R2 for IF ranged from 0 to 0.02 and P-values from 0.48 to 1.00. In females, R2 for pain ratings ranged from 0.01 to 0.11 and P-values from 0.14 to 0.59. R2 for IF ranged from 0 to 0.04 and P-values from 0.41 to 0.90. In conclusion, vitamin D status did not predict muscle pain or strength after EE-induced muscle damage in young healthy men and women. PMID:21209718

  18. Central Projection of Pain Arising from Delayed Onset Muscle Soreness (DOMS) in Human Subjects

    PubMed Central

    Zimmermann, Katharina; Leidl, Caroline; Kaschka, Miriam; Carr, Richard W.; Terekhin, Pavel; Handwerker, Hermann O.; Forster, Clemens

    2012-01-01

    Delayed onset muscle soreness (DOMS) is a subacute pain state arising 24–48 hours after a bout of unaccustomed eccentric muscle contractions. Functional magnetic resonance imaging (fMRI) was used to examine the patterns of cortical activation arising during DOMS-related pain in the quadriceps muscle of healthy volunteers evoked by either voluntary contraction or physical stimulation. The painful movement or physical stimulation of the DOMS-affected thigh disclosed widespread activation in the primary somatosensory and motor (S1, M1) cortices, stretching far beyond the corresponding areas somatotopically related to contraction or physical stimulation of the thigh; activation also included a large area within the cingulate cortex encompassing posteroanterior regions and the cingulate motor area. Pain-related activations were also found in premotor (M2) areas, bilateral in the insular cortex and the thalamic nuclei. In contrast, movement of a DOMS-affected limb led also to activation in the ipsilateral anterior cerebellum, while DOMS-related pain evoked by physical stimulation devoid of limb movement did not. PMID:23056613

  19. Groin pain

    MedlinePlus

    Pain - groin; Lower abdominal pain; Genital pain; Perineal pain ... Common causes of groin pain include: Pulled muscle, tendon, or ligaments in the leg: This problem often occurs in people who play sports such as ...

  20. Human esophageal response during chest pain induced by swallowing cold liquids.

    PubMed

    Meyer, G W; Castell, D O

    1981-11-06

    Normal persons often note chest or back pain during rapid ingestion of cold liquids, commonly believed to result from cold-induced "spasm" of esophageal muscle. We studied the effects of swallowing cold liquids on esophageal function in five normal subjects, aged 20 to 44 years, by comparing their response to cold ice cream (-5 degrees C) and room temperature ice cream mix (20 degrees C). Decreased peristaltic amplitude was seen during cold ice cream ingestion, primarily in the midesophagus. When seven subjects rapidly ingested ice cream until chest pain was produced and maintained for at least 60 s, complete absence of motor activity in the distal esophagus occurred, with slow return to normal during the ensuing five minutes. Our studies indicate that ingestion of cold liquids significantly depresses peristaltic amplitudes and frequency of peristalsis in normal persons, and pain is associated with complete absence of motor activity in the body of the esophagus, rather than esophageal "spasm" as commonly believed.

  1. The effect of local vs remote experimental pain on motor learning and sensorimotor integration using a complex typing task.

    PubMed

    Dancey, Erin; Murphy, Bernadette A; Andrew, Danielle; Yielder, Paul

    2016-08-01

    Recent work demonstrated that capsaicin-induced acute pain improved motor learning performance; however, baseline accuracy was very high, making it impossible to discern the impact of acute pain on motor learning and retention. In addition, the effects of the spatial location of capsaicin application were not explored. Two experiments were conducted to determine the interactive effects of acute pain vs control (experiment 1) and local vs remote acute pain (experiment 2) on motor learning and sensorimotor processing. For both experiments, somatosensory evoked potential (SEP) amplitudes and motor learning acquisition and retention (accuracy and response time) data were collected at baseline, after application, and after motor learning. Experiment 1: N11 (P < 0.05), N13 (P < 0.05), and N30 (P < 0.05) SEP peak amplitudes increased after motor learning in both groups, whereas the N20 SEP peak increased in the control group (P < 0.05). At baseline, the intervention group outperformed the control group in accuracy (P < 0.001). Response time improved after motor learning (P < 0.001) and at retention (P < 0.001). Experiment 2: The P25 SEP peak decreased in the local group after application of capsaicin cream (P < 0.01), whereas the N30 SEP peaks increased after motor learning in both groups (P < 0.05). Accuracy improved in the local group at retention (P < 0.005), and response time improved after motor learning (P < 0.005) and at retention (P < 0.001). This study suggests that acute pain may increase focal attention to the body part used in motor learning, contributing to our understanding of how the location of pain impacts somatosensory processing and the associated motor learning.

  2. 40 CFR 158.250 - Experimental use permit data requirements for human exposure.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Experimental use permit data requirements for human exposure. 158.250 Section 158.250 Protection of Environment ENVIRONMENTAL PROTECTION... Experimental use permit data requirements for human exposure. No data for applicator exposure and...

  3. 40 CFR 158.250 - Experimental use permit data requirements for human exposure.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Experimental use permit data requirements for human exposure. 158.250 Section 158.250 Protection of Environment ENVIRONMENTAL PROTECTION... Experimental use permit data requirements for human exposure. No data for applicator exposure and...

  4. 40 CFR 158.250 - Experimental use permit data requirements for human exposure.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Experimental use permit data requirements for human exposure. 158.250 Section 158.250 Protection of Environment ENVIRONMENTAL PROTECTION... Experimental use permit data requirements for human exposure. No data for applicator exposure and...

  5. 40 CFR 158.250 - Experimental use permit data requirements for human exposure.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Experimental use permit data requirements for human exposure. 158.250 Section 158.250 Protection of Environment ENVIRONMENTAL PROTECTION... Experimental use permit data requirements for human exposure. No data for applicator exposure and...

  6. 40 CFR 158.250 - Experimental use permit data requirements for human exposure.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Experimental use permit data requirements for human exposure. 158.250 Section 158.250 Protection of Environment ENVIRONMENTAL PROTECTION... Experimental use permit data requirements for human exposure. No data for applicator exposure and...

  7. Spatial sensory organization and body representation in pain perception.

    PubMed

    Haggard, Patrick; Iannetti, Gian Domenico; Longo, Matthew R

    2013-02-18

    Pain is a subjective experience that protects the body. This function implies a special relation between the brain mechanisms underlying pain perception and representation of the body. All sensory systems involve the body for the trivial reason that sensory receptors are located in the body. The nociceptive system of detecting noxious stimuli comprises two classes of peripheral afferents, Aδ and C nociceptors, that cover almost the entire body surface. We review evidence from experimental studies of pain in humans and other animals suggesting that Aδ skin nociceptors project to a spatially-organised, somatotopic map in the primary somatosensory cortex. While the relation between pain perception and homeostatic regulation of bodily systems is widely acknowledged, the organization of nociceptive information into spatial maps of the body has received little attention. Importantly, the somatotopic neural organization of pain systems can shed light on pain-related plasticity and pain modulation. Finally, we show that the neural coding of noxious stimuli, and consequent experience of pain, are both strongly influenced when cognitive representations of the body are activated by viewing the body, as opposed to viewing another object - an effect we term 'visual analgesia'. We argue that pain perception involves some of the representational properties of exteroceptive senses, such as vision and touch. Pain, however, has the unique feature that the content of representation is the body itself, rather than any external object of perception. We end with some suggestions regarding how linking pain to body representation could shed light on clinical conditions, notably chronic pain.

  8. The Effect of Intrathecal Administration of Muscimol on Modulation of Neuropathic Pain Symptoms Resulting from Spinal Cord Injury; an Experimental Study

    PubMed Central

    Hosseini, Marjan; Karami, Zohreh; Janzadenh, Atousa; Jameie, Seyed Behnamedin; Haji Mashhadi, Zahra; Yousefifard, Mahmoud; Nasirinezhad, Farinaz

    2014-01-01

    Introduction: Neuropathic pain can be very difficult to treat and it is one of the important medical challenging about pain treatments. Muscimol as a new agonist of gamma-Aminobutyric acid receptor type A (GABAA) have been introduced for pain management. Thus, the present study was performed to evaluate the pain alleviating effect of intrathecal injection of different doses of muscimol as GABAA receptor agonist in spinal cord injury (SCI) model of neuropathic pain. Methods: In the present experimental study, male Wistar rats were treated by muscimol 0.01, 0.1 or 1 µg/10ul, intrathecally (i.t.) three weeks after induction of spinal cord injury using compression injury model. Neuropathic pain symptoms were assessed at before treatment, 15 minutes, one hour and three hours after muscimol administration. The time of peak effect and optimum dosage was assessed by repeated measures analysis of variance and analysis of covariance, respectively. Results: Muscimol with the dose of 0.01 µg in 15 minutes caused to improve the thermal hyperalgesia (df: 24, 5; F= 6.6; p<0.001), mechanical hyperalgesia (df: 24, 5; F= 7.8; p<0.001), cold allodynia (df: 24, 5; F= 6.96; p<0.001), and mechanical allodynia (df: 24, 5; F= 15.7; p<0.001). The effect of doses of 0.1 µg and 1 µg were also significant. In addition, the efficacy of different doses of muscimol did not have difference on thermal hyperalgesia (df: 24, 5; F= 1.52; p= 0.24), mechanical hyperalgesia (df: 24, 5; F= 0.3; p= -0.75), cold allodynia (df: 24, 5; F= 0.8; p= -0.56), and mechanical allodynia (df: 24, 5; F= 1.75; p= 0.86). Conclusion: The finding of the present study revealed that using muscimol with doses of 0.01µg, 0.1µg, and 1 µg reduces the symptoms of neuropathic pain. In addition, the effect of GABAA agonist is short term and its effectiveness gradually decreases by time. PMID:26495371

  9. Effects of prolonged gum chewing on pain and fatigue in human jaw muscles.

    PubMed

    Farella, M; Bakke, M; Michelotti, A; Martina, R

    2001-04-01

    Gum chewing has been accepted as an adjunct to oral hygiene, as salivary stimulant and vehicle for various agents, as well as for jaw muscle training. The aim of this study was to investigate the effects of prolonged gum chewing on pain, fatigue and pressure tenderness of the masticatory muscles. Fifteen women without temporomandibular disorders (TMD) were requested to perform one of the following chewing tasks in three separate sessions: chewing a very hard gum, chewing a soft gum, and empty-chewing with no bolus. Unilateral chewing of gum or empty chewing was performed for 40 min at a constant rate of 80 cycles/min. In each session, perceived muscle pain and masticatory fatigue were rated on visual analog scales (VAS) before, throughout, and after the chewing task. Pressure pain thresholds (PPTs) of masseter and anterior temporalis muscles were assessed before and immediately after the chewing tasks, and again after 24 h. The VAS scores for pain and fatigue significantly increased only during the hard gum chewing, and after 10 min of recovery VAS scores had decreased again, almost to their baseline values. No significant changes were found for PPTs either after hard or soft gum chewing. The findings indicate that the jaw muscles recover quickly from prolonged chewing activity in subjects without TMD.

  10. Effects of 50 Hz electromagnetic fields on electroencephalographic alpha activity, dental pain threshold and cardiovascular parameters in humans.

    PubMed

    Ghione, Sergio; Seppia, Cristina Del; Mezzasalma, Lorena; Bonfiglio, Luca

    Recent studies indicate that exposure to extremely low frequency magnetic fields (ELF MFs) influences human electroencephalographic (EEG) alpha activity and pain perception. In the present study we analyse the effect on electrical EEG activity in the alpha band (8-13 Hz) and on nociception in 40 healthy male volunteers after 90-min exposure of the head to 50 Hz ELF MFs at a flux density of 40 or 80 microT in a double-blind randomized sham-controlled study. Since cardiovascular regulation is functionally related to pain modulation, we also measured blood pressure (BP) and heart rate (HR) during treatment. Alpha activity after 80 microT magnetic treatment almost doubled compared to sham treatment. Pain threshold after 40 microT magnetic treatment was significantly lower than after sham treatment. No effects were found for BP and HR. We suggest that these results may be explained by a modulation of sensory gating processes through the opioidergic system, that in turn is influenced by magnetic exposure.

  11. Serum protein changes in a rat model of chronic pain show a correlation between animal and humans

    PubMed Central

    Bellei, Elisa; Vilella, Antonietta; Monari, Emanuela; Bergamini, Stefania; Tomasi, Aldo; Cuoghi, Aurora; Guerzoni, Simona; Manca, Letizia; Zoli, Michele; Pini, Luigi Alberto

    2017-01-01

    In previous works we showed the overexpression of some proteins in biological fluids from patients suffering chronic pain. In this proteomic study we analysed serum from a rat model of neuropathic pain obtained by the chronic constriction injury (CCI) of sciatic nerve, at two time intervals, 2 and 5 weeks after the insult, to find proteins involved in the expression or mediation of pain. Sham-operated and CCI rats were treated with saline or indomethacin. Two weeks after ligation, we identified three serum proteins overexpressed in CCI rats, two of which, alpha-1-macroglobulin and vitamin D-binding protein (VDBP), remained increased 5 weeks post-surgery; at this time interval, we found increased levels of further proteins, namely apolipoprotein A-I (APOA1), apolipoprotein E (APOE), prostaglandin-H2 D-isomerase (PTGDS) and transthyretin (TTR), that overlap the overexpressed proteins found in humans. Indomethacin treatment reversed the effects of ligation. The qPCR analysis showed that transcript levels of APOA1, APOE, PTGDS and VDBP were overexpressed in the lumbar spinal cord (origin of sciatic nerve), but not in the striatum (an unrelated brain region), of CCI rats treated with saline 5 weeks after surgery, demonstrating that the lumbar spinal cord is a possible source of these proteins. PMID:28145509

  12. The Human as an Experimental System in Molecular Genetics.

    ERIC Educational Resources Information Center

    White, Ray; Caskey, C. Thomas

    1988-01-01

    Discusses insights discovered from research into human biology that are raising possibilities for therapy, prevention of disease, and challenges to society in the form of ethical decisions about the appropriate application of genetic information. (Author/RT)

  13. Experimental investigations in hamsters and rabbits with DNA extracted from human uterine tumors.

    PubMed

    Nastac, E; Athanasiu, P; Predescu, E; Stoian, M; Hozoc, M; Perju, A

    1980-01-01

    Experimental inoculation of a DNA preparation extracted from a fragment of non-irradiated human uterine cervix carcinoma was followed by the appearance of neoplasia in four hamsters and of lymphosarcoma in one rabbit. Similar DNA preparations obtained from three cases of irradiated human uterine cervix carcinoma and from a human uterine fibroma proved to have no biological activity.

  14. Rumpelstiltskin: The Pains of Early Retirement in "The Human Stain," "The Station Agent," and "Bad Santa"

    ERIC Educational Resources Information Center

    Beck, Bernard

    2004-01-01

    Far too many Americans and people in other societies face the pain of losing work, so that deprivation is not a rare event. But sometimes, and especially in a popular culture, it is not the job that is lost, but the promise that the job and the one who performed it would be valued. The calamity is to be good at one's trade and to find that it…

  15. Genetic and environmental factors in experimental and human cancer

    SciTech Connect

    Takayama, S.; Takebe, H.; Gelboin, H.V.; MaChahon, B.; Matsushima, T.; Sugimura, T.

    1980-01-01

    Recently technological advances in assaying mutagenic principles have revealed that there are many mutagens in the environment, some of which might be carcinogenic to human beings. Other advances in genetics have shown that genetic factors might play an important role in the induction of cancer in human beings, e.g., the high incidence of skin cancers in patients with xeroderma pigmentosum. These proceedings deal with the relationships between genetic and environmental factors in carcinogenesis. The contributors cover mixed-function oxidases, pharmacogenetics, twin studies, DNA repair, immunology, and epidemiology.

  16. Muscle pain inhibits cutaneous touch perception.

    PubMed

    Stohler, C S; Kowalski, C J; Lund, J P

    2001-06-01

    The processing of noxious and non-noxious sensations differs between chronic pain syndromes, and we believe that studies of sensory processing in the presence of pain will help to clarify the aetiology of the conditions. Here we measured in humans the threshold-level mechanosensitivity in tonic experimental muscle pain. We found (1) that muscle pain induced by hypertonic saline reduced cutaneous threshold-level mechanosensitivity at the site of pain and at the mirror site in the contralateral face, (2) that this effect outlasted the sensation of pain, (3) that it was more pronounced when the painful area was reported to be large, and (4) that the loss of mechanosensitivity was greater in males than females. Comparing our findings to results obtained with other pain models, all classes of nociceptors do not seem to have the same effect on cutaneous mechanosensitivity. The observed threshold-level hypoesthesia is consistent with the hypothesis that the increased mechanical thresholds found in clinic cases of temporomandibular disorders and cervicobrachialgia are a direct result of the activation of muscle nociceptors.

  17. An Experimental Study of the Emergence of Human Communication Systems

    ERIC Educational Resources Information Center

    Galantucci, Bruno

    2005-01-01

    The emergence of human communication systems is typically investigated via 2 approaches with complementary strengths and weaknesses: naturalistic studies and computer simulations. This study was conducted with a method that combines these approaches. Pairs of participants played video games requiring communication. Members of a pair were…

  18. Experimental 3-D SAR Human Target Signature Analysis

    DTIC Science & Technology

    2014-07-21

    through the wall structure that the radar signal must travel to get to the target, such as through and around studs . The different features from the...drywall made of wood stud , gypsum, insulating material, and vinyl coating. The second wall structure is made of cinder blocks and is a more challenging... wall synthetic aperture radar (SAR) imaging from an experimental L-band through- wall SAR prototype. Tools and algorithms for 3-D visualization are

  19. Pain emotion and homeostasis.

    PubMed

    Panerai, Alberto E

    2011-05-01

    Pain has always been considered as part of a defensive strategy, whose specific role is to signal an immediate, active danger. This definition partially fits acute pain, but certainly not chronic pain, that is maintained also in the absence of an active noxa or danger and that nowadays is considered a disease by itself. Moreover, acute pain is not only an automatic alerting system, but its severity and characteristics can change depending on the surrounding environment. The affective, emotional components of pain have been and are the object of extensive attention and research by psychologists, philosophers, physiologists and also pharmacologists. Pain itself can be considered to share the same genesis as emotions and as a specific emotion in contributing to the maintenance of the homeostasis of each unique subject. Interestingly, this role of pain reaches its maximal development in the human; some even argue that it is specific for the human primate.

  20. Sweet taste and chorda tympani transection alter capsaicin-induced lingual pain perception in adult human subjects.

    PubMed

    Schöbel, N; Kyereme, J; Minovi, A; Dazert, S; Bartoshuk, L; Hatt, H

    2012-10-10

    Sweetness signals the nutritional value of food and may moreover be accompanied by a sensory suppression that leads to higher pain tolerance. This effect is well documented in infant rats and humans. However, it is still debated whether sensory suppression is also present in adult humans. Thus, we investigated the effects of sweet taste on the perception of the painful trigeminal stimulus capsaicin in two groups of healthy adult human subjects. A solution of 100 μM capsaicin was applied to the tip of the subject's tongues in order to stimulate trigeminal Aδ- and C-fiber nociceptors. When swallowed, 1M sucrose reduced the capsaicin-induced burning sensation by 29% (p ≤ 0.05) whereas a solution of similar taste intensity containing 1 μM quinine did not. Similarly, sucrose application to the frontal hemitongue suppressed the perception of the burning sensation induced by contralaterally applied capsaicin by 25% (p ≤ 0.01). We furthermore investigated the effects of documented unilateral transection of the chorda tympani nerve on capsaicin perception. In accordance with the ipsi-to-contralateral effect of sucrose on capsaicin perception in healthy subjects, hemiageusic subjects were more sensitive for capsaicin on the tongue contralateral to the taste nerve lesion (+38%; p ≤ 0.01). Taken together, these results argue I) for the existence of food intake-induced sensory suppression, if not analgesia, in adult humans and II) a centrally mediated suppression of trigeminal sensation by taste inputs that III) becomes disinhibited upon peripheral taste nerve lesion.

  1. Chronic Pain

    MedlinePlus

    ... a problem you need to take care of. Chronic pain is different. The pain signals go on for ... there is no clear cause. Problems that cause chronic pain include Headache Low back strain Cancer Arthritis Pain ...

  2. Abdominal pain

    MedlinePlus

    Stomach pain; Pain - abdomen; Belly ache; Abdominal cramps; Bellyache; Stomachache ... Almost everyone has pain in the abdomen at some point. Most of the time, it is not serious. How bad your pain is ...

  3. Flank pain

    MedlinePlus

    Pain - side; Side pain ... Flank pain can be a sign of a kidney problem. But, since many organs are in this area, other causes are possible. If you have flank pain and fever , chills, blood in the urine, or ...

  4. Heel pain

    MedlinePlus

    Pain - heel ... Heel pain is most often the result of overuse. However, it may be caused by an injury. Your heel ... on the heel Conditions that may cause heel pain include: Swelling and pain in the Achilles tendon ...

  5. Acute pain experience in individuals with autism spectrum disorders: a review.

    PubMed

    Moore, David J

    2015-05-01

    In addition to the diagnostic criteria for autism spectrum disorder, a number of clinically important comorbid complaints, including sensory abnormalities, are also discussed. One difference often noted in these accounts is hyposensitivity to pain; however, evidence for this is limited. The purpose of the current review therefore was to examine sensitivity to pain of individuals with autism spectrum disorder. This review is interested in reports which consider differences in subjective experience of pain (i.e. different pain thresholds) and differences in behavioural response to pain (i.e. signs of pain-related distress). Studies were included if they were conducted with human subjects, included a clearly diagnosed autism spectrum disorder population and reported data pertaining to pain experience relative to the neurotypical population. Studies were classified as being self/parent report, clinical observations, observations of response to medical procedures or experimental examination of pain. Both self/parent report and clinical observations appeared to report hyposensitivity to pain, whereas observations of medical procedures and experimental manipulation suggested normal or hypersensitive responses to pain. This review suggests that contrary to classical reports, individuals with autism spectrum disorder do not appear to have systematically altered pain responses or thresholds. More systematic experimental examination of this area is needed to understand responses to pain of individuals with autism spectrum disorder.

  6. [From Nuremberg to the ethics committees in human experimentation].

    PubMed

    Demarez, Jean-Paul

    2008-02-01

    During the Nuremberg trials, the accusation prompted the creation of an ad hoc committee to advise on human experiments carried out on prisoners during wartime in the USA. Precisely a charge that had been brought against Karl Brandt and his colleagues. This committee was the forerunner of the Independent Committees, to which the Declaration of Helsinki assigned a role in analysing the ethics of research projects in humans. From 1980 onwards, in industrialised countries, the legislation regarding clinical trials began to incorporate similar structures, IRBs in the United States of America, Ethics Committees elsewhere, and the ''Committee for the Protection of Persons" in France. However, at that time, in spite of the misleading words, we went from ethics to law, from rules of conduct intended for researchers to legal regulations organising relations between sponsors, investigators and persons participating in biomedical research, which is not the same thing.

  7. Experimental performance evaluation of human balance control models.

    PubMed

    Huryn, Thomas P; Blouin, Jean-Sébastien; Croft, Elizabeth A; Koehle, Michael S; Van der Loos, H F Machiel

    2014-11-01

    Two factors commonly differentiate proposed balance control models for quiet human standing: 1) intermittent muscle activation and 2) prediction that overcomes sensorimotor time delays. In this experiment we assessed the viability and performance of intermittent activation and prediction in a balance control loop that included the neuromuscular dynamics of human calf muscles. Muscles were driven by functional electrical stimulation (FES). The performance of the different controllers was compared based on sway patterns and mechanical effort required to balance a human body load on a robotic balance simulator. All evaluated controllers balanced subjects with and without a neural block applied to their common peroneal and tibial nerves, showing that the models can produce stable balance in the absence of natural activation. Intermittent activation required less stimulation energy than continuous control but predisposed the system to increased sway. Relative to intermittent control, continuous control reproduced the sway size of natural standing better. Prediction was not necessary for stable balance control but did improve stability when control was intermittent, suggesting a possible benefit of a predictor for intermittent activation. Further application of intermittent activation and predictive control models may drive prolonged, stable FES-controlled standing that improves quality of life for people with balance impairments.

  8. Experimental Models in Syrian Golden Hamster Replicate Human Acute Pancreatitis

    PubMed Central

    Wang, Yunan; Kayoumu, Abudurexiti; Lu, Guotao; Xu, Pengfei; Qiu, Xu; Chen, Liye; Qi, Rong; Huang, Shouxiong; Li, Weiqin; Wang, Yuhui; Liu, George

    2016-01-01

    The hamster has been shown to share a variety of metabolic similarities with humans. To replicate human acute pancreatitis with hamsters, we comparatively studied the efficacy of common methods, such as the peritoneal injections of caerulein, L-arginine, the retrograde infusion of sodium taurocholate, and another novel model with concomitant administration of ethanol and fatty acid. The severity of pancreatitis was evaluated by serum amylase activity, pathological scores, myeloperoxidase activity, and the expression of inflammation factors in pancreas. The results support that the severity of pathological injury is consistent with the pancreatitis induced in mice and rat using the same methods. Specifically, caerulein induced mild edematous pancreatitis accompanied by minimal lung injury, while L-arginine induced extremely severe pancreatic injury including necrosis and neutrophil infiltration. Infusion of Na-taurocholate into the pancreatic duct induced necrotizing pancreatitis in the head of pancreas and lighter inflammation in the distal region. The severity of acute pancreatitis induced by combination of ethanol and fatty acids was between the extent of caerulein and L-arginine induction, with obvious inflammatory cells infiltration. In view of the advantages in lipid metabolism features, hamster models are ideally suited for the studies of pancreatitis associated with altered metabolism in humans. PMID:27302647

  9. Correlation between experimental human and murine skin sensitization induction thresholds.

    PubMed

    Api, Anne Marie; Basketter, David; Lalko, Jon

    2015-01-01

    Quantitative risk assessment for skin sensitization is directed towards the determination of levels of exposure to known sensitizing substances that will avoid the induction of contact allergy in humans. A key component of this work is the predictive identification of relative skin sensitizing potency, achieved normally by the measurement of the threshold (the "EC3" value) in the local lymph node assay (LLNA). In an extended series of studies, the accuracy of this murine induction threshold as the predictor of the absence of a sensitizing effect has been verified by conduct of a human repeated insult patch test (HRIPT). Murine and human thresholds for a diverse set of 57 fragrance chemicals spanning approximately four orders of magnitude variation in potency have been compared. The results confirm that there is a useful correlation, with the LLNA EC3 value helping particularly to identify stronger sensitizers. Good correlation (with half an order of magnitude) was seen with three-quarters of the dataset. The analysis also helps to identify potential outlier types of (fragrance) chemistry, exemplified by hexyl and benzyl salicylates (an over-prediction) and trans-2-hexenal (an under-prediction).

  10. Effects of Extracorporeal Shock Wave Therapy on Pain in Patients With Chronic Refractory Coccydynia: A Quasi-Experimental Study

    PubMed Central

    Haghighat, Shila; Mashayekhi Asl, Mahboobeh

    2016-01-01

    Background Several nonsurgical and surgical treatment modalities are available for patients with chronic coccydynia, with controversial results. Extracorporeal shock wave therapy (ECSWT) is effective in the treatment of many musculoskeletal disorders; however, it has not been tested for chronic coccydynia. Objectives We performed the current study to determine the effects of ECSWT on pain in patients with chronic coccydynia. Patients and Methods This quasi-interventional clinical study included 10 patients with chronic coccydynia without acute fracture. All the patients received ECSWT with a radial probe delivering 3,000 shock waves of 2 bar per session at 21 Hz frequency directed to the coccyx. Each patient received four sessions of ECSWT at one-week intervals. The pain severity was recorded according to the visual analog scale (VAS) at one, two, three, and four weeks after initiation of therapy. The VAS score was also evaluated at one and six months after ending the therapy. Results Most of the participants were women (90.0%), and the participants’ mean age was 39.1 ± 9.1 (ranging from 28 to 52) years. The VAS score did not decrease significantly seven months after therapy when compared to baseline (3.3 ± 3.6 vs. 7.3 ± 2.1; P = 0.011). However, the VAS score at two months (2.6 ± 2.9 vs. 7.3 ± 2.1; P = 0.007) and at four weeks (3.2 ± 2.8 vs. 7.3 ± 2.1; P = 0.007) significantly decreased when compared to baseline. The decrease in VAS scores was not persistent after cessation of the therapy. Conclusions ECSWT is an effective modality in relieving the pain intensity in patients with refractory chronic coccydynia for the early period after intervention. PMID:27843777

  11. Cortical influences on brainstem circuitry responsible for conditioned pain modulation in humans.

    PubMed

    Youssef, Andrew M; Macefield, Vaughan G; Henderson, Luke A

    2016-07-01

    Conditioned pain modulation (CPM) is a powerful endogenous analgesic mechanism which can completely inhibit incoming nociceptor signals at the primary synapse. The circuitry responsible for CPM lies within the brainstem and involves the subnucleus reticularis dorsalis (SRD). While the brainstem is critical for CPM, the cortex can significantly modulate its expression, likely via the brainstem circuitry critical for CPM. Since higher cortical regions such as the anterior, mid-cingulate, and dorsolateral prefrontal cortices are activated by noxious stimuli and show reduced activations during other analgesic responses, we hypothesized that these regions would display reduced responses during CPM analgesia. Furthermore, we hypothesized that functional connectivity strength between these cortical regions and the SRD would be stronger in those that express CPM analgesia compared with those that do not. We used functional magnetic resonance imaging to determine sites recruited during CPM expression and their influence on the SRD. A lack of CPM analgesia was associated with greater signal intensity increases during each test stimulus in the presence of the conditioning stimulus compared to test stimuli alone in the mid-cingulate and dorsolateral prefrontal cortices and increased functional connectivity with the SRD. In contrast, those subjects exhibiting CPM analgesia showed no change in the magnitude of signal intensity increases in these cortical regions or strength of functional connectivity with the SRD. These data suggest that during multiple or widespread painful stimuli, engagement of the prefrontal and cingulate cortices prevents the generation of CPM analgesia, raising the possibility altered responsiveness in these cortical regions underlie the reduced CPM observed in individuals with chronic pain. Hum Brain Mapp 37:2630-2644, 2016. © 2016 Wiley Periodicals, Inc.

  12. Bacteriology of experimental gingivitis in young adult humans.

    PubMed Central

    Moore, W E; Holdeman, L V; Smibert, R M; Good, I J; Burmeister, J A; Palcanis, K G; Ranney, R R

    1982-01-01

    From replicate trials of experimental gingivitis in four periodontally healthy subjects, 166 bacterial species and subspecies were detected among 3,034 randomly selected isolates from 96 samples. Of these bacteria, Actinomyces naeslundii (serotype III and phenotypically similar strains that were unreactive with available antisera), Actinomyces odontolyticus (serotype I and phenotypically similar strains that were unreactive with available antisera), Fusobacterium nucleatum, Lactobacillus species D-2, Streptococcus anginosus, Veillonella parvula, and Treponema species A appeared to be the most likely etiological agents of gingivitis. Statistical interpretations indicated that the greatest source of microbiological variation of the total flora observed was person-to-person differences in the floras. The next greatest source of variation was the inflammatory status of the sample sites. Person-to-person differences were smallest at experimental day 4. The floras became more diverse with time and as gingivitis developed and progressed. Analyses indicated that sequential colonization by certain species was repeatable and therefore probably predictable. Variation was relatively small between replicate trials, between two sites on the same teeth sampled on the same day, and between the same sites sampled at the same relative time in a replicate trial. PMID:7141708

  13. The effects of failure feedback and pain-related fear on pain report, pain tolerance, and pain avoidance in chronic low back pain patients.

    PubMed

    van den Hout, J H; Vlaeyen, J W; Houben, R M; Soeters, A P; Peters, M L

    2001-05-01

    The aim of this study was to investigate the influence of non-pain-related failure experiences and pain-related fear on pain report, pain tolerance and pain avoidance in chronic low back pain (CLBP) patients. Moreover, the mediating and moderating role of negative affectivity (trait-NA) in the relationship between failure experiences and pain was examined. Seventy-six patients were divided into high and low pain-related fear groups and within each group they were randomly assigned to the failure or success feedback condition. In the first part of the study patients completed a 'social empathy test' and experimenter 1 subsequently delivered false failure or success feedback. A second experimenter, who was blind for the condition, subsequently administered two lifting tasks in order to obtain measures of pain report, tolerance and avoidance. Failure feedback did have an effect on pain avoidance but unexpectedly, and not as hypothesized, pain avoidance was reduced instead of enhanced. With regard to pain report and pain tolerance similar patterns were found, but these were not statistically significant. The effect of failure feedback on pain avoidance was moderated by trait-NA. Only in the subgroup of patients who scored low on trait-NA did failure feedback decrease pain avoidance. State-NA did not mediate the effects of feedback. In line with previous findings, pain-related fear resulted in lower pain tolerance. Moreover, this study was the first to show that pain-related fear predicted higher pain report in CLBP patients. Pain-related fear did not predict pain avoidance when pre-lifting pain and gender were controlled for. Finally, pre-lifting pain turned out to be the strongest predictor with regard to all pain measures. The role of pain-related fear and unexpected findings with regard to feedback are discussed as well as some clinical implications.

  14. Experimental Reservoirs of Human Pathogens: The Vibrio Cholerae Paradigm (7th Annual SFAF Meeting, 2012)

    ScienceCinema

    Colwell, Rita [University of Maryland

    2016-07-12

    Rita Colwell on "Experimental Reservoirs of Human Pathogens: The Vibrio cholerae paradigm" at the 2012 Sequencing, Finishing, Analysis in the Future Meeting held June 5-7, 2012 in Santa Fe, New Mexico.

  15. Efficacy of Herpes Simplex Virus Vector Encoding the Human Preproenkephalin Gene for Treatment of Facial Pain in Mice

    PubMed Central

    Ma, Fei; Wang, Chunmei; Yoder, William E.; Westlund, Karin N.; Carlson, Charles R.; Miller, Craig S.; Danaher, Robert J.

    2016-01-01

    Aims To determine whether herpes simplex virus–based vectors can efficiently transduce mouse trigeminal ganglion (TG) neurons and attenuate preexisting nerve injury–induced whisker pad mechanical hypersensitivity in a trigeminal inflammatory compression (TIC) neuropathic pain model. Methods Tissue transduction efficiencies of replication-conditional and replication-defective vectors to mouse whisker pads after topical administration and subcutaneous injection were assessed using quantitative real-time PCR (qPCR). Tissue tropism and transgene expression were assessed using qPCR and reverse-transcriptase qPCR following topical application of the vectors. Whisker pad mechanical sensitivities of TIC-injured mice were determined using graduated von Frey fibers before and after application of human preproenkephalin expressing replication-conditional vector (KHPE). Data were analyzed using one-way analysis of variance (ANOVA) and post hoc tests. Results Transduction of target TGs was 8- to 50-fold greater after topical application than subcutaneous injection and ≥ 100-fold greater for replication-conditional than replication-defective vectors. Mean KHPE loads remained constant in TGs (4.5–9.8 × 104 copies/TG) over 3 weeks but were below quantifiable levels (10 copies/tissue) within 2 weeks of application in other nontarget cephalic tissues examined. Transgene expression in TGs was maximal during 2 weeks after topical application (100–200 cDNA copies/mL) and was below quantifiable levels (1 cDNA copy/mL) in all nontarget tissues. Topical KHPE administration reduced TIC-related mechanical hypersensitivity on whisker pads 4-fold (P < .05) for at least 1 week. Conclusion Topically administered KHPE produced a significant antinociceptive effect in the TIC mouse model of chronic facial neuropathic pain. This is the first report in which a gene therapeutic approach reduced trigeminal pain–related behaviors in an established pain state in mice. PMID:26817032

  16. Liver Stem Cells: Experimental Findings and Implications for Human Liver Disease.

    PubMed

    Michalopoulos, George K; Khan, Zahida

    2015-10-01

    Evidence from human histopathology and experimental studies with rodents and zebrafish has shown that hepatocytes and cholangiocytes may function as facultative stem cells for each other in conditions of impaired regeneration. The interpretation of the findings derived from these studies has generated considerable discussion and some controversies. This review examines the evidence obtained from the different experimental models and considers implications that these studies may have for human liver disease.

  17. Targeting Epigenetic Mechanisms for Chronic Pain: A Valid Approach for the Development of Novel Therapeutics.

    PubMed

    Ligon, Casey O; Moloney, Rachel D; Greenwood-Van Meerveld, Beverley

    2016-04-01

    Chronic pain is a multifaceted and complex condition. Broadly classified into somatic, visceral, or neuropathic pain, it is poorly managed despite its prevalence. Current drugs used for the treatment of chronic pain are limited by tolerance with long-term use, abuse potential, and multiple adverse side effects. The persistent nature of pain suggests that epigenetic machinery may be a critical factor driving chronic pain. In this review, we discuss the latest insights into epigenetic processes, including DNA methylation, histone modifications, and microRNAs, and we describe their involvement in the pathophysiology of chronic pain and whether epigenetic modifications could be applied as future therapeutic targets for chronic pain. We provide evidence from experimental models and translational research in human tissue that have enhanced our understanding of epigenetic processes mediating nociception, and we then speculate on the potential future use of more specific and selective agents that target epigenetic mechanisms to attenuate pain.

  18. [Experimental estimation of proteome size for cells and human plasma].

    PubMed

    Naryzhny, S N; Zgoda, V G; Maynskova, M A; Ronzhina, N L; Belyakova, N V; Legina, O K; Archakov, A I

    2015-01-01

    Huge range of concentrations of different protein and insufficient sensitivity of methods for detection of proteins at a single molecule level does not yet allow obtaining the whole image of human proteome. In our investigations, we tried to evaluate the size of different proteomes (cells and plasma). The approach used is based on detection of protein spots in 2-DE after staining by protein dyes with different sensitivities. The function representing the dependence of the number of protein spots on sensitivity of protein dyes was generated. Next, by extrapolation of this function curve to theoretical point of the maximum sensitivity (detection of a single smallest polypeptide) it was calculated that a single human cell (HepG2) may contain minimum 70,000 proteoforms, and plasma--1.5 mln. Utilization of this approach to other, smaller proteomes showed the competency of this extrapolation. For instance, the size of mycoplas ma (Acholeplasma laidlawii) was estimated in 1100 proteoforms, yeast (Saccharomyces cerevisiae)--40,000, E. coli--6200, P. furiosus--3400. In hepatocytes, the amount of proteoforms was the same as in HepG2--70,000. Significance of obtained data is in possibilities to estimating the proteome organization and planning next steps in its study.

  19. Foxo/atrogin induction in human and experimental myositis.

    PubMed

    Lee, Han-Kyu; Rocnik, Edward; Fu, Qinghao; Kwon, Bumsup; Zeng, Ling; Walsh, Kenneth; Querfurth, Henry

    2012-05-01

    Skeletal muscle atrophy can occur rapidly in various fasting, cancerous, systemic inflammatory, deranged metabolic or neurogenic states. The ubiquitin ligase Atrogin-1 (MAFbx) is induced in animal models of these conditions, causing excessive myoprotein degradation. It is unknown if Atrogin upregulation also occurs in acquired human myositis. Intracellular β-amyloid (Aβi), phosphorylated neurofilaments, scattered infiltrates and atrophy involving selective muscle groups characterize human sporadic Inclusion Body Myositis (sIBM). In Polymyositis (PM), inflammation is more pronounced and atrophy is symmetric and proximal. IBM and PM share various inflammatory markers. We found that forkhead family transcription factor Foxo3A is directed to the nucleus and Atrogin-1 transcript is increased in both conditions. Expression of Aβ in transgenic mice and differentiated C2C12 myotubes was sufficient to upregulate Atrogin-1 mRNA and cause atrophy. Aβi reduces levels of p-Akt and downstream p-Foxo3A, resulting in Foxo3A translocation and Atrogin-1 induction. In a mouse model of autoimmune myositis, cellular inflammation alone was associated with similar Foxo3A and Atrogin changes. Thus, either Aβi accumulation or cellular immune stimulation may independently drive muscle atrophy in sIBM and PM, respectively, through pathways converging on Foxo and Atrogin-1. In sIBM it is additionally possible that both mechanisms synergize.

  20. Use of reward-penalty structures in human experimentation

    NASA Technical Reports Server (NTRS)

    Stein, A. C.; Allen, R. W.; Schwartz, S. H.

    1978-01-01

    The use of motivational techniques in human performance research is reviewed and an example study employing a reward-penalty structure to simulate the motivations inherent in a real-world situation is presented. Driver behavior in a decision-making driving scenario was studied. The task involved control of an instrumented car on a cooperative test course. Subjects were penalized monetarily for tickets and accidents and rewarded for saving driving time. Two groups were assigned different ticket penalties. The group with the highest penalties tended to drive more conservatively. However, the average total payoff to each group was the same, as the conservative drivers traded off slower driving times with lower ticket penalties.

  1. Experimental infection of murine and human macrophages with Cystoisospora belli.

    PubMed

    Resende, Deisy V; Lages-Silva, Eliane; Assis, Dnieber C; Prata, Aluízio; Oliveira-Silva, Márcia B

    2009-08-01

    Extraintestinal cystoisosporosis by Cystoisospora belli has already been reported in HIV/AIDS patients, generally involving preferential invasion of mesenteric and trachaeobronchial lymph nodes, liver and spleen by unizoic cysts of this parasite, which may infect macrophages. To test this hypothesis, murine and human macrophages were exposed to sporozoites of C. belli and cultures were observed daily after contact with these cells. The parasites penetrated and multiplied by endodyogeny in both cell types and inserted themselves inside perinuclear vacuoles. After 48 h, extracellular parasites were removed from macrophage cultures and incubated in Monkey Kidney Rhesus cells (MK2) where there was intense multiplication. This is the first report of infection of macrophages by this parasite, which supports the hypothesis that these could act as C. belli host cells in extraintestinal sites.

  2. Tuskegee redux: Evolution of legal mandates for human experimentation

    PubMed Central

    Levine, Robert S.; Williams, Jamila C.; Kilbourne, Barbara A.; Juarez, Paul D.

    2013-01-01

    Human health experiments systematically expose people to conditions beyond the boundaries of medical evidence. Such experiments have included legal-medical collaboration, exemplified in the US by the PHS Syphilis Study (Tuskegee). That medical experiment was legal, conforming to segregationist protocols and specific legislative authorization which excluded a selected group of African Americans from any medical protection from syphilis. Subsequent corrective action outlawed unethical medical experiments but did not address other forms of collaboration, including PHS submission to laws which may have placed African American women at increased risk from AIDS and breast cancer. Today, anti-lobbying law makes it a felony for PHS workers to openly question legally anointed suspension of medical evidence. African Americans and other vulnerable populations may thereby face excess risks -- not only from cancer, but also from motor vehicle crashes, firearm assault, end stage renal disease and other problems -- with PHS workers as silent partners. PMID:23124504

  3. Tuskegee redux: evolution of legal mandates for human experimentation.

    PubMed

    Levine, Robert S; Williams, Jamila C; Kilbourne, Barbara A; Juarez, Paul D

    2012-11-01

    Human health experiments systematically expose people to conditions beyond the boundaries of medical evidence. Such experiments have included legal-medical collaboration, exemplified in the U.S. by the Public Health Service (PHS) Syphilis Study (Tuskegee). That medical experiment was legal, conforming to segregationist protocols and specific legislative authorization which excluded a selected group of African Americans from any medical protection from syphilis. Subsequent corrective action outlawed unethical medical experiments but did not address other forms of collaboration, including PHS submission to laws which may have placed African American women at increased risk from AIDS and breast cancer. Today, anti-lobbying law makes it a felony for PHS workers to openly challenge legally anointed suspension of medical evidence. African Americans and other vulnerable populations may thereby face excess risks-not only from cancer, but also from motor vehicle crashes, firearm assault, end stage renal disease, and other problems-with PHS workers as silent partners.

  4. An experimental study of the emergence of human communication systems.

    PubMed

    Galantucci, Bruno

    2005-09-10

    The emergence of human communication systems is typically investigated via 2 approaches with complementary strengths and weaknesses: naturalistic studies and computer simulations. This study was conducted with a method that combines these approaches. Pairs of participants played video games requiring communication. Members of a pair were physically separated but exchanged graphic signals through a medium that prevented the use of standard symbols (e.g., letters). Communication systems emerged and developed rapidly during the games, integrating the use of explicit signs with information implicitly available to players and silent behavior-coordinating procedures. The systems that emerged suggest 3 conclusions: (a) signs originate from different mappings; (b) sign systems develop parsimoniously; (c) sign forms are perceptually distinct, easy to produce, and tolerant to variations.

  5. GABAergic pathway in a rat model of chronic neuropathic pain: modulation after intrathecal transplantation of a human neuronal cell line.

    PubMed

    Vaysse, L; Sol, J C; Lazorthes, Y; Courtade-Saidi, M; Eaton, M J; Jozan, S

    2011-02-01

    Current understanding of chronic pain points a decrease in level of the inhibitory neurotransmitter GABA, in the spinal dorsal horn, leading to an imbalance between excitatory and inhibitory pathways. A subcloned derivative of the human NT2 cell line (hNT2.17) which, after neuronal differentiation, secretes different inhibitory neurotransmitters such as GABA and glycine has been recently isolated. In this study, we have investigated the effect of this new cell line on peripheral nerve injury induced by chronic constriction (CCI) and notably the effect on the cellular GABAergic pathway. Our data show that the decrease in GABA expression in the spinal dorsal horn of injured animals is concomitant with a decline of its synthetic enzyme GAD67-Ir and mRNA but not GAD65. Interestingly, in transplanted animals we observed a strong induction of GAD67 mRNA with one week after graft, which is followed by a recovery of GAD67 and GABA Ir. This effect paralleled a reduction of hindpaw hypersensitivity and thermal hyperalgesia induced by CCI. These results suggest that hNT2.17 GABA cells can modulate neuropathic pain after CCI certainly by minimizing the imbalance and restoring the cellular GABAergic pathway.

  6. [Experimental study on electrical impedance properties of human hepatoma cells].

    PubMed

    Fang, Yun; Tang, Zhiyuan; Zhang, Qian; Zhao, Xin; Ma, Qing

    2014-10-01

    The AC impedance of human hepatoma SMMC-7721 cells were measured in our laboratory by Agilent 4294A impedance analyzer in the frequency range of 0.01-100 MHz. And then the effect of hematocrit on electrical impedance characteristics of hepatoma cells was observed by electrical impedance spectroscopy, Bode diagram, Nyquist diagram and Nichols diagram. The results showed that firstly, there is a frequency dependence, i.e., the increment of real part and the imaginary part of complex electrical impedance (δZ', δZ"), the increment of the amplitude modulus of complex electrical impedance (δ[Z *]) and phase angle (δθ) were all changed with the increasing frequency. Secondly, it showed cell volume fraction (CVF) dependence, i. e. , the increment of low-frequency limit (δZ'0, δ[Z*] 0), peak (δZ"(p), δθ(p)), area and radius (Nyquist diagram, Nichols diagram) were all increased along with the electric field frequency. Thirdly, there was the presence of two characteristic frequencies: the first characteristic frequency (f(c1)) and the second characteristic frequency (f(c2)), which were originated respectively in the polarization effects of two interfaces that the cell membrane and extracellular fluid, cell membrane and cytoplasm. A conclusion can be drawn that the electrical impedance spectroscopy is able to be used to observe the electrical characteristics of human hepatoma cells, and therefore this method can be used to investigate the electrophysiological mechanisms of liver cancer cells, and provide research tools and observation parameters, and it also has important theoretical value and potential applications for screening anticancer drugs.

  7. Stable, synthetic analogs of diadenosine tetraphosphate inhibit rat and human P2X3 receptors and inflammatory pain

    PubMed Central

    Viatchenko-Karpinski, Viacheslav; Novosolova, Natalia; Ishchenko, Yevheniia; Azhar, M Ameruddin; Wright, Michael; Tsintsadze, Vera; Kamal, Ahmed; Burnashev, Nail; Voitenko, Nana; Giniatullin, Rashid; Lozovaya, Natalia

    2016-01-01

    Background A growing body of evidence suggests that ATP-gated P2X3 receptors (P2X3Rs) are implicated in chronic pain. We address the possibility that stable, synthetic analogs of diadenosine tetraphosphate (Ap4A) might induce antinociceptive effects by inhibiting P2X3Rs in peripheral sensory neurons. Results The effects of two stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) are studied firstly in vitro on HEK293 cells expressing recombinant rat P2XRs (P2X2Rs, P2X3Rs, P2X4Rs, and P2X7Rs) and then using native rat brain cells (cultured trigeminal, nodose, or dorsal root ganglion neurons). Thereafter, the action of these stable, synthetic Ap4A analogs on inflammatory pain and thermal hyperalgesia is studied through the measurement of antinociceptive effects in formalin and Hargreaves plantar tests in rats in vivo. In vitro inhibition of rat P2X3Rs (not P2X2Rs, P2X4Rs nor P2X7Rs) is shown to take place mediated by high-affinity desensitization (at low concentrations; IC50 values 100–250 nM) giving way to only weak partial agonism at much higher concentrations (EC50 values ≥ 10 µM). Similar inhibitory activity is observed with human recombinant P2X3Rs. The inhibitory effects of AppNHppA on nodose, dorsal root, and trigeminal neuron whole cell currents suggest that stable, synthetic Ap4A analogs inhibit homomeric P2X3Rs in preference to heteromeric P2X2/3Rs. Both Ap4A analogs mediate clear inhibition of pain responses in both in vivo inflammation models. Conclusions Stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) being weak partial agonist provoke potent high-affinity desensitization-mediated inhibition of homomeric P2X3Rs at low concentrations. Therefore, both analogs demonstrate clear potential as potent analgesic agents for use in the management of chronic pain associated with heightened P2X3R activation. PMID:27030723

  8. Experimental human endotoxemia enhances brain activity during social cognition.

    PubMed

    Kullmann, Jennifer S; Grigoleit, Jan-Sebastian; Wolf, Oliver T; Engler, Harald; Oberbeck, Reiner; Elsenbruch, Sigrid; Forsting, Michael; Schedlowski, Manfred; Gizewski, Elke R

    2014-06-01

    Acute peripheral inflammation with corresponding increases in peripheral cytokines affects neuropsychological functions and induces depression-like symptoms. However, possible effects of increased immune responses on social cognition remain unknown. Therefore, this study investigated the effects of experimentally induced acute inflammation on performance and neural responses during a social cognition task assessing Theory of Mind (ToM) ability. In this double-blind randomized crossover functional magnetic resonance imaging study, 18 healthy right-handed male volunteers received an injection of bacterial lipopolysaccharide (LPS; 0.4 ng/kg) or saline, respectively. Plasma levels of pro- and anti-inflammatory cytokines as well as mood ratings were analyzed together with brain activation during a validated ToM task (i.e. Reading the Mind in the Eyes Test). LPS administration induced pronounced transient increases in pro- (IL-6, TNF-α) and anti-inflammatory (IL-10, IL-1ra) cytokines as well as decreases in mood. Social cognition performance was not affected by acute inflammation. However, altered neural activity was observed during the ToM task after LPS administration, reflected by increased responses in the fusiform gyrus, temporo-parietal junction, superior temporal gyrus and precuneus. The increased task-related neural responses in the LPS condition may reflect a compensatory strategy or a greater social cognitive processing as a function of sickness.

  9. HEW Proposed Policy on the Protection of Human Subjects: Experimentation and the Institutionalized Mentally Disabled

    ERIC Educational Resources Information Center

    Washington University Law Quarterly, 1975

    1975-01-01

    Underlying bases for federal interest in experimentation on human subjects, including abuses of investigative processes and efforts at regulation, are explored. Focus is on recent HEW rules on the protection of human subjects, which will have a significant impact on many research institutions. (LBH)

  10. Low concentrations of human neutrophil peptide ameliorate experimental murine colitis

    PubMed Central

    Maeda, Takuro; Sakiyama, Toshio; Kanmura, Shuji; Hashimoto, Shinichi; Ibusuki, Kazunari; Tanoue, Shiroh; Komaki, Yuga; Arima, Shiho; Nasu, Yuichiro; Sasaki, Fumisato; Taguchi, Hiroki; Numata, Masatsugu; Uto, Hirofumi; Tsubouchi, Hirohito; Ido, Akio

    2016-01-01

    Human neutrophil peptides (HNPs) not only have antimicrobial properties, but also exert multiple immunomodulatory effects depending on the concentration used. We have previously demonstrated that the intraperitoneal administration of high-dose HNP-1 (100 µg/day) aggravates murine dextran sulfate sodium (DSS)-induced colitis, suggesting a potential pro-inflammatory role for HNPs at high concentrations. However, the role of low physiological concentrations of HNPs in the intestinal tract remains largely unknown. The aim of this study was to examine the effects of low concentrations of HNPs on intestinal inflammation. We first examined the effects of the mild transgenic overexpression of HNP-1 in DSS-induced colitis. HNP-1 transgenic mice have plasma HNP-1 levels similar to the physiological concentrations in human plasma. Compared to wild-type mice treated with DSS, HNP-1 transgenic mice treated with DSS had significantly lower clinical and histological scores, and lower colonic mRNA levels of pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α. We then injected low-dose HNP-1 (5 µg/day) or phosphate-buffered saline (PBS) intraperitoneally into C57BL/6N and BALB/c mice administered DSS. The HNP-1-treated mice exhibited significantly milder colitis with reduced expression levels of pro-inflammatory cytokines compared with the PBS-treated mice. Finally, we examined the in vitro effects of HNP-1 on the expression of cytokines associated with macrophage activation. Low physiological concentrations of HNP-1 did not significantly affect the expression levels of IL-1β, TNF-α, IL-6 or IL-10 in colonic lamina propria mononuclear cells activated with heat-killed Escherichia coli, suggesting that the anti-inflammatory effects of HNP-1 on murine colitis may not be exerted by direct action on intestinal macrophages. Collectively, our data demonstrated a biphasic dose-dependent effect of HNP-1 on DSS-induced colitis: an amelioration at

  11. Low concentrations of human neutrophil peptide ameliorate experimental murine colitis.

    PubMed

    Maeda, Takuro; Sakiyama, Toshio; Kanmura, Shuji; Hashimoto, Shinichi; Ibusuki, Kazunari; Tanoue, Shiroh; Komaki, Yuga; Arima, Shiho; Nasu, Yuichiro; Sasaki, Fumisato; Taguchi, Hiroki; Numata, Masatsugu; Uto, Hirofumi; Tsubouchi, Hirohito; Ido, Akio

    2016-12-01

    Human neutrophil peptides (HNPs) not only have antimicrobial properties, but also exert multiple immunomodulatory effects depending on the concentration used. We have previously demonstrated that the intraperitoneal administration of high-dose HNP-1 (100 µg/day) aggravates murine dextran sulfate sodium (DSS)-induced colitis, suggesting a potential pro-inflammatory role for HNPs at high concentrations. However, the role of low physiological concentrations of HNPs in the intestinal tract remains largely unknown. The aim of this study was to examine the effects of low concentrations of HNPs on intestinal inflammation. We first examined the effects of the mild transgenic overexpression of HNP-1 in DSS-induced colitis. HNP-1 transgenic mice have plasma HNP-1 levels similar to the physiological concentrations in human plasma. Compared to wild-type mice treated with DSS, HNP-1 transgenic mice treated with DSS had significantly lower clinical and histological scores, and lower colonic mRNA levels of pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α. We then injected low-dose HNP-1 (5 µg/day) or phosphate-buffered saline (PBS) intraperitoneally into C57BL/6N and BALB/c mice administered DSS. The HNP-1-treated mice exhibited significantly milder colitis with reduced expression levels of pro-inflammatory cytokines compared with the PBS-treated mice. Finally, we examined the in vitro effects of HNP-1 on the expression of cytokines associated with macrophage activation. Low physiological concentrations of HNP-1 did not significantly affect the expression levels of IL-1β, TNF-α, IL-6 or IL-10 in colonic lamina propria mononuclear cells activated with heat-killed Escherichia coli, suggesting that the anti-inflammatory effects of HNP-1 on murine colitis may not be exerted by direct action on intestinal macrophages. Collectively, our data demonstrated a biphasic dose-dependent effect of HNP-1 on DSS-induced colitis: an

  12. Postural Responses to a Suddenly Released Pulling Force in Older Adults with Chronic Low Back Pain: An Experimental Study

    PubMed Central

    Lee, Pei-Yun; Lin, Sang-I; Liao, Yu-Ting; Lin, Ruey-Mo; Hsu, Che-Chia; Huang, Kuo-Yuan; Chen, Yi-Ting

    2016-01-01

    Chronic low back pain (CLBP), one of the most common musculoskeletal conditions in older adults, might affect balance and functional independence. The purpose of this study was to investigate the postural responses to a suddenly released pulling force in older adults with and without CLBP. Thirty community-dwelling older adults with CLBP and 26 voluntary controls without CLBP were enrolled. Participants were required to stand on a force platform while, with one hand, they pulled a string that was fastened at the other end to a 2-kg or to a 4-kg force in the opposite direction at a random order. The number of times the participants lost their balance and motions of center of pressure (COP) when the string was suddenly released were recorded. The results demonstrated that although the loss of balance rates for each pulling force condition did not differ between groups, older adults with CLBP had poorer postural responses: delayed reaction, larger displacement, higher velocity, longer path length, and greater COP sway area compared to the older controls. Furthermore, both groups showed larger postural responses in the 4-kg pulling force condition. Although aging is generally believed to be associated with declining balance and postural control, these findings highlight the effect of CLBP on reactive balance when responding to an externally generated force in an older population. This study also suggests that, for older adults with CLBP, in addition to treating them for pain and disability, reactive balance evaluation and training, such as reaction and movement strategy training should be included in their interventions. Clinicians and older patients with CLBP need to be made aware of the significance of impaired reactive balance and the increased risk of falls when encountering unexpected perturbations. PMID:27622646

  13. Pathways to human experimentation, 1933-1945: Germany, Japan, and the United States.

    PubMed

    Baader, Gerhard; Lederer, Susan E; Low, Morris; Schmaltz, Florian; Schwerin, Alexander V

    2005-01-01

    The history of human experimentation in the twelve years between Hitler's rise to power and the end of the Second World War is notorious in the annals of the twentieth century. The horrific experiments conducted at Dachau, Auschwitz, Ravensbrueck, Birkenau, and other National Socialist concentration camps reflected an extreme indifference to human life and human suffering. Unfortunately, they do not reflect the extent and complexity of the human experiments undertaken in the years between 1933 and 1945. Following the prosecution of twenty-three high-ranking National Socialist physicians and medical administrators for war crimes and crimes against humanity in the Nuremberg Medical Trial (United States v. Karl Brandt et al.), scholars have rightly focused attention on the nightmarish researches conducted by a small group of investigators on concentration camp inmates. Less well known are alternative pathways that brought investigators to undertake human experimentation in other laboratories, settings, and nations.

  14. Relevance of experimental animal studies to the human experience

    SciTech Connect

    Fry, R.J.M.

    1982-01-01

    Animal experiments are being used to examine a number of physical and biological factors that influence risk estimations though not usually in coordination with epidemiologists. It is clear that the different mechanisms involved in different types of tumors are reflected in the diversity of dose-response relationships. The forms of the dose-response relationships are influenced by both the initial events and their expression. Evidence is accumulating that many initiated cells do not get expressed as overt cancers and host factors may play a major role in the expression of potential tumor cells. There is a need for information about the relationship of the natural incidence and susceptibility to radiation induction for more tumor types. Such experiments will help answer the question of which risk estimate models are appropriate for different tumor types and can be carried out on animals. Perhaps because of the importance of host factors risk estimates as a percentage of the natural incidence appear to be similar for human beings and mice for a small number of tumor types. The elucidation of the mechanisms involved in different tissues while a slow business remains an important role of animal experiments.

  15. Neural response to emotional stimuli during experimental human endotoxemia.

    PubMed

    Kullmann, Jennifer S; Grigoleit, Jan-Sebastian; Lichte, Philipp; Kobbe, Philipp; Rosenberger, Christina; Banner, Christina; Wolf, Oliver T; Engler, Harald; Oberbeck, Reiner; Elsenbruch, Sigrid; Bingel, Ulrike; Forsting, Michael; Gizewski, Elke R; Schedlowski, Manfred

    2013-09-01

    Increases in peripheral cytokines during acute inflammation may affect various neuropsychological functions. The aim of this functional magnetic resonance imaging (fMRI) study was to investigate the effects of acute endotoxemia on mood and the neural response to emotionally aversive visual stimuli in healthy human subjects. In a double-blind, randomized crossover study, 18 healthy males received a bolus injection of bacterial lipopolysaccharide (LPS; 0.4 ng/kg) or saline. Plasma levels of pro- and anti-inflammatory cytokines and cortisol as well as mood ratings were analyzed together with the blood-oxygen-level dependent (BOLD) response during the presentation of aversive versus neutral pictures. Endotoxin administration induced pronounced transient increases in plasma levels of TNF-α, IL-1ra, IL-6, IL-10, and cortisol. Positive mood was decreased and state anxiety increased. In addition, activation of right inferior orbitofrontal cortex (OFC) in response to emotional visual stimuli was significantly increased in the LPS condition. Increased prefrontal activation during the presentation of emotional material may reflect enhanced cognitive regulation of emotions as an adaptive response during an acute inflammation. These findings may have implications for the putative role of inflammatory processes in the pathophysiology of depression.

  16. Conditioning of the masseter inhibitory reflex by homotopically applied painful heat in humans.

    PubMed

    Andersen, O K; Svensson, P; Ellrich, J; Arendt-Nielsen, L

    1998-12-01

    During contraction of the jaw-closing muscles, afferent input from the intraoral and perioral region can elicit two bilateral suppression periods (SP1 and SP2, respectively) in the masseter electromyogram (EMG). Non-painful electrical stimulation 2 cm from the left labial commissure was used in the present study to evoke these trigeminal inhibitory reflexes. The subjects maintained a level of 50% of their maximum masseter EMG. The degree of suppression was quantified as the percentage suppression of the mean EMG activity in a fixed post-stimulus interval (SP2, 40-90 ms). Further, brief (200 ms) painful radiant heat conditioning stimuli were delivered to the ipsilateral cheek, in order to investigate the influence of nociceptive input on the (non-nociceptive) trigeminal masseter inhibitory reflex. Nine different conditions combining radiant heat and electrical stimuli were used. Twelve stimuli were presented for each condition. The radiant heat preceded the electrical test stimuli by fixed inter-stimulus intervals (ISI), ranging from 100 ms to 500 ms. At 250-350 ms ISIs, the bilateral SP2 suppression was significantly reduced to less than 10%, in comparison to an average suppression degree of 32.5% without conditioning stimuli. The subjects perceived the heat stimulus before the electrical stimulus for a majority of the 12 pairs of stimuli at these ISIs. No differences were found in the VAS ratings for the different conditions. For the contralateral SP1, larger suppression was seen for the 300 ms ISI compared with stimulation without conditioning heat stimuli. Onset and offset for the SP1 was, however, only detected in three subjects using a criteria of 20% suppression of the pre-stimulus activity. A pre-pulse inhibitory effect onto inter-neurons in the SP2 pathways or habituation of the same inter-neurons by the heat stimuli are suggested as possible explanations for the interaction between the non-nociceptive and nociceptive input in the present study.

  17. Bioavailability of fluoride in drinking water: a human experimental study.

    PubMed

    Maguire, A; Zohouri, F V; Mathers, J C; Steen, I N; Hindmarch, P N; Moynihan, P J

    2005-11-01

    It has been suggested that systemic fluoride absorption from drinking water may be influenced by the type of fluoride compound in the water and by water hardness. Using a human double-blind cross-over trial, we conducted this study to measure c(max), T(max), and Area Under the Curve (AUC) for plasma F concentration against time, following the ingestion of naturally fluoridated hard and soft waters, artificially fluoridated hard and soft waters, and a reference water. Mean AUC over 0 to 8 hours was 1330, 1440, 1679, 1566, and 1328 ng F.min.mL(-1) for naturally fluoridated soft, naturally fluoridated hard, artificially fluoridated soft, artificially fluoridated hard, and reference waters, respectively, with no statistically significant differences among waters for AUC, c(max), or T(max). Any differences in fluoride bioavailability between drinking waters in which fluoride is present naturally or added artificially, or the waters are hard or soft, were small compared with large within- and between-subject variations in F absorption. Abbreviations used: F, fluoride; AUC, Area under the Curve for plasma F concentration against time; AUC(0-3), Area under the Curve for plasma F concentration against time for 0 to 3 hours following water ingestion; AUC(0-8), Area under the Curve for plasma F concentration against time for 0 to 8 hours following water ingestion; c(max), maximum plasma F concentration corrected for baseline plasma F and dose (i.e., F concentration of individual waters); T(max), time of c(max).

  18. Experimental study of Human Adenoviruses interactions with clays

    NASA Astrophysics Data System (ADS)

    Bellou, Maria; Syngouna, Vasiliki; Paparrodopoulos, Spyros; Vantarakis, Apostolos; Chrysikopoulos, Constantinos

    2014-05-01

    Clays are used to establish low permeability liners in landfills, sewage lagoons, water retention ponds, golf course ponds, and hazardous waste sites. Human adenoviruses (HAdVs) are waterborne viruses which have been used as viral indicators of fecal pollution. The objective of this study was to investigate the survival of HAdV in static and dynamic clay systems. The clays used as a model were crystalline aluminosilicates: kaolinite and bentonite. The adsorption and survival of HAdVs onto these clays were characterized at two different controlled temperatures (4 and 25o C) under static and dynamic batch conditions. Control tubes, in the absence of clay, were used to monitor virus inactivation due to factors other than adsorption to clays (e.g. inactivation or sorption onto the tubes walls). For both static and dynamic batch experiments, samples were collected for a maximum period of seven days. This seven day time - period was determined to be sufficient for the virus-clay systems to reach equilibrium. To infer the presence of infectious HAdV particles, all samples were treated with Dnase and the extraction of viral nucleid acid was performed using a commercial viral RNA kit. All samples were analyzed by Real - Time PCR which was used to quantify viral particles in clays. Samples were also tested for virus infectivity by A549 cell cultures. Exposure time intervals in the range of seven days (0.50-144 hours) resulted in a load reduction of 0.74 to 2.96 logs for kaolinite and a reduction of 0.89 to 2.92 for bentonite. Furthermore, virus survival was higher onto bentonite than kaolinite (p

  19. Activation of necroptosis in human and experimental cholestasis

    PubMed Central

    Afonso, Marta B; Rodrigues, Pedro M; Simão, André L; Ofengeim, Dimitry; Carvalho, Tânia; Amaral, Joana D; Gaspar, Maria M; Cortez-Pinto, Helena; Castro, Rui E; Yuan, Junying; Rodrigues, Cecília M P

    2016-01-01

    Cholestasis encompasses liver injury and inflammation. Necroptosis, a necrotic cell death pathway regulated by receptor-interacting protein (RIP) 3, may mediate cell death and inflammation in the liver. We aimed to investigate the role of necroptosis in mediating deleterious processes associated with cholestatic liver disease. Hallmarks of necroptosis were evaluated in liver biopsies of primary biliary cholangitis (PBC) patients and in wild-type and RIP3-deficient (RIP3−/−) mice subjected to common bile duct ligation (BDL). The functional link between RIP3, heme oxygenase-1 (HO-1) and antioxidant response was investigated in vivo after BDL and in vitro. We demonstrate increased RIP3 expression and mixed lineage kinase domain-like protein (MLKL) phosphorylation in liver samples of human PBC patients, coincident with thioflavin T labeling, suggesting activation of necroptosis. BDL resulted in evident hallmarks of necroptosis, concomitant with progressive bile duct hyperplasia, multifocal necrosis, fibrosis and inflammation. MLKL phosphorylation was increased and insoluble aggregates of RIP3, MLKL and RIP1 formed in BLD liver tissue samples. Furthermore, RIP3 deficiency blocked BDL-induced necroinflammation at 3 and 14 days post-BDL. Serum hepatic enzymes, fibrogenic liver gene expression and oxidative stress decreased in RIP3−/− mice at 3 days after BDL. However, at 14 days, cholestasis aggravated and fibrosis was not halted. RIP3 deficiency further associated with increased hepatic expression of HO-1 and accumulation of iron in BDL mice. The functional link between HO-1 activity and bile acid toxicity was established in RIP3-deficient primary hepatocytes. Necroptosis is triggered in PBC patients and mediates hepatic necroinflammation in BDL-induced acute cholestasis. Targeting necroptosis may represent a therapeutic strategy for acute cholestasis, although complementary approaches may be required to control progression of chronic cholestatic liver disease

  20. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7

    PubMed Central

    Minett, Michael S.; Pereira, Vanessa; Sikandar, Shafaq; Matsuyama, Ayako; Lolignier, Stéphane; Kanellopoulos, Alexandros H.; Mancini, Flavia; Iannetti, Gian D.; Bogdanov, Yury D.; Santana-Varela, Sonia; Millet, Queensta; Baskozos, Giorgios; MacAllister, Raymond; Cox, James J.; Zhao, Jing; Wood, John N.

    2015-01-01

    Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7-null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids. PMID:26634308

  1. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7.

    PubMed

    Minett, Michael S; Pereira, Vanessa; Sikandar, Shafaq; Matsuyama, Ayako; Lolignier, Stéphane; Kanellopoulos, Alexandros H; Mancini, Flavia; Iannetti, Gian D; Bogdanov, Yury D; Santana-Varela, Sonia; Millet, Queensta; Baskozos, Giorgios; MacAllister, Raymond; Cox, James J; Zhao, Jing; Wood, John N

    2015-12-04

    Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7-null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids.

  2. Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery

    PubMed Central

    Hay, Justin L.; Okkerse, Pieter; van Amerongen, Guido; Groeneveld, Geert Jan

    2016-01-01

    Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug's pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain. The integrated, multi-modal pain task battery presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, the UVB inflammatory model which includes a thermal task and a paradigm for inhibitory conditioned pain modulation. These human pain models have been tested for predicative validity and reliability both in their own right and in combination, and can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. This allows a drug to be fully characterized and profiled for analgesic effect which is especially useful for drugs with a novel or untested mechanism of action. PMID:27166581

  3. Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models

    PubMed Central

    O’Neill, Jessica; Sikandar, Shafaq; McMahon, Stephen B; Dickenson, Anthony H

    2015-01-01

    Abstract The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of rat dorsal horn neurones and enhanced perceptual responses of human subjects to both mechanical and thermal stimulation. Additional heat rekindling produces markers of central sensitisation in both species, including enhanced receptive field sizes. Importantly, we also showed a correlation in the evoked activity of rat spinal neurones to human thermal pain thresholds. The parallel results in rats and humans validate the translational use of both models and the potential for such models for preclinical assessment of prospective analgesics in inflammatory pain states. Key points Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology

  4. Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models.

    PubMed

    O'Neill, Jessica; Sikandar, Shafaq; McMahon, Stephen B; Dickenson, Anthony H

    2015-09-01

    Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively. The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of

  5. Exercise-induced pain intensity predicted by pre-exercise fear of pain and pain sensitivity

    PubMed Central

    Bishop, Mark D; Horn, Maggie E; George, Steven Z

    2011-01-01

    Objectives Our primary goals were to determine whether pre-existing fear of pain and pain sensitivity contributed to post-exercise pain intensity. Methods Delayed onset muscle pain was induced in the trunk extensors of 60 healthy volunteers using an exercise paradigm. Levels of fear of pain and experimental pain sensitivity were measured before exercise. Pain intensity in the low back was collected at 24 and 48 hours post-exercise. Participants were grouped based on pain intensity. Group membership was used as the dependent variable in separate regression models for 24 and 48 hours. Predictor variables included fear, pain sensitivity, torque lost during the exercise protocol, and demographic variables. Results The final models predicting whether a participant reported clinically meaningful pain intensity at 24 hours only included baseline fear of pain at each level of pain intensity tested. The final model at 48 hours included average baseline pain sensitivity and the loss of muscle performance during the exercise protocol for one level of pain intensity tested (greater than 35mm out of 100). Discussion Combined, these findings suggest that the initial reports of pain after injury maybe more strongly influenced by fear while the inflammatory process and pain sensitivity may play a larger role for later pain intensity reports. PMID:21415719

  6. Long-Term Effects of Interprofessional Biopsychosocial Rehabilitation for Adults with Chronic Non-Specific Low Back Pain: A Multicentre, Quasi-Experimental Study

    PubMed Central

    Semrau, Jana; Hentschke, Christian; Buchmann, Jana; Meng, Karin; Vogel, Heiner; Faller, Hermann; Bork, Hartmut; Pfeifer, Klaus

    2015-01-01

    Background Improvement of the long-term effectiveness of multidisciplinary ortho-paedic rehabilitation (MOR) in the management of chronic non-specific low back pain (CLBP) remains a central issue for health care in Germany. We developed an interprofessional and interdisciplinary, biopsychosocial rehabilitation concept named “PASTOR” to promote self-management in adults with CLBP and compared its effectiveness with the current model of MOR. Methods A multicentre quasi-experimental study with three measurement time points was implemented. 680 adults aged 18 to 65 with CLBP were assed for eligibil-ity in three inpatient rehabilitation centres in Germany. At first the effects of the MOR, with a total extent of 48 hours (control group), were assessed. Thereafter, PASTOR was implemented and evaluated in the same centres (intervention group). It consisted of six interprofessional modules, which were provided on 12 days in fixed groups, with a total extent of 48 hours. Participants were assessed with self-report measures at baseline, discharge, and 12 months for functional ability (primary outcome) using the Hannover Functional Ability Questionnaire (FFbH-R) and vari-ous secondary outcomes (e.g. pain, health status, physical activity, pain coping, pain-related cognitions). Results In total 536 participants were consecutively assigned to PASTOR (n=266) or MOR (n=270). At 12 months, complete data of 368 participants was available. The adjusted between-group difference in the FFbH-R at 12 months was 6.58 (95% CI 3.38 to 9.78) using complete data and 3.56 (95% CI 0.45 to 6.67) using available da-ta, corresponding to significant small-to-medium effect sizes of d=0.42 (p<0.001) and d=0.10 (p=0.025) in favour of PASTOR. Further improvements in secondary out-comes were also observed in favour of PASTOR. Conclusion The interprofessional and interdisciplinary, biopsychosocial rehabilita-tion program PASTOR shows some improvements of the long-term effectiveness of inpatient

  7. Cancer pain

    SciTech Connect

    Swerdlow, M.; Ventafridda, V.

    1987-01-01

    This book contains 13 chapters. Some of the chapter titles are: Importance of the Problem; Neurophysiology and Biochemistry of Pain; Assessment of Pain in Patients with Cancer; Drug Therapy; Chemotherapy and Radiotherapy for Cancer Pain; Sympton Control as it Relates to Pain Control; and Palliative Surgery in Cancer Pain Treatment.

  8. Curine, an alkaloid isolated from Chondrodendron platyphyllum inhibits prostaglandin E2 in experimental models of inflammation and pain.

    PubMed

    Leite, Fagner Carvalho; Ribeiro-Filho, Jaime; Costa, Hermann Ferreira; Salgado, Paula Regina Rodrigues; Calheiros, Andrea Surrage; Carneiro, Alan Brito; de Almeida, Reinaldo Nobrega; Dias, Celidarque da Silva; Bozza, Patricia T; Piuvezam, Marcia Regina

    2014-08-01

    Curine is a bisbenzylisoquinoline alkaloid that is isolated from Chondrodendron platyphyllum, a plant that is used to treat malaria, inflammation, and pain. Recent reports have demonstrated the antiallergic effects of curine at nontoxic doses. However, its anti-inflammatory and analgesic properties remain to be elucidated. This study investigated the anti-inflammatory and analgesic effects of curine in mice. We analyzed the effects of an oral treatment with curine in the formation of paw edema, vascular permeability, abdominal contortion, licking behavior, and hyperalgesia using different inflammatory stimuli. Curine significantly inhibited the formation of paw edema by decreasing vascular permeability, inhibited the acetic acid-induced writhing response, inhibited the licking behavior during inflammation but not during the neurogenic phase of the formalin test, and inhibited carrageenan-induced hyperalgesia. Finally, curine inhibited prostaglandin E2 production in vitro without affecting cyclooxygenase-2 expression. The effects of curine treatment were similar to the effects of indomethacin, but were different from the effects of morphine treatment, suggesting that the analgesic effects of curine do not result from the direct inhibition of neuronal activation but instead depend on anti-inflammatory mechanisms that, at least in part, result from the inhibition of prostaglandin E2 production. In conclusion, curine presents anti-inflammatory and analgesic effects at nontoxic doses and has the potential for use in anti-inflammatory drug development.

  9. Development and Validation of a Virtual Human Vignette to Compare Nurses’ Assessment and Intervention Choices for Pain in Critically Ill Children

    PubMed Central

    LaFond, Cynthia M.; Van Hulle Vincent, Catherine; Lee, Sangyoon; Corte, Colleen; Hershberger, Patricia E.; Johnson, Andrew; Park, Chang G.; Wilkie, Diana J.

    2014-01-01

    Introduction As virtual experiences are increasingly used in healthcare training and research, it is important that adequate processes are applied for developing valid scenarios. We describe the development and validation of virtual human (VH) vignettes, computer-generated scenarios with animated patients and clinical information, for a mixed-methods study regarding nurses’ assessment and intervention choices for critically-ill children’s pain. Methods We followed the Case Development and Review Process for High-Fidelity Simulation Case Scenarios, including use of validated written vignettes and content experts. Forty nurses described their pain assessment and intervention choices for the newly derived VH vignettes and completed a pain questionnaire. Nurses’ reports of VH vignette consistency with their professional experience and recognition of VH facial expressions were evaluated to establish face validity. Their pain ratings for the VH and written (questionnaire) vignettes were evaluated for convergent validity. Qualitative content analysis, descriptive statistics, correlations, and paired t-tests were employed. Results Most nurses (68.4%) supported vignette consistency with their professional experience. Facial expression recognition was 98.4%. Smiling children’s pain was rated significantly lower than grimacing children in both VH and written vignettes. Pain was rated significantly lower for grimacing children in the VH vignettes than the written vignettes. VH vignette pain ratings were strongly correlated with their written counterparts. Conclusions This process was effective for developing VH vignettes that demonstrated good face validity with participants and convergent validity with written vignettes. VH vignettes may be useful in studying the influence of facial actions on nurses’ choices for children’s pain assessment and treatment. PMID:25514587

  10. Perceptual distortions of the human body image produced by local anaesthesia, pain and cutaneous stimulation

    PubMed Central

    Gandevia, S C; Phegan, C M L

    1999-01-01

    Knowledge of the size and orientation of the hand is essential if it is to be moved accurately in space. We used two psychophysical methods to determine whether the perceived size of a body part changes when its sensory input is changed: first, the selection of scaled drawings which matched the apparent size of a body part, and second, a motor task in which the subject drew the body part to depict its perceived size.Complete anaesthesia of the thumb (with a digital nerve block) significantly increased its perceived size by 60–70% when assessed with both psychophysical methods. During this anaesthesia, the perceived size of the adjacent index finger or digits on the contralateral side was unaltered. However, the size of the unanaesthetized lips increased (by ∼50%).Marked sensory loss for the lips (produced by topical anaesthetics) significantly increased their perceived size when assessed with both methods of measurement. There was a small increase in apparent size of the thumb.To determine whether changes in perceived size could also be produced by an elevation of peripheral inputs, innocuous electrical stimulation of the digital nerves and also painful cooling of the digit were used. Both procedures produced small but significant increases in perceived size of the stimulated part.The results highlight lability in the perceived size of parts of the body and how this affects motor output. The data may reveal perceptual consequences of acute changes in central somatosensory maps, changes which are known to occur with deafferentation. PMID:9852339

  11. Perceptual distortions of the human body image produced by local anaesthesia, pain and cutaneous stimulation.

    PubMed

    Gandevia, S C; Phegan, C M

    1999-01-15

    1. Knowledge of the size and orientation of the hand is essential if it is to be moved accurately in space. We used two psychophysical methods to determine whether the perceived size of a body part changes when its sensory input is changed: first, the selection of scaled drawings which matched the apparent size of a body part, and second, a motor task in which the subject drew the body part to depict its perceived size. 2. Complete anaesthesia of the thumb (with a digital nerve block) significantly increased its perceived size by 60-70% when assessed with both psychophysical methods. During this anaesthesia, the perceived size of the adjacent index finger or digits on the contralateral side was unaltered. However, the size of the unanaesthetized lips increased (by approximately 50%). 3. Marked sensory loss for the lips (produced by topical anaesthetics) significantly increased their perceived size when assessed with both methods of measurement. There was a small increase in apparent size of the thumb. 4. To determine whether changes in perceived size could also be produced by an elevation of peripheral inputs, innocuous electrical stimulation of the digital nerves and also painful cooling of the digit were used. Both procedures produced small but significant increases in perceived size of the stimulated part. 5. The results highlight lability in the perceived size of parts of the body and how this affects motor output. The data may reveal perceptual consequences of acute changes in central somatosensory maps, changes which are known to occur with deafferentation.

  12. Cell therapy of pain: Characterization of human fetal chromaffin cells at early adrenal medulla development.

    PubMed

    Zhou, H; Aziza, J; Sol, J C; Courtade-Saïdi, M; Chatelin, S; Evra, C; Parant, O; Lazorthes, Y; Jozan, S

    2006-04-01

    Adult adrenal chromaffin cells are being utilized for therapeutic transplantation. With the prospect of using fetal chromaffin cells in pain therapy, we studied their phenotype, proliferative power, function, and growth in vitro and in situ in order to determine the optimal time for implantation. Between 7 and 10 gestational weeks (GW), we isolated, in vitro, two types of chromaffin cells with a noradrenergic phenotype akin to that observed, in situ. Among the adherent chromaffin cells first observed in vitro, only a few samples expressed met-enkephalin, whereas almost all the neurosphere-like colonies, which appeared later, expressed it. However, neither of the two types of populations expressed an adrenergic phenotype in line with that observed in situ. At the upper limits of the voluntary abortion period authorized in France, this phenotype (12 GW) and met-enkephalin expression (13 GW) were evidenced in situ. For the first time in man, we demonstrate the secretion of noradrenaline in vitro by the two populations of cells. Consistent with this result, we also noted dopamine beta hydroxylase (DbetaH) mRNA expression in vitro and in situ within this period. These observations on the expression of these biological factors indicate that 9-10 GW would be the best stage for sampling these cells for preclinical transplantation experiments.

  13. Scientific misconduct and unethical human experimentation: historic parallels and moral implications.

    PubMed

    Lefor, Alan T

    2005-01-01

    Although a great deal of human experimentation has been performed to elucidate information otherwise not obtainable, there are many recorded instances of unethical human experimentation. There is also a history of crimes that were committed and disguised as human experiments, best exemplified by the activities of some physicians in Nazi Germany from 1933 until 1945. As a direct result of these activities, a war-crimes trial after World War II resulted in the creation of the Nuremberg Code, to guide future human experimentation. Despite this, unethical experiments were conducted at major academic institutions in the United States in the years after World War II by otherwise normal physicians who did not feel that the Nuremberg Code applied to them personally. There are several possible explanations for such activities, but the desire for personal advancement is prominent among these. Episodes of scientific misconduct such as falsification of experimental data or of personal qualifications seem to be more commonly reported recently and have also been described in the popular press. This activity may also be motivated by desire for personal advancement, giving it a parallel to the conduct of unethical human experimentation. Education may be the best way to prevent these activities that may have similar motivating factors.

  14. Leishmania infection: painful or painless?

    PubMed

    Borghi, Sergio M; Fattori, Victor; Conchon-Costa, Ivete; Pinge-Filho, Phileno; Pavanelli, Wander R; Verri, Waldiceu A

    2017-02-01

    The complex life cycle and immunopathological features underpinning the interaction of Leishmania parasites and their mammalian hosts poses frequent poorly explored and inconclusively resolved questions. The altered nociceptive signals over the course of leishmaniasis remain an intriguing issue for nociceptive and parasitology researchers. Experimental investigations have utilized behavioral, morphological, and neuro-immune approaches in the study of experimental cutaneous leishmaniasis (CL). The data generated indicates new venues for the study of the pathological characteristics of nociceptive processing in this parasitic disease. Leishmania-induced pain may be easily observed in mice and rats. However, nociceptive data is more complex in human investigations, including the occurrence of painless lesions in mucocutaneous and cutaneous leishmaniasis. Data from recent decades indicate that humans can also be affected by pain-related symptoms, often distinct from the region of body infection. The molecular and cellular mechanisms underlying such variable nociceptive states in humans during the course of leishmaniasis are an active area of research. The present article reviews nociception in leishmaniasis, including in experimental models of CL and clinical reports.

  15. Pain processing in four regions of human cingulate cortex localized with co-registered PET and MR imaging.

    PubMed

    Vogt, B A; Derbyshire, S; Jones, A K

    1996-07-01

    Neurosurgical and positron emission tomography (PET) human studies and animal electrophysiological studies show that part of the anterior cingulate cortex (ACC) is nociceptive. Since the contribution of the ACC to pain processing is poorly understood, this study employed PET and magnetic resonance (MR) image co-registration in grouped and individual cases to locate regions of altered relative regional cerebral blood flow (rCBF). Seven right-handed, neurologically intact males were subjects; each received neuropsychological and pain threshold testing. Subjects were scanned during infusion of H2[15O]: four randomized scans during innocuous heat stimulation to the back of the left hand and four scans during noxious but bearable heat to the same place. The averaged rCBF values during innocuous stimuli were subtracted from those during noxious stimuli and statistical parametric maps (SPMs) for the group were computed to identify regions of altered relative rCBF. Finally, single-subject PET images of elevated and reduced rCBF were co-registered with MR images and projected onto reconstructions of the medial surface of the hemisphere. The SPM analysis of the group showed one site with elevated rCBF in the midcingulate cortex and one in the perigenual cortex predominantly contralateral to the side of stimulation. There were bilateral sites of reduced rCBF in the cingulofrontal transitional cortex and in the posterior cingulate cortex (PCC). Co-registered PET and MR images for individuals showed that only one case had a single, large region of elevated rCBF, while the others had a number of smaller regions. Six cases had at least one significant elevation of rCBF in the right hemisphere that primarily involved area 24b'; five of these cases also had an elevation in area 32', while the seventh case had elevated rCBF in these areas in the left hemisphere. The rostral site of elevated rCBF in the group was at the border of areas 24/24' and areas 32/32' although most cases had

  16. Foetal pain?

    PubMed

    Derbyshire, Stuart W G

    2010-10-01

    The majority of commentary on foetal pain has looked at the maturation of neural pathways to decide a lower age limit for foetal pain. This approach is sensible because there must be a minimal necessary neural development that makes pain possible. Very broadly, it is generally agreed that the minimal necessary neural pathways for pain are in place by 24 weeks gestation. Arguments remain, however, as to the possibility of foetal pain before or after 24 weeks. Some argue that the foetus can feel pain earlier than 24 weeks because pain can be supported by subcortical structures. Others argue that the foetus cannot feel pain at any stage because it is maintained in a state of sedation in the womb and lacks further neural and conceptual development necessary for pain. Much of this argument rests on the definition of terms such as 'wakefulness' and 'pain'. If a behavioural and neural reaction to a noxious stimulus is considered sufficient for pain, then pain is possible from 24 weeks and probably much earlier. If a conceptual subjectivity is considered necessary for pain, however, then pain is not possible at any gestational age. Regardless of how pain is defined, it is clear that pain for conceptual beings is qualitatively different than pain for non-conceptual beings. It is therefore a mistake to draw an equivalence between foetal pain and pain in the older infant or adult.

  17. Neck Pain

    MedlinePlus

    ... injuries and conditions that cause pain and restrict motion. Neck pain causes include: Muscle strains. Overuse, such ... body then forms bone spurs that affect joint motion and cause pain. Nerve compression. Herniated disks or ...

  18. Ankle pain

    MedlinePlus

    Pain - ankle ... Ankle pain is often due to an ankle sprain. An ankle sprain is an injury to the ligaments, which ... the joint. In addition to ankle sprains, ankle pain can be caused by: Damage or swelling of ...

  19. Knee pain

    MedlinePlus

    Pain - knee ... Knee pain can have different causes. Being overweight puts you at greater risk for knee problems. Overusing your knee can trigger knee problems that cause pain. If you have a history of arthritis, it ...

  20. Elbow pain

    MedlinePlus

    Pain - elbow ... Elbow pain can be caused by many problems. A common cause in adults is tendinitis . This is inflammation and ... a partial dislocation ). Other common causes of elbow pain are: Bursitis -- inflammation of a fluid-filled cushion ...

  1. Eye pain

    MedlinePlus

    Ophthalmalgia; Pain - eye ... Pain in the eye can be an important symptom of a health problem. Make sure you tell your health care provider if you have eye pain that does not go away. Tired eyes or ...

  2. Wrist pain

    MedlinePlus

    Pain - wrist; Pain - carpal tunnel; Injury - wrist; Arthritis - wrist; Gout - wrist; Pseudogout - wrist ... Carpal tunnel syndrome: A common cause of wrist pain is carpal tunnel syndrome . You may feel aching, ...

  3. Foot pain

    MedlinePlus

    Pain - foot ... Foot pain may be due to: Aging Being on your feet for long periods of time Being overweight A ... sports activity Trauma The following can cause foot pain: Arthritis and gout . Common in the big toe, ...

  4. Phantom Pain

    MedlinePlus

    ... be an effective treatment for some types of chronic pain. In acupuncture, the practitioner inserts extremely fine, sterilized ... and Stroke. http://www.ninds.nih.gov/disorders/chronic_pain/detail_chronic_pain.htm. Accessed Sept. 16, 2014. ...

  5. Hip pain

    MedlinePlus

    ... pain involves any pain in or around the hip joint. You may not feel pain from your hip ... 2012:chap 48. Read More Hip fracture surgery Hip joint replacement Patient Instructions Hip fracture - discharge Hip or ...

  6. Depression, Pain, and Pain Behavior.

    ERIC Educational Resources Information Center

    Keefe, Francis J.; And Others

    1986-01-01

    Examined the degree to which depression predicted pain and pain behavior. The Beck Depression Inventory was administered to 207 low back pain patients. Depression and physical findings were the most important predictors of pain and pain behavior. Depression proved significant even after controlling for important demographic and medical status…

  7. Using multilevel growth curve modeling to examine emotional modulation of temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR).

    PubMed

    Rhudy, Jamie L; Martin, Satin L; Terry, Ellen L; Delventura, Jennifer L; Kerr, Kara L; Palit, Shreela

    2012-11-01

    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).

  8. Pain and functional imaging.

    PubMed Central

    Ingvar, M

    1999-01-01

    Functional neuroimaging has fundamentally changed our knowledge about the cerebral representation of pain. For the first time it has been possible to delineate the functional anatomy of different aspects of pain in the medial and lateral pain systems in the brain. The rapid developments in imaging methods over the past years have led to a consensus in the description of the central pain responses between different studies and also to a definition of a central pain matrix with specialized subfunctions in man. In the near future we will see studies where a systems perspective allows for a better understanding of the regulatory mechanisms in the higher-order frontal and parietal cortices. Also, pending the development of experimental paradigms, the functional anatomy of the emotional aspects of pain will become better known. PMID:10466155

  9. Activation of the prostaglandin system in response to sleep loss in healthy humans: Potential mediator of increased spontaneous pain

    PubMed Central

    Haack, Monika; Lee, Erin; Cohen, Daniel; Mullington, Janet M.

    2009-01-01

    Insufficient duration of sleep is a highly prevalent behavioral pattern in society that has been shown to cause an increase in spontaneous pain and sensitivity to noxious stimuli. Prostaglandins (PG), in particular PGE2, are key mediators of inflammation and pain, and we investigated whether PGE2 is a potential mediator in sleep-loss induced changes in nociceptive processing. Twenty-four participants (7 females, age 35. 17.1yrs) stayed for 7 days in the Clinical Research Center. After two baseline days, participants were randomly assigned to either three days of 88 hours of total sleep deprivation (TSD, N=15) or 8 hours of sleep per night (N=9), followed by a night of recovery sleep. Participants rated the intensity of various pain-related symptoms every two hours across waking periods on computerized visual analog scales. PGE2 was measured in 24h-urine collections during baseline and third sleep deprivation day. Spontaneous pain, including headache, muscle pain, stomach pain, generalized body pain, and physical discomfort significantly increased by 5 to 14 units on a 100-unit scale during TSD, compared to the sleep condition. Urinary PGE2 metabolite significantly increased by about 30% in TSD over sleep condition. TSD-induced increase in spontaneous pain, in particular headache and muscle pain, was significantly correlated with increase in PGE2 metabolite. Activation of the PGE2 system appears to be a potential mediator of increased spontaneous pain in response to insufficient sleep. PMID:19560866

  10. Central sensitization: implications for the diagnosis and treatment of pain.

    PubMed

    Woolf, Clifford J

    2011-03-01

    Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the

  11. Altered expression of the voltage-gated calcium channel subunit α2δ-1: A comparison between two experimental models of epilepsy and a sensory nerve ligation model of neuropathic pain

    PubMed Central

    Nieto-Rostro, M.; Sandhu, G.; Bauer, C.S.; Jiruska, P.; Jefferys, J.G.R.; Dolphin, A.C.

    2014-01-01

    The auxiliary α2δ-1 subunit of voltage-gated calcium channels is up-regulated in dorsal root ganglion neurons following peripheral somatosensory nerve damage, in several animal models of neuropathic pain. The α2δ-1 protein has a mainly presynaptic localization, where it is associated with the calcium channels involved in neurotransmitter release. Relevant to the present study, α2δ-1 has been shown to be the therapeutic target of the gabapentinoid drugs in their alleviation of neuropathic pain. These drugs are also used in the treatment of certain epilepsies. In this study we therefore examined whether the level or distribution of α2δ-1 was altered in the hippocampus following experimental induction of epileptic seizures in rats, using both the kainic acid model of human temporal lobe epilepsy, in which status epilepticus is induced, and the tetanus toxin model in which status epilepticus is not involved. The main finding of this study is that we did not identify somatic overexpression of α2δ-1 in hippocampal neurons in either of the epilepsy models, unlike the upregulation of α2δ-1 that occurs following peripheral nerve damage to both somatosensory and motor neurons. However, we did observe local reorganization of α2δ-1 immunostaining in the hippocampus only in the kainic acid model, where it was associated with areas of neuronal cell loss, as indicated by absence of NeuN immunostaining, dendritic loss, as identified by areas where microtubule-associated protein-2 immunostaining was missing, and reactive gliosis, determined by regions of strong OX42 staining. PMID:24641886

  12. Blaming god for our pain: human suffering and the divine mind.

    PubMed

    Gray, Kurt; Wegner, Daniel M

    2010-02-01

    Believing in God requires not only a leap of faith but also an extension of people's normal capacity to perceive the minds of others. Usually, people perceive minds of all kinds by trying to understand their conscious experience (what it is like to be them) and their agency (what they can do). Although humans are perceived to have both agency and experience, humans appear to see God as possessing agency, but not experience. God's unique mind is due, the authors suggest, to the uniquely moral role He occupies. In this article, the authors propose that God is seen as the ultimate moral agent, the entity people blame and praise when they receive anomalous harm and help. Support for this proposition comes from research on mind perception, morality, and moral typecasting. Interestingly, although people perceive God as the author of salvation, suffering seems to evoke even more attributions to the divine.

  13. Ethical regulation or regulating ethics? The need for both internal and external governance of human experimentation.

    PubMed

    Tomossy, George F

    2002-10-01

    Research regulation is a timely topic for discussions in bioethics and public health policy. This response to articles in the previous special issue of the Monash Bioethics Review emphasises the importance of having both internal and external controls on human experimentation. Unless both elements are incorporated into research ethics governance frameworks, they will ultimately fail to achieve what should be their primary goal: human subject protection.

  14. Monitoring Non-Invasive Cardiac Output and Stroke Volume during Experimental Human Hypovolaemia and Resuscitation

    DTIC Science & Technology

    2011-01-01

    Methods. Healthy human subjects (n¼21) underwent central hypovolaemia through progressive lower body negative pressure (LBNP) until the onset of presyncope...lower body negative pressure (LBNP), a well-established experimental model of central hypovolaemia.15 We assessed how well the investiga- tional methods...JJ, Schreuder JJ. Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 1993; 74: 2566–73 8

  15. Cadmium osteotoxicity in experimental animals: Mechanisms and relationship to human exposures

    SciTech Connect

    Bhattacharyya, Maryka H.

    2009-08-01

    Extensive epidemiological studies have recently demonstrated increased cadmium exposure correlating significantly with decreased bone mineral density and increased fracture incidence in humans at lower exposure levels than ever before evaluated. Studies in experimental animals have addressed whether very low concentrations of dietary cadmium can negatively impact the skeleton. This overview evaluates results in experimental animals regarding mechanisms of action on bone and the application of these results to humans. Results demonstrate that long-term dietary exposures in rats, at levels corresponding to environmental exposures in humans, result in increased skeletal fragility and decreased mineral density. Cadmium-induced demineralization begins soon after exposure, within 24 h of an oral dose to mice. In bone culture systems, cadmium at low concentrations acts directly on bone cells to cause both decreases in bone formation and increases in bone resorption, independent of its effects on kidney, intestine, or circulating hormone concentrations. Results from gene expression microarray and gene knock-out mouse models provide insight into mechanisms by which cadmium may affect bone. Application of the results to humans is considered with respect to cigarette smoke exposure pathways and direct vs. indirect effects of cadmium. Clearly, understanding the mechanism(s) by which cadmium causes bone loss in experimental animals will provide insight into its diverse effects in humans. Preventing bone loss is critical to maintaining an active, independent lifestyle, particularly among elderly persons. Identifying environmental factors such as cadmium that contribute to increased fractures in humans is an important undertaking and a first step to prevention.

  16. Shoulder pain

    MedlinePlus

    Pain - shoulder ... changes around the rotator cuff can cause shoulder pain. You may have pain when lifting the arm above your head or ... The most common cause of shoulder pain occurs when rotator cuff tendons ... The tendons become inflamed or damaged. This condition ...

  17. Pelvic Pain

    MedlinePlus

    Pelvic pain occurs mostly in the lower abdomen area. The pain might be steady, or it might come and go. If the pain is severe, it might get in the way ... re a woman, you might feel a dull pain during your period. It could also happen during ...

  18. Using experimental human influenza infections to validate a viral dynamic model and the implications for prediction.

    PubMed

    Chen, S C; You, S H; Liu, C Y; Chio, C P; Liao, C M

    2012-09-01

    The aim of this work was to use experimental infection data of human influenza to assess a simple viral dynamics model in epithelial cells and better understand the underlying complex factors governing the infection process. The developed study model expands on previous reports of a target cell-limited model with delayed virus production. Data from 10 published experimental infection studies of human influenza was used to validate the model. Our results elucidate, mechanistically, the associations between epithelial cells, human immune responses, and viral titres and were supported by the experimental infection data. We report that the maximum total number of free virions following infection is 10(3)-fold higher than the initial introduced titre. Our results indicated that the infection rates of unprotected epithelial cells probably play an important role in affecting viral dynamics. By simulating an advanced model of viral dynamics and applying it to experimental infection data of human influenza, we obtained important estimates of the infection rate. This work provides epidemiologically meaningful results, meriting further efforts to understand the causes and consequences of influenza A infection.

  19. Somatostatin and its 2A receptor in dorsal root ganglia and dorsal horn of mouse and human: expression, trafficking and possible role in pain

    PubMed Central

    2014-01-01

    Background Somatostatin (SST) and some of its receptor subtypes have been implicated in pain signaling at the spinal level. In this study we have investigated the role of SST and its sst2A receptor (sst2A) in dorsal root ganglia (DRGs) and spinal cord. Results SST and sst2A protein and sst2 transcript were found in both mouse and human DRGs, sst2A-immunoreactive (IR) cell bodies and processes in lamina II in mouse and human spinal dorsal horn, and sst2A-IR nerve terminals in mouse skin. The receptor protein was associated with the cell membrane. Following peripheral nerve injury sst2A-like immunoreactivity (LI) was decreased, and SST-LI increased in DRGs. sst2A-LI accumulated on the proximal and, more strongly, on the distal side of a sciatic nerve ligation. Fluorescence-labeled SST administered to a hind paw was internalized and retrogradely transported, indicating that a SST-sst2A complex may represent a retrograde signal. Internalization of sst2A was seen in DRG neurons after systemic treatment with the sst2 agonist octreotide (Oct), and in dorsal horn and DRG neurons after intrathecal administration. Some DRG neurons co-expressed sst2A and the neuropeptide Y Y1 receptor on the cell membrane, and systemic Oct caused co-internalization, hypothetically a sign of receptor heterodimerization. Oct treatment attenuated the reduction of pain threshold in a neuropathic pain model, in parallel suppressing the activation of p38 MAPK in the DRGs Conclusions The findings highlight a significant and complex role of the SST system in pain signaling. The fact that the sst2A system is found also in human DRGs and spinal cord, suggests that sst2A may represent a potential pharmacologic target for treatment of neuropathic pain. PMID:24521084

  20. Changes in chronic low back pain and cardiovascular risk factors using a homeopathic human chorionic gonadotropin–based weight loss program: a case report

    PubMed Central

    Morningstar, Mark W.; Strauchman, Megan N.

    2011-01-01

    Objective The purpose of this case report is to describe the changes in body weight and biochemical markers in a patient who completed a homeopathic human chorionic gonadotropin protocol. Case Report A 52-year-old man reported to an integrative medical center (including chiropractic and osteopathic physicians) for chronic low back pain. The patient reported a 20-year history of chronic, episodic low back pain. A course of spinal manipulative therapy was delivered; however, because of the lack of resolution of symptoms, a radiographic examination was performed, the result of which was essentially normal. Laboratory studies demonstrated hypercholesterolemia, hyperlipidemia, uricemia, and elevated blood glucose. A dietary change in treatment approach was selected. Intervention and Outcome The patient was instructed to take 10 drops of a homeopathic human chorionic gonadotropin product under the tongue 5 times daily. His total daily energy (calorie) was limited for the first 30 days of the program while on the homeopathic product. After 4 months, the patient lost a total of 71 lb, pain and disability scores improved, and reductions in serum cardiovascular markers were noted. Conclusion The findings of this study showed that weight loss seemed to affect the patient's chronic low back pain and cardiovascular risk factors. PMID:22654693

  1. Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain

    PubMed Central

    Watanabe, Hiroyuki; Fitting, Sylvia; Hussain, Muhammad Z.; Kononenko, Olga; Iatsyshyna, Anna; Yoshitake, Takashi; Kehr, Jan; Alkass, Kanar; Druid, Henrik; Wadensten, Henrik; Andren, Per E.; Nylander, Ingrid; Wedell, Douglas H.; Krishtal, Oleg; Hauser, Kurt F.; Nyberg, Fred; Karpyak, Victor M.; Yakovleva, Tatjana; Bakalkin, Georgy

    2015-01-01

    Lateralization of the processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria, and pain, the μ-, δ-, and κ-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and 5 “classical” neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg (LER) and Met-enkephalin-Arg-Phe, preferential δ-/μ- and κ-/μ-opioid agonists, demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B (Dyn B) strongly correlated with LER in the left, but not in the right ACC suggesting different mechanisms of the conversion of this κ-opioid agonist to δ-/μ-opioid ligand in the 2 hemispheres; in the right ACC, Dyn B may be cleaved by PACE4, a proprotein convertase regulating left–right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlies in part lateralization of higher functions, including positive and negative emotions and pain in the human brain. PMID:23960211

  2. Asymmetry of the endogenous opioid system in the human anterior cingulate: a putative molecular basis for lateralization of emotions and pain.

    PubMed

    Watanabe, Hiroyuki; Fitting, Sylvia; Hussain, Muhammad Z; Kononenko, Olga; Iatsyshyna, Anna; Yoshitake, Takashi; Kehr, Jan; Alkass, Kanar; Druid, Henrik; Wadensten, Henrik; Andren, Per E; Nylander, Ingrid; Wedell, Douglas H; Krishtal, Oleg; Hauser, Kurt F; Nyberg, Fred; Karpyak, Victor M; Yakovleva, Tatjana; Bakalkin, Georgy

    2015-01-01

    Lateralization of the processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria, and pain, the μ-, δ-, and κ-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and 5 "classical" neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg (LER) and Met-enkephalin-Arg-Phe, preferential δ-/μ- and κ-/μ-opioid agonists, demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B (Dyn B) strongly correlated with LER in the left, but not in the right ACC suggesting different mechanisms of the conversion of this κ-opioid agonist to δ-/μ-opioid ligand in the 2 hemispheres; in the right ACC, Dyn B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlies in part lateralization of higher functions, including positive and negative emotions and pain in the human brain.

  3. Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?

    PubMed Central

    Freitag, Caroline M.; Miller, Richard J.

    2014-01-01

    Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others) have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain. PMID:25191225

  4. Improvement of the experimental setup to assess cutaneous bioavailability on human skin models: dynamic protocol.

    PubMed

    Dreher, F; Patouillet, C; Fouchard, F; Zanini, M; Messager, A; Roguet, R; Cottin, M; Leclaire, J; Benech-Kieffer, F

    2002-01-01

    Human skin models, such as EpiDerm and Episkin, are not easily mounted into static or dynamic diffusion cells that are commonly used to perform bioavailability studies with human skin ex vivo. For various reasons, such as fragility, small sample size, and other morphological constraints, skin absorption studies with human skin models are often carried out on the delimited skin surface obtained by gluing a ring onto the reconstituted epidermis and manually exchanging the receptor solution. However, such an experimental setup is prone to artifacts. Discontinuous removal of the receptor fluid leads to alternating sink conditions, and an area of application smaller than the area in contact with the receptor fluid, as well as imperfect seal of the glued ring, may result in inaccurate penetration rates. Human skin models were shown to be relatively easily mounted into In-Line cells (PermeGear Inc.), vertical diffusion cells which appear to be appropriately designed for such a purpose. In-Line cells allowed accurate determination of solute penetration as well as automated sampling of receptor fluid. Excised human skin can be mounted into these cells as well, making it possible to compare penetration rates through different types of skin samples under identical conditions. Using mannitol as a reference compound, penetration profiles and epidermal distribution similar to those obtained with human skin ex vivo were obtained both with EpiDerm and Episkin. Under the present conditions, human skin models were more permeable to mannitol than excised human skin, which was only slightly permeable to mannitol. Due to these experimental innovations and to the good agreement with the absorption characteristics through human skin ex vivo, EpiDerm and Episkin seem to be promising human skin models for testing the cutaneous bioavailability of topical products in vitro.

  5. Experimental Approaches for Defining Functional Roles of Microbes in the Human Gut

    PubMed Central

    Dantas, Gautam; Sommer, Morten O.A.; Degnan, Patrick H.; Goodman, Andrew L.

    2016-01-01

    The complex and intimate relationship between humans and their gut microbial communities is becoming less obscure, due in part to large-scale gut microbial genome-sequencing projects and culture-independent surveys of the composition and gene content of these communities. These studies build upon, and are complemented by, experimental efforts to define underlying mechanisms of host-microbe interactions in simplified model systems. This review highlights the intersection of these approaches. Experimental studies now leverage the advances in high-throughput DNA sequencing that have driven the explosion of microbial genome and community profiling projects, and the loss-of-function and gain-of-function strategies long employed in model organisms are now being extended to microbial genes, species, and communities from the human gut. These developments promise to deepen our understanding of human gut host–microbiota relationships and are readily applicable to other host-associated and free-living microbial communities. PMID:24024637

  6. An experimental design for quantification of cardiovascular responses to music stimuli in humans.

    PubMed

    Chang, S-H; Luo, C-H; Yeh, T-L

    2004-01-01

    There have been several researches on the relationship between music and human physiological or psychological responses. However, there are cardiovascular index factors that have not been explored quantitatively due to the qualitative nature of acoustic stimuli. This study proposes and demonstrates an experimental design for quantification of cardiovascular responses to music stimuli in humans. The system comprises two components: a unit for generating and monitoring quantitative acoustic stimuli and a portable autonomic nervous system (ANS) analysis unit for quantitative recording and analysis of the cardiovascular responses. The experimental results indicate that the proposed system can exactly achieve the goal of full control and measurement for the music stimuli, and also effectively support many quantitative indices of cardiovascular response in humans. In addition, the analysis results are discussed and predicted in the future clinical research.

  7. Interleukin 10 Mediated By Herpes Simplex Virus Vectors Suppresses Neuropathic Pain Induced by Human Immunodeficiency Virus gp120 in Rats

    PubMed Central

    Zheng, Wenwen; Huang, Wan; Liu, Shue; Levitt, Roy C.; Candiotti, Keith A.; Lubarsky, David A.; Hao, Shuanglin

    2014-01-01

    Background Human Immunodeficiency Virus (HIV)-associated sensory neuropathy is a common neurological complication of HIV infection affecting up to 30% of HIV-positive individuals. However, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments for HIV-neuropathic pain (NP). In this study, we tested the hypothesis that inhibition of proinflammatory factors with overexpression of interleukin (IL)-10 reduces HIV-related NP in a rat model. Methods NP was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. The hindpaws of rats were inoculated with nonreplicating herpes simplex virus (HSV) vectors expressing antiinflammatory cytokine IL-10 or control vector. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The mechanical threshold response was assessed over time using the area under curves (AUC). The expression of phosphorylated p38 mitogen-activated kinase, as tumor necrosis factor alpha, stromal cell-derived factor-1α (SDF-1α), and C-X-C chemokine receptor type 4 in both the lumbar spinal cord and the L4/5 dorsal root ganglia (DRG) was examined at 14 and 28 days after vector inoculation using Western blots. Results We found that in the gp120-induced NP model, IL-10 overexpression mediated by the HSV vector resulted in a significant elevation of the mechanical threshold that was apparent on day 3 after vector inoculation compared with the control vector (P<0.0001). The antiallodynic effect of the single HSV vector inoculation expressing IL-10 lasted more than 28 days. The AUC in the HSV vector expressing IL-10 was increased compared with that in the control vector (P<0.0001). HSV vectors expressing IL-10 reversed the upregulation of phosphorylated p38 mitogen-activated kinase, as tumor necrosis factor alpha, stromal cell-derived factor-1α (SDF-1α), and C-X-C chemokine receptor type 4 expression at 14 and/or 28

  8. Low-back pain.

    PubMed

    Violante, Francesco S; Mattioli, Stefano; Bonfiglioli, Roberta

    2015-01-01

    Low-back pain is one of the most common painful conditions experienced by humans throughout their life. Some occupational risk factors (namely, heavy manual material handling) may also contribute to the development of low-back pain: due to the high prevalence of both low-back pain and manual material handling in the adult working population, it has been estimated that low-back pain is probably the most common occupational disorder worldwide. Lifetime prevalence of low-back pain has been reported to be as high as 84%, depending on the case definition used, and no age group is spared, even children. Although low-back pain is not a lethal condition, it was estimated at the third rank among all diseases by disability-adjusted life-years in 2010 in the USA, after ischemic heart disease and chronic obstructive pulmonary disease, and at the first rank by years lived with disability. It also ranked high (13th) globally for the same year, in disability-adjusted life-years. Low-back pain is currently classified as nonspecific/specific as to putative cause and as acute (lasting less than 6 weeks), subacute (6-12 weeks), or chronic (more than 12 weeks) according to duration of symptoms. The distinction between nonspecific/specific and acute/subacute/chronic low-back pain is useful not only for epidemiologic studies, but also (mainly) for choosing the appropriate strategy for the diagnosis and treatment of the disorder. Workplace risk factors for low-back pain include manual lifting and whole-body vibration exposure. This chapter will provide an overview of modern concepts of low-back pain (in general) and will then outline some distinctive features of work-related low-back pain.

  9. Human environmental and occupational exposures to boric acid: reconciliation with experimental reproductive toxicity data.

    PubMed

    Bolt, Hermann M; Başaran, Nurşen; Duydu, Yalçın

    2012-01-01

    The reproductive toxicity of boric acid and borates is a matter of current regulatory concern. Based on experimental studies in rats, no-observed-adverse-effect levels (NOAELs) were found to be 17.5 mg boron (B)/kg body weight (b.w.) for male fertility and 9.6 mg B/kg b.w. for developmental toxicity. Recently, occupational human field studies in highly exposed cohorts were reported from China and Turkey, with both studies showing negative results regarding male reproduction. A comparison of the conditions of these studies with the experimental NOAEL conditions are based on reported B blood levels, which is clearly superior to a scaling according to estimated B exposures. A comparison of estimated daily B exposure levels and measured B blood levels confirms the preference of biomonitoring data for a comparison of human field studies. In general, it appears that high environmental exposures to B are lower than possible high occupational exposures. The comparison reveals no contradiction between human and experimental reproductive toxicity data. It clearly appears that human B exposures, even in the highest exposed cohorts, are too low to reach the blood (and target tissue) concentrations that would be required to exert adverse effects on reproductive functions.

  10. Eating Frequency, Food Intake, and Weight: A Systematic Review of Human and Animal Experimental Studies

    PubMed Central

    Raynor, Hollie A.; Goff, Matthew R.; Poole, Seletha A.; Chen, Guoxun

    2015-01-01

    Eating frequently during the day, or “grazing,” has been proposed to assist with managing food intake and weight. This systematic review assessed the effect of greater eating frequency (EF) on intake and anthropometrics in human and animal experimental studies. Studies were identified through the PubMed electronic database. To be included, studies needed to be conducted in controlled settings or use methods that carefully monitored food intake, and measure food intake or anthropometrics. Studies using human or animal models of disease states (i.e., conditions influencing glucose or lipid metabolism), aside from being overweight or obese, were not included. The 25 reviewed studies (15 human and 10 animal studies) contained varying study designs, EF manipulations (1–24 eating occasions per day), lengths of experimentation (230 min to 28 weeks), and sample sizes (3–56 participants/animals per condition). Studies were organized into four categories for reporting results: (1) human studies conducted in laboratory/metabolic ward settings; (2) human studies conducted in field settings; (3) animal studies with experimental periods <1 month; and (4) animal studies with experimental periods >1 month. Out of the 13 studies reporting on consumption, 8 (61.5%) found no significant effect of EF. Seventeen studies reported on anthropometrics, with 11 studies (64.7%) finding no significant effect of EF. Future, adequately powered, studies should examine if other factors (i.e., disease states, physical activity, energy balance and weight status, long-term increased EF) influence the relationship between increased EF and intake and/or anthropometrics. PMID:26734613

  11. Sexual pain.

    PubMed

    Boardman, Lori A; Stockdale, Colleen K

    2009-12-01

    Sexual pain is an underrecognized and poorly treated constellation of disorders that significantly impact affected women and their partners. Recognized as a form of chronic pain, sexual pain disorders are heterogeneous and include dyspareunia (superficial and deep), vaginismus, vulvodynia, vestibulitis, and noncoital sexual pain disorder. Women too often tolerate pain in the belief that this will meet their partners' needs. This article provides a review of the terminology and definition of the condition, theories on the pathophysiology, diagnostic considerations, and recommendations on the management of female sexual pain.

  12. Developmental origins of health and disease: experimental and human evidence of fetal programming for metabolic syndrome.

    PubMed

    de Gusmão Correia, M L; Volpato, A M; Águila, M B; Mandarim-de-Lacerda, C A

    2012-07-01

    The concept of developmental origins of health and disease has been defined as the process through which the environment encountered before birth, or in infancy, shapes the long-term control of tissue physiology and homeostasis. The evidence for programming derives from a large number of experimental and epidemiological observations. Several nutritional interventions during diverse phases of pregnancy and lactation in rodents are associated with fetal and neonatal programming for metabolic syndrome. In this paper, recent experimental models and human epidemiological studies providing evidence for the fetal programming associated with the development of metabolic syndrome and related diseases are revisited.

  13. Pain: A Statistical Account

    PubMed Central

    Thacker, Michael A.; Moseley, G. Lorimer

    2017-01-01

    Perception is seen as a process that utilises partial and noisy information to construct a coherent understanding of the world. Here we argue that the experience of pain is no different; it is based on incomplete, multimodal information, which is used to estimate potential bodily threat. We outline a Bayesian inference model, incorporating the key components of cue combination, causal inference, and temporal integration, which highlights the statistical problems in everyday perception. It is from this platform that we are able to review the pain literature, providing evidence from experimental, acute, and persistent phenomena to demonstrate the advantages of adopting a statistical account in pain. Our probabilistic conceptualisation suggests a principles-based view of pain, explaining a broad range of experimental and clinical findings and making testable predictions. PMID:28081134

  14. Reward and motivation in pain and pain relief

    PubMed Central

    Navratilova, Edita; Porreca, Frank

    2015-01-01

    Pain is fundamentally unpleasant, a feature that protects the organism by promoting motivation and learning. Relief of aversive states, including pain, is rewarding. The aversiveness of pain, as well as the reward from relief of pain, is encoded by brain reward/motivational mesocorticolimbic circuitry. In this Review, we describe current knowledge of the impact of acute and chronic pain on reward/motivation circuits gained from preclinical models and from human neuroimaging. We highlight emerging clinical evidence suggesting that anatomical and functional changes in these circuits contribute to the transition from acute to chronic pain. We propose that assessing activity in these conserved circuits can offer new outcome measures for preclinical evaluation of analgesic efficacy to improve translation and speed drug discovery. We further suggest that targeting reward/motivation circuits may provide a path for normalizing the consequences of chronic pain to the brain, surpassing symptomatic management to promote recovery from chronic pain. PMID:25254980

  15. Reward and motivation in pain and pain relief.

    PubMed

    Navratilova, Edita; Porreca, Frank

    2014-10-01

    Pain is fundamentally unpleasant, a feature that protects the organism by promoting motivation and learning. Relief of aversive states, including pain, is rewarding. The aversiveness of pain, as well as the reward from relief of pain, is encoded by brain reward/motivational mesocorticolimbic circuitry. In this Review, we describe current knowledge of the impact of acute and chronic pain on reward/motivation circuits gained from preclinical models and from human neuroimaging. We highlight emerging clinical evidence suggesting that anatomical and functional changes in these circuits contribute to the transition from acute to chronic pain. We propose that assessing activity in these conserved circuits can offer new outcome measures for preclinical evaluation of analgesic efficacy to improve translation and speed drug discovery. We further suggest that targeting reward/motivation circuits may provide a path for normalizing the consequences of chronic pain to the brain, surpassing symptomatic management to promote recovery from chronic pain.

  16. Modeling Mycobacterium tuberculosis early granuloma formation in experimental human lung tissue.

    PubMed

    Parasa, Venkata Ramanarao; Rahman, Muhammad Jubayer; Ngyuen Hoang, Anh Thu; Svensson, Mattias; Brighenti, Susanna; Lerm, Maria

    2014-02-01

    The widely used animal models for tuberculosis (TB) display fundamental differences from human TB. Therefore, a validated model that recapitulates human lung TB is attractive for TB research. Here, we describe a unique method for establishment of TB infection in an experimental human lung tissue model. The model is based on cell lines derived from human lungs and primary macrophages from peripheral blood, and displays characteristics of human lung tissue, including evenly integrated macrophages throughout the epithelium, production of extracellular matrix, stratified epithelia and mucus secretion. Establishment of experimental infection in the model tissue with Mycobacterium tuberculosis, the bacterium that causes TB, resulted in clustering of macrophages at the site of infection, reminiscent of early TB granuloma formation. We quantitated the extent of granuloma formation induced by different strains of mycobacteria and validated our model against findings in other TB models. We found that early granuloma formation is dependent on ESAT-6, which is secreted via the type VII secretion machinery of virulent mycobacteria. Our model, which can facilitate the discovery of the interactions between mycobacteria and host cells in a physiological environment, is the first lung tissue model described for TB.

  17. Pain in Times of Stress

    PubMed Central

    AHMAD, Asma Hayati; ZAKARIA, Rahimah

    2015-01-01

    Stress modulates pain perception, resulting in either stress-induced analgesia or stress-induced hyperalgesia, as reported in both animal and human studies. The responses to stress include neural, endocrine, and behavioural changes, and built-in coping strategies are in place to address stressors. Peculiar to humans are additional factors that modulate pain that are experienced in times of stress, notably psychological factors that potentially influence the directionality of pain perception. PMID:27006638

  18. PBPK modeling for PFOS and PFOA: validation with human experimental data.

    PubMed

    Fàbrega, Francesc; Kumar, Vikas; Schuhmacher, Marta; Domingo, José L; Nadal, Martí

    2014-10-15

    In recent years, because of the potential human toxicity, concern on perfluoroalkyl substances (PFASs) has increased notably with special attention to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Unfortunately, there is currently an important knowledge gap on the burdens of these chemicals in most human tissues, as the reported studies have been mainly focused on plasma. In order to overcome these limitations, the use of physiologically-based pharmacokinetic (PBPK) models has been extended. The present study was aimed at testing an existing PBPK model for their predictability of PFOS and PFOA in a new case-study, and also to adapt it to estimate the PFAS content in human tissue compartments. Model validation was conducted by means of PFOA and PFOS concentrations in food and human drinking water from Tarragona County (Catalonia, Spain), and being the predicted results compared with those experimentally found in human tissues (blood, liver, kidney, liver and brain) of subjects from the same area of study. The use of human-derived partition coefficient (Pk) data was proven as more suitable for application to this PBPK model than rat-based Pk values. However, the uncertainty and variability of the data are still too high to get conclusive results. Consequently, further efforts should be carried out to reduce parametric uncertainty of PBPK models. More specifically, a deeper knowledge on the distribution of PFOA and PFOS within the human body should be obtained by enlarging the number of biological monitoring studies on PFASs.

  19. Pain Assessment

    MedlinePlus

    ... acupuncture, chiropractic care, massage or other manual therapies, yoga, herbal and nutritional therapies, or others. This information helps the health care provider understand the nature of the pain or the potential benefits of treatment. The goals of the comprehensive pain ...

  20. Anal Pain

    MedlinePlus

    ... change in bowel habit or rectal bleeding. A hemorrhoid that develops quickly or is particularly painful may ... your doctor. The blood clot of a thrombosed hemorrhoid, although painful, can't break loose and travel, ...

  1. Back Pain

    MedlinePlus

    ... specific points on the body. Some people with low back pain report that acupuncture helps relieve their symptoms. Massage. ... Accessed May 29, 2015. Adult acute and subacute low back pain. Bloomington, Minn.: Institute for Clinical Systems Improvement. http:// ...

  2. Period Pain

    MedlinePlus

    ... You may also have other symptoms, such as lower back pain, nausea, diarrhea, and headaches. Period pain is not ... Taking a hot bath Doing relaxation techniques, including yoga and meditation You might also try taking over- ...

  3. Finger pain

    MedlinePlus

    Pain - finger ... Nearly everyone has had finger pain at some time. You may have: Tenderness Burning Stiffness Numbness Tingling Coldness Swelling Change in skin color Redness Many conditions, such ...

  4. Back Pain

    MedlinePlus

    ... Oh, my aching back!", you are not alone. Back pain is one of the most common medical problems, ... 10 people at some point during their lives. Back pain can range from a dull, constant ache to ...

  5. Breast Pain

    MedlinePlus

    ... before your period and sometimes continuing through your menstrual cycle. The pain may be moderate or severe, and ... breasts. Throughout the month, not related to your menstrual cycle. Postmenopausal women sometimes have breast pain, but breast ...

  6. Hip Pain

    MedlinePlus

    ... clues about the underlying cause. Problems within the hip joint itself tend to result in pain on the ... tendons and other soft tissues that surround your hip joint. Hip pain can sometimes be caused by diseases ...

  7. Predicting transition to chronic pain

    PubMed Central

    Apkarian, A. Vania; Baliki, Marwan N.; Farmer, Melissa A.

    2016-01-01

    Purpose of review Most individuals who develop pain following an inciting event will return to a healthy state as the injury heals. However, a small percentage continue to suffer, that is, transition to chronic pain. Chronic pain may persist for years and is accompanied by cognitive abnormalities, as well as diminished quality of life. In animals, persistent pain is characterized by peripheral and spinal cord reorganization, and recent evidence in humans also indicates cortical reorganization. Yet, despite more than 30 years of research, there is little agreement on the neural mechanisms that mediate the transition from acute to chronic pain. Recent findings In a longitudinal brain-imaging study, individuals who developed an intense back pain episode were followed over a 1-year period, during which pain and brain parameters were collected repeatedly. A smaller number of healthy individuals and chronic back pain patients were also studied concomitantly, as positive and negative controls. At the time of entry into the study, strength of synchrony between the medial prefrontal cortex and nucleus accumbens (i.e. functional connectivity) was predictive (>80% accuracy) of individuals who subsequently transition to chronicity 1 year later. Summary Properties of the brain’s emotional learning circuitry predict the transition to chronic pain. The involvement of this circuitry in pain remains mostly unexplored. Future human and animal model studies are necessary to unravel underlying mechanisms driving pain chronicity, with the potential of advancing novel therapeutics for preventing pain chronification. PMID:23823463

  8. [Baccio Baldini (1517-1589), protomedicus on the medical court between humanism and experimentalism].

    PubMed

    Marinozzi, Silvia; Giuffra, Valentina; Kieffer, Fanny

    2015-01-01

    The article aims to shed light on some particular aspects of the activity and the scientific thought of Baccio Baldini, Director of the Laurentian Library and Court physician of the Medici family in Florence. The analysis of his work as a humanist and the recovery of some unpublished documents enable to define the figure of Baldini as a paradigmatic example of the court physicians of modern age in Italy, highlighting the complementarity between humanism and experimentalism in the Renaissance medicine.

  9. From meta-omics to causality: experimental models for human microbiome research.

    PubMed

    Fritz, Joëlle V; Desai, Mahesh S; Shah, Pranjul; Schneider, Jochen G; Wilmes, Paul

    2013-05-03

    Large-scale 'meta-omic' projects are greatly advancing our knowledge of the human microbiome and its specific role in governing health and disease states. A myriad of ongoing studies aim at identifying links between microbial community disequilibria (dysbiosis) and human diseases. However, due to the inherent complexity and heterogeneity of the human microbiome, cross-sectional, case-control and longitudinal studies may not have enough statistical power to allow causation to be deduced from patterns of association between variables in high-resolution omic datasets. Therefore, to move beyond reliance on the empirical method, experiments are critical. For these, robust experimental models are required that allow the systematic manipulation of variables to test the multitude of hypotheses, which arise from high-throughput molecular studies. Particularly promising in this respect are microfluidics-based in vitro co-culture systems, which allow high-throughput first-pass experiments aimed at proving cause-and-effect relationships prior to testing of hypotheses in animal models. This review focuses on widely used in vivo, in vitro, ex vivo and in silico approaches to study host-microbial community interactions. Such systems, either used in isolation or in a combinatory experimental approach, will allow systematic investigations of the impact of microbes on the health and disease of the human host. All the currently available models present pros and cons, which are described and discussed. Moreover, suggestions are made on how to develop future experimental models that not only allow the study of host-microbiota interactions but are also amenable to high-throughput experimentation.

  10. Prevention of murine experimental autoimmune orchitis by recombinant human interleukin-6.

    PubMed

    Li, Lu; Itoh, Masahiro; Ablake, Maila; Macrì, Battesimo; Bendtzen, Klaus; Nicoletti, Ferdinando

    2002-02-01

    We studied the effect of exogenously administered recombinant human interleukin (IL)-6 on the development of experimental autoimmune orchitis (EAO) in C3H/Hej mice. IL-6 significantly reduced histological signs of EAO and appearance of delayed type hypersensitivity against the immunizing testicular germinal cells. The effect was seen even though the cytokine was administered for only 6 consecutive days and 2 weeks after immunization.

  11. Experimental mouse tumour models: what can be learnt about human cancer immunology?

    PubMed

    Dranoff, Glenn

    2011-12-02

    The recent demonstration that cancer immunotherapy extends patient survival has reinvigorated interest in elucidating the role of immunity in tumour pathogenesis. Experimental mouse tumour models have provided key mechanistic insights into host antitumour immune responses, and these have guided the development of novel treatment strategies. To accelerate the translation of these findings into clinical benefits, investigators need to gain a better understanding of the strengths and limitations of mouse model systems as tools for deciphering human antitumour immune responses.

  12. The effect of combined treatment of opioids with methylphenidate on nociception in rats and pain in human.

    PubMed

    Yamamotová, A; Fricová, J; Rokyta, R; Šlamberová, R

    2016-12-22

    Methylphenidate hydrochloride (MPH/Ritalin) is a stimulant used for off-label management of cancer-related fatigue and sedation; however, its use in pain treatment is still relatively rare. This study 1) compares the antinociceptive effect of MPH and its combination with morphine (MOR) in adult male Wistar rats after a single administration of MPH, MOR or their combination, and 2) compares the analgesic effects of opioids and Ritalin combined therapy with opioid monotherapy in patients with cancer pain. To objectively assess physical activity during a three-week monitoring period, patients were equipped with Actiwatch Score Actigraph. Patients performed daily evaluations of pain intensity and frequency, and the extent to which pain interfered with their daily life. Our research with rats supports the evidence that MPH in lower doses has the ability to enhance the analgesic properties of morphine when the two drugs are used in combination. Results from the patient arm of our study found that short-term treatment had no significant effect on intensity or frequency of pain, however it decreased the overall burden of pain; the combined treatment of opioid and Ritalin also showed anti-sedation effects and resulted in mild improvement in one of our patient's quality of life.

  13. [Assessment of the Effect of Pain on Autonomic Nervous System in Human Body Using Heart Rate Variability Analysis].

    PubMed

    Fu, Qingbiao; Liu, Chunlin; Zhang, Fang; Fang, Yi; Shen, Dai; Zhang, Jian

    2015-12-01

    The purpose of this study is to discuss the feasibility of establishing capsaicin pain model and the possibility to evaluate different degrees of pain by the heart rate variability (HRV). It also aims to investigate the changes of autonomic nervous activity of volunteers during the process of pain caused by capsaicin. A total of 30 volunteers were selected, who were physically and mentally healthy, into the study. To assess the effects of capsaicin on the healthy volunteers, we recorded the Visual Analogue Scale (VAS) scores after the capsaicin stimulus. Additionally, the electrocardiogram signals and HRV analysis index before and after stimulating were also recorded, respectively. More specifically, the HRV analysis indexes included the time domain index, the frequency domain index, and the nonlinear analysis index. The results demonstrated that the activity of the autonomic nerves was enhanced in the process of capsaicin stimulus, especially for the sympathetic nerve, which exhibited a significantly differences in HRV. In conclusion, the degree of pain can be reflected by the HRV. It is feasible to establish a capsaicin pain model. And in further experiments, HRV analysis could be used as a reference index for quantitative evaluation of pain.

  14. Patellofemoral Pain.

    PubMed

    Dutton, Rebecca A; Khadavi, Michael J; Fredericson, Michael

    2016-02-01

    Patellofemoral pain is characterized by insidious onset anterior knee pain that is exaggerated under conditions of increased patellofemoral joint stress. A variety of risk factors may contribute to the development of patellofemoral pain. It is critical that the history and physical examination elucidate those risk factors specific to an individual in order to prescribe an appropriate and customized treatment plan. This article aims to review the epidemiology, risk factors, diagnosis, and management of patellofemoral pain.

  15. Experimental Investigation of Human Adaptation to Change in Agent's Strategy through a Competitive Two-Player Game

    NASA Astrophysics Data System (ADS)

    Terada, Kazunori; Yamada, Seiji; Ito, Akira

    We conducted an experimental investigation on human adaptation to change in an agent's strategy through a competitive two-player game. Modeling the process of human adaptation to agents is important for designing intelligent interface agents and adaptive user interfaces that learn a user's preferences and behavior strategy. However, few studies on human adaptation to such an agent have been done. We propose a human adaptation model for a two-player game. We prepared an on-line experimental system in which a participant and an agent play a repeated penny-matching game with a bonus round. We then conducted experiments in which different opponent agents (human or robot) change their strategy during the game. The experimental results indicated that, as expected, there is an adaptation phase when a human is confronted with a change in the opponent agent's strategy, and adaptation is faster when a human is competing with robot than with another human.

  16. Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans

    PubMed Central

    von Bernuth, Horst; Picard, Capucine; Puel, Anne; Casanova, Jean-Laurent

    2013-01-01

    Most Toll-like-receptors (TLRs) and interleukin-1 receptors (IL-1Rs) signal via myeloid differentiation primary response 88 (MyD88) and interleukin-1 receptor-associated kinase 4 (IRAK-4). The combined roles of these two receptor families in the course of experimental infections have been assessed in MyD88- and IRAK-4-deficient mice for almost fifteen years. These animals have been shown to be susceptible to 46 pathogens: 27 bacteria, 8 viruses, 7 parasites, and 4 fungi. Humans with inborn MyD88 or IRAK-4 deficiency were first identified in 2003. They suffer from naturally occurring life-threatening infections caused by a small number of bacterial species, although the incidence and severity of these infections decrease with age. Mouse TLR- and IL-1R-dependent immunity mediated by MyD88 and IRAK-4 seems to be vital to combat a wide array of experimentally administered pathogens at most ages. By contrast, human TLR- and IL-1R-dependent immunity mediated by MyD88 and IRAK-4 seems to be effective in the natural setting against only a few bacteria and is most important in infancy and early childhood. The roles of TLRs and IL-1Rs in protective immunity deduced from studies in mutant mice subjected to experimental infections should therefore be reconsidered in the light of findings for natural infections in humans carrying mutations as discussed in this review. PMID:23255009

  17. Evaluating a Human Rights-Based Advocacy Approach to Expanding Access to Pain Medicines and Palliative Care: Global Advocacy and Case Studies from India, Kenya, and Ukraine.

    PubMed

    Lohman, Diederik; Amon, Joseph J

    2015-12-10

    Palliative care has been defined as care that is person-centered and attentive to physical symptoms and psychological, social, and existential distress in patients with severe or life-threatening illness. The identification of access to palliative care and pain treatment as a human rights issue first emerged among palliative care advocates, physicians, and lawyers in the 1990s, with a basis in the right to health and the right to be free from cruel, inhuman, and degrading treatment. Using a case study approach, we evaluate the results of a human rights-based advocacy approach on access to pain medicine and palliative care in India, Kenya, and Ukraine. In each country, human rights advocacy helped raise awareness of the issue, identify structural barriers to care, define government obligations, and contribute to the reform of laws, policies, and practices impeding the availability of palliative care services. In addition, advocacy efforts stimulated civil society engagement and high-level political leadership that fostered the implementation of human rights-based palliative care programs. Globally, access to palliative care was increasingly recognized by human rights bodies and within global health and drug policy organizations as a government obligation central to the right to health.

  18. Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model: a study protocol: A randomized, double-blind, placebo-controlled, crossover trial with an enriched design.

    PubMed

    Springborg, Anders D; Jensen, Elisabeth K; Taylor, Bradley K; Werner, Mads U

    2016-11-01

    Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion.The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose-response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization.Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days-days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169

  19. Pain and palliative medicine.

    PubMed

    Chang, Victor T; Sorger, Brooke; Rosenfeld, Kenneth E; Lorenz, Karl A; Bailey, Amos F; Bui, Trinh; Weinberger, Lawrence; Montagnini, Marcos

    2007-01-01

    Severe pain is highly prevalent, with rates of 40% to 70% in patients with advanced cancer, liver disease, heart failure, human immunodeficiency virus, and renal failure. Wide variations in pain assessment and reporting methods and the measurement of multiple symptoms should be addressed in future studies. Regarding psychological approaches, determining whether hypnotherapy or other individual psychotherapeutic interventions reduce pain and/or psychological distress in a palliative care population is difficult. Interest is increasing in the concept of demoralization syndromes and the role of posttraumatic stress disorder in modulating responses to pain at the end of life. We review evidence from multiple studies that the use of rehabilitative therapy improves functional status and pain control among patients with advanced cancer, and we raise the possibility that rehabilitation therapy will be helpful in patients with other advanced diseases. We summarize ongoing clinical trials of electronic order sets, clinical care pathways, and care management pathways to improve pain management in palliative care. Wagner's Chronic Illness Model provides a way of analyzing how healthcare systems can be changed to provide adequate and continuing pain management in palliative care. Much work remains to ensure that pain is recognized, treated, and monitored effectively.

  20. Fantastic plastic? Experimental evaluation of polyurethane bone substitutes as proxies for human bone in trauma simulations.

    PubMed

    Smith, Martin J; James, Stephen; Pover, Tim; Ball, Nina; Barnetson, Victoria; Foster, Bethany; Guy, Carl; Rickman, John; Walton, Virginia

    2015-09-01

    Recent years have seen steady improvements in the recognition and interpretation of violence related injuries in human skeletal remains. Such work has at times benefited from the involvement of biological anthropologists in forensic casework and has often relied upon comparison of documented examples with trauma observed in skeletal remains. In cases where no such example exists investigators must turn to experimentation. The selection of experimental samples is problematic as animal proxies may be too dissimilar to humans and human cadavers may be undesirable for a raft of reasons. The current article examines a third alternative in the form of polyurethane plates and spheres marketed as viable proxies for human bone in ballistic experiments. Through subjecting these samples to a range of impacts from both modern and archaic missile weapons it was established that such material generally responds similarly to bone on a broad, macroscopic scale but when examined in closer detail exhibits a range of dissimilarities that call for caution in extrapolating such results to real bone.

  1. A portable experimental apparatus for human olfactory fMRI experiments.

    PubMed

    Sezille, C; Messaoudi, B; Bertrand, A; Joussain, P; Thévenet, M; Bensafi, M

    2013-08-15

    Human olfactory perception can be measured using psychophysical tools or more complex odor generating devices systems, namely olfactometers. The present paper is aimed at presenting a new inexpensive, non-voluminous portable olfactometer adapted for human fMRI experiments. The system adjusts odorant stimulus presentation to human nasal respiration and records behavioral responses in the same experimental device. Validation by psychophysical measures and photo-ionization detection showed a linear increase in both odor intensity perception and vapor concentration as a function of odorant concentration. Further validation by brain imaging revealed neural activation in typical olfactory areas. In summary, the system represents a new low-cost, easy-use, easy-maintenance portable olfactometry tool for brain imaging, opening up new possibilities for investigating neural response to odors using event-related fMRI designs.

  2. Evaluation of the analgesic efficacy and psychoactive effects of AZD1940, a novel peripherally acting cannabinoid agonist, in human capsaicin-induced pain and hyperalgesia.

    PubMed

    Kalliomäki, Jarkko; Annas, Peter; Huizar, Karin; Clarke, Cyril; Zettergren, Annika; Karlsten, Rolf; Segerdahl, Märta

    2013-03-01

    The aim of the present study was to investigate the effects of AZD1940, a novel peripherally acting cannabinoid CB(1) /CB(2) receptor agonist, on capsaicin-induced pain and hyperalgesia, as well as on biomarkers of cannabinoid central nervous system (CNS) effects. The present study was a randomized, double-blind, placebo-controlled, four-sequence, two-period, cross-over study in 44 male healthy volunteers aged 20-45 years. The effects of two single oral doses of AZD1940 (400 and 800 μg) were compared with placebo. Pain intensity after intradermal capsaicin injections in the forearm was assessed on a continuous visual analogue scale (VAS; 0-100 mm). Primary and secondary hyperalgesia induced by application of capsaicin cream on the calf were assessed by measuring heat pain thresholds and the area of mechanical allodynia, respectively. The CNS effects were assessed at baseline and up to 24 h after dosing using a visual analogue mood scales (VAMS) for feeling 'stimulated', 'high', 'anxious', 'sedated' or 'down'. AZD1940 did not significantly attenuate ongoing pain or primary or secondary hyperalgesia compared with placebo. Mild CNS effects for AZD1940were observed on the VAMS for 'high' and 'sedated'. Dose-dependent mild-to-moderate CNS-related and gastrointestinal adverse events were reported following treatment with AZD1940. No evidence of analgesic efficacy was found for a peripherally acting CB(1)/CB(2) receptor agonist in the human capsaicin pain model. The emergence of mild dose-dependent CNS effects suggests that the dose range predicted from preclinical data had been attained.

  3. Temporomandibular pain

    PubMed Central

    Prasad, S Raghavendra; Kumar, N Ravi; Shruthi, HR; Kalavathi, SD

    2016-01-01

    Temporomandibular joint pain has various medical and dental etiological factors. The etiology of the temporomandibular joint pain is enigmatic, no single etiological factor is regarded as the cause. Its distribution is also not confined to a single area. This article presents the basic etiologic factors, its epidemiology, distribution of pain, classification of patients and the psychosocial behavior of patients suffering with temporomandibular pain. As overwhelming majority of medical and dental conditions/issues related to etiology of temporomandibular pain in patients have traditionally been presented and interpreted from the clinician's point of view. PMID:27601822

  4. Self-Administration of Cannabinoids by Experimental Animals and Human Marijuana Smokers

    PubMed Central

    Justinova, Zuzana; Goldberg, Steven R.; Heishman, Stephen J.; Tanda, Gianluigi

    2009-01-01

    Drug self-administration behavior has been one of the most direct and productive approaches for studying the reinforcing effects of psychoactive drugs, which are critical in determining their abuse potential. Cannabinoids, which are usually abused by humans in the form of marijuana, have become the most frequently abused illicit class of drugs in the United States. The early elucidation of the structure and stereochemistry of delta-9-tetrahydrocannabinol (THC) in 1964, which is now recognized as the principal psychoactive ingredient in marijuana, activated cannabinoid research worldwide. This review examines advances in research on cannabinoid self-administration behavior by humans and laboratory animals. There have been numerous laboratory demonstrations of the reinforcing effects of cannabinoids in human subjects, but reliable self-administration of cannabinoids by laboratory animals has only recently been demonstrated. It has now been shown that strong and persistent self-administration behavior can be maintained in experimentally and drug-naïve squirrel monkeys by doses of THC comparable to those in marijuana smoke inhaled by humans. Furthermore, reinforcing effects of some synthetic CB1 cannabinoid agonists have been recently reported using intravenous and intracerebroventricular self-administration procedures in rats and mice. These findings support previous conclusions that THC has a pronounced abuse liability comparable to other drugs of abuse under certain experimental conditions. Self-administration of THC by squirrel monkeys provides the most reliable animal model for human marijuana abuse available to date. This animal model now makes it possible to study the relative abuse liability of other natural and synthetic cannabinoids and to preclinically assess new therapeutic strategies for the treatment or prevention of marijuana abuse in humans. PMID:15932767

  5. Cross-cultural conceptions of pain and pain control

    PubMed Central

    2002-01-01

    Pain is a ubiquitous feature of the human experience. This paper presents an anthropology of pain. Anthropology is defined as the cross-cultural and comparative study of human behavior. Pain can be acute and episodic, and pain can be constant and uninterrupted. Acute pain, lasting for minutes or hours, is reported at some time by virtually all adults and by most juveniles and is indicated by the cries and facial expressions of toddlers and infants. This universality of pain as a part of the human condition has been established by the research of many biological, physical, and social scientists. Ethnographers, physicians, and public health experts describe pain complaints for a variety of modern, industrial societies and traditional, undeveloped societies. Pain is the most frequent complaint brought to the offices of physicians in North America, and it is a focus of attention in the literate medical traditions of China, India, and Islamic cultures. Hence, the study of pain and the cultural perceptions of pain are prominent foci of anthropologists. Given that the goal of medicine is to offer medical care to all people who seek it, the practice of modern medicine may be assisted by an exploration of the possibility of cultural differences in medical beliefs and practices in the multiethnic and racially diverse patient populations today. PMID:16333427

  6. Abdominal Pain (Stomach Pain), Short-Term

    MedlinePlus

    ... myhealthfinder Immunization Schedules Nutrient Shortfall Questionnaire Abdominal Pain (Stomach Pain), Short-termJust about everyone has had a " ... time or another. But sudden severe abdominal pain (stomach pain), also called acute pain, shouldn't be ...

  7. Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain

    PubMed Central

    Apkarian, A.V.; Hashmi, J.A.; Baliki, M.N.

    2010-01-01

    We review recent advances in brain imaging in humans, concentrating on advances in our understanding of the human brain in clinical chronic pain. Understanding regarding anatomical and functional reorganization of the brain in chronic pain is emphasized. We conclude by proposing a brain model for the transition of the human from acute to chronic pain. PMID:21146929

  8. Temporal characteristics of cold pain perception.

    PubMed

    Frölich, Michael A; Bolding, Mark S; Cutter, Gary R; Ness, Timothy J; Zhang, Kui

    2010-08-09

    Adaptation to a sustained stimulus is an important phenomenon in psychophysical experiments. When studying the response to an experimental task, the investigator has to account for the change in perceived stimulus intensity with repeated stimulus application and, if the stimulus is sustained, for the change in intensity during the presentation. An example of a sustained stimulus is the cold pressor task (CPT). The task has been used both as an experimental pain task and to study cardiovascular physiology. In functional imaging research, the CPT has been used to evaluate cognitive processing of a noxious stimulus. Investigators typically model the stimulus in a block design as a categorical (on-off) stimulus and do not account for a temporal change in stimulus perception. If the perceived stimulus changes over time, the results may be misleading. Therefore, we characterized the time course of cold pain in human volunteers and developed a model of the temporal characteristics of perceived cold pain. Fifteen healthy participants underwent cold pain testing by immersing their right foot into a container filled with ice water (2 degrees C) for 30s alternating with a 30s immersion into a container filled with tepid water 32 degrees C (control). Participants rated the pain intensity using an electronic slide algometer. Using a mixed general linear model (effectively a polynomial regression model), we determined that pain ratings follow a crescendo-decrescendo pattern that can be described well using a quadratic model. We conclude that the time course of quantitative perception differs fundamentally from the time course of stimulus presentation. This may be important when looking for the physiological correlates of perception as opposed to the presence of a stimulus per se.

  9. Components of plastic: experimental studies in animals and relevance for human health

    PubMed Central

    Talsness, Chris E.; Andrade, Anderson J. M.; Kuriyama, Sergio N.; Taylor, Julia A.; vom Saal, Frederick S.

    2009-01-01

    Components used in plastics, such as phthalates, bisphenol A (BPA), polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A (TBBPA), are detected in humans. In addition to their utility in plastics, an inadvertent characteristic of these chemicals is the ability to alter the endocrine system. Phthalates function as anti-androgens while the main action attributed to BPA is oestrogen-like activity. PBDE and TBBPA have been shown to disrupt thyroid hormone homeostasis while PBDEs also exhibit anti-androgen action. Experimental investigations in animals indicate a wide variety of effects associated with exposure to these compounds, causing concern regarding potential risk to human health. For example, the spectrum of effects following perinatal exposure of male rats to phthalates has remarkable similarities to the testicular dysgenesis syndrome in humans. Concentrations of BPA in the foetal mouse within the range of unconjugated BPA levels observed in human foetal blood have produced effects in animal experiments. Finally, thyroid hormones are essential for normal neurological development and reproductive function. Human body burdens of these chemicals are detected with high prevalence, and concentrations in young children, a group particularly sensitive to exogenous insults, are typically higher, indicating the need to decrease exposure to these compounds. PMID:19528057

  10. Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice

    SciTech Connect

    Giavazzi, R.; Garofalo, A.; Bani, M.R.; Abbate, M.; Ghezzi, P.; Boraschi, D.; Mantovani, A.; Dejana, E. )

    1990-08-01

    This study has examined the effect of the cytokine interleukin 1 (IL-1) on metastasis formation by the human melanoma A375M in nude mice. We have found that human recombinant IL-1 beta (a single injection greater than 0.01 micrograms per mouse i.v. given before tumor cells) induced an augmentation of experimental lung metastases from the A375M tumor cells in nude mice. This effect was rapidly induced and reversible within 24 h after IL-1 injection. A similar effect was induced by human recombinant IL-1 alpha and human recombinant tumor necrosis factor, but not by human recombinant interleukin 6. 5-(125I)odo-2'-deoxyuridine-radiolabeled A375M tumor cells injected i.v. remained at a higher level in the lungs of nude mice receiving IL-1 than in control mice. In addition, IL-1 injected 1 h, but not 24 h, after tumor cells enhanced lung colonization as well, thus suggesting an effect of IL-1 on the vascular transit of tumor cells. These findings may explain the observation of enhanced secondary localization of tumor cells at inflammatory sites and suggest that modulation of secondary spread should be carefully considered when assessing the ability of this cytokine to complement cytoreductive therapies.

  11. The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals.

    PubMed

    Cegielski, J P; McMurray, D N

    2004-03-01

    The oral traditions of medicine and public health have it that malnutrition is an important risk factor for the development of tuberculosis (TB). Malnutrition profoundly affects cell-mediated immunity (CMI), and CMI is the principle host defense against TB. It makes biological sense. Although most health professionals readily accept this principle, much of this belief is based on uncontrolled observations such as disaster situations or on backwards logic from the cachexia common among TB patients. In fact, the evidence in humans is surprisingly thin from the perspective of scientific rigor. And few data, if any, quantify the extent of the relative or attributable risk of TB due to malnutrition. Moreover, until recently, data from experimental animals were based on animal models that were largely not relevant to human TB infection and disease. This article reviews the scientific data supporting the contention that malnutrition is an important risk factor for TB concentrating on observations in humans and on experimental animal studies based on a highly relevant animal model. If it is true, malnutrition may account for a greater population attributable risk of TB than HIV infection, and certainly a much more correctable one.

  12. Experimental identification and analytical modelling of human walking forces: Literature review

    NASA Astrophysics Data System (ADS)

    Racic, V.; Pavic, A.; Brownjohn, J. M. W.

    2009-09-01

    Dynamic forces induced by humans walking change simultaneously in time and space, being random in nature and varying considerably not only between different people but also for a single individual who cannot repeat two identical steps. Since these important aspects of walking forces have not been adequately researched in the past, the corresponding lack of knowledge has reflected badly on the quality of their mathematical models used in vibration assessments of pedestrian structures such as footbridges, staircases and floors. To develop better force models which can be used with more confidence in the structural design, an adequate experimental and analytical approach must be taken to account for their complexity. This paper is the most comprehensive review published to date, of 270 references dealing with different experimental and analytical characterizations of human walking loading. The source of dynamic human-induced forces is in fact in the body motion. To date, human motion has attracted a lot of interest in many scientific branches, particularly in medical and sports science, bioengineering, robotics, and space flight programs. Other fields include biologists of various kinds, physiologists, anthropologists, computer scientists (graphics and animation), human factors and ergonomists, etc. It resulted in technologically advanced tools that can help understanding the human movement in more detail. Therefore, in addition to traditional direct force measurements utilizing a force plate and an instrumented treadmill, this review also introduces methods for indirect measurement of time-varying records of walking forces via combination of visual motion tracking (imaging) data and known body mass distribution. The review is therefore an interdisciplinary article that bridges the gaps between biomechanics of human gait and civil engineering dynamics. Finally, the key reason for undertaking this review is the fact that human-structure dynamic interaction and

  13. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

    PubMed

    Zhang, Xiao-Liang; Pang, Wei; Hu, Xin-Tian; Li, Jia-Li; Yao, Yong-Gang; Zheng, Yong-Tang

    2014-11-18

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China.

  14. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress

    PubMed Central

    ZHANG, Xiao-Liang; PANG, Wei; HU, Xin-Tian; LI, Jia-Li; YAO, Yong-Gang; ZHENG, Yong-Tang

    2014-01-01

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China’s growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China’s life sciences and pharmaceutical industry, and enhance China’s position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China. PMID:25465081

  15. [Thrombolytic efficacy of a Lys-plasminogen-urokinase combination: studies in experimental animals and humans].

    PubMed

    Latorre, J; Foncuberta, J; Rosendo, A; Elez, J

    1990-01-01

    During animal experimental phase, lis-pg combined with UK produced a thrombolysis of about a 62.5%. This effect is accompanied by an important fibrinolytic system activation, a decrease in fibrinogen levels (0.37 +/- 0.2 gr/l) and an increase PDF/Fg (120.5 +/- 30 ng/ml). Such thrombolytic stage produced diverse hemorrhagic complications in experimental animals. During human clinical trial stage, then patients with Deep Venous Thrombosis (DVT) at proximal lower limbs level were submitted to diverse treatment protocols with Lis-Plasminogen (Lis-plg) and Urokinase (UK). After preliminary outcomes we can conclude that administration of Lis-plg followed by UK increases the fibrinolytic activity but also increases the risk of hemorrhagic complications. This second effect is not probably caused by an specific absorption on the thrombo surface, but by an increase of circulating plasminogen levels Lis-plg exogenous-induced.

  16. [Christian responsibility and experimental medicine. Experiments with and on humans, experiments on animals].

    PubMed

    Grosse, Heinrich W

    2002-01-01

    The Jewish-Christian convictions that man was created as the image of God founded the "ethics of unavailability" which contrast with the utilitarian "ethics of interests." As man s nature is imperfect according to biblical understanding, those responsible in the field of experimental medicine should counteract all tendencies in society which promote an utopian definition of health and an eugenic mentality (idea of the "perfection of mankind"). Consequently, scientists must reflect their own image of man and the effects of their actions on this image. The goals of experimental medicine must also be examined under the aspect of fairness: do they only benefit a minority in the rich industrial nations? As in research on humans, the ethical evaluation of animal experiments must consider the question of the underlying image of humanity and the responsibility of mankind connected to it. Because of changes in society's values, the validity of traditional anthropocentrism is increasingly questioned. However, this does not affect the view of the special position of man as the bearer of responsibility. Even though there are different biblical statements on the relationship between man and animal, the Christian maxim to minimise violence towards animals can be derived from them. In the case of animal experiments this means: experiments which cause the animals severe suffering must be avoided by waiving the potential gain of knowledge from them. In general: in an ethical discussion on medical experiments using humans or animals, the public must be informed completely and involved effectively. A moratorium must be possible before plans become facts. Thinking about ethical problems in the area of experimental medicine should not be separated from the far-reaching questions about changes in our lifestyle and consumer behaviour.

  17. Safe and effective pain management in elders.

    PubMed

    Varner, Joyce McCullers

    2012-01-01

    The elderly are often either untreated or undertreated for pain. The consequences of undertreatment for pain can have a devastating impact on health and quality of life, resulting in depression, anxiety, social isolation, cognitive impairment, immobility, and sleep disturbances. Reasons cited by healthcare professionals for inadequate pain control include lack of training, inappropriate pain assessment, and reluctance to prescribe opioids, however, the undertreatment of pain can be legally considered to constitute neglect, abuse, or negligence. The appropriate treatment of pain is humane and with good diagnostic efforts, proper consideration of appropriate medications and monitoring for adverse effects, healthcare providers can help to successfully control pain.

  18. The Stress Model of Chronic Pain: Evidence from Basal Cortisol and Hippocampal Structure and Function in Humans

    ERIC Educational Resources Information Center

    Vachon-Presseau, Etienne; Roy, Mathieu; Martel, Marc-Olivier; Caron, Etienne; Marin, Marie-France; Chen, Jeni; Albouy, Genevieve; Plante, Isabelle; Sullivan, Michael J.; Lupien, Sonia J.; Rainville, Pierre

    2013-01-01

    Recent theories have suggested that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor. The present study examined the associations between basal levels of cortisol collected over seven consecutive days, the hippocampal volumes and brain activation to thermal stimulations…

  19. Relevance of the glutathione system in temporal lobe epilepsy: evidence in human and experimental models.

    PubMed

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Pérez-Cruz, Claudia; Montesinos-Correa, Hortencia; Rivera-Espinosa, Liliana; Sampieri, Aristides; Carmona-Aparicio, Liliana

    2014-01-01

    Oxidative stress, which is a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with diseases that are systemic as well as diseases that affect the central nervous system. Epilepsy is a chronic neurological disorder, and temporal lobe epilepsy represents an estimated 40% of all epilepsy cases. Currently, evidence from human and experimental models supports the involvement of oxidative stress during seizures and in the epileptogenesis process. Hence, the aim of this review was to provide information that facilitates the processing of this evidence and investigate the therapeutic impact of the biochemical status for this specific pathology.

  20. Two different calibrated-leak balloons: experimental work and application in humans.

    PubMed

    Debrun, G M; Vinuela, F V; Fox, A J; Kan, S

    1982-01-01

    Two different types of latex calibrated-leak balloon catheters have been developed. One consists of a Teflon catheter with a detachable latex balloon and is used to embolize branches of the external carotid artery. The other consists of a Silastic catheter with a nondetachable latex balloon and is used to embolize brain arteriovenous malformations. An experimental model and animal experiments have determined the best conditions for safe and reproducible embolization with isobutyl-2 cyanoacrylate (IBC-2). Selective catheterization of branches of external carotid, middle cerebral, anterior cerebral, and posterior cerebral arteries in humans is facilitated, and embolization with IBC-2 has been achieved with these balloon catheters.

  1. Low back pain - chronic

    MedlinePlus

    Nonspecific back pain; Backache - chronic; Lumbar pain - chronic; Pain - back - chronic; Chronic back pain - low ... Low back pain is common. Almost everyone has back pain at some time in their life. Often, the exact cause of ...

  2. A New Differential Pressure Flow Meter for Measurement of Human Breath Flow: Simulation and Experimental Investigation.

    PubMed

    Bridgeman, Devon; Tsow, Francis; Xian, Xiaojun; Forzani, Erica

    2016-03-01

    The development and performance characterization of a new differential pressure-based flow meter for human breath measurements is presented in this article. The device, called a "Confined Pitot Tube," is comprised of a pipe with an elliptically shaped expansion cavity located in the pipe center, and an elliptical disk inside the expansion cavity. The elliptical disk, named Pitot Tube, is exchangeable, and has different diameters, which are smaller than the diameter of the elliptical cavity. The gap between the disk and the cavity allows the flow of human breath to pass through. The disk causes an obstruction in the flow inside the pipe, but the elliptical cavity provides an expansion for the flow to circulate around the disk, decreasing the overall flow resistance. We characterize the new sensor flow experimentally and theoretically, using Comsol Multiphysics(®) software with laminar and turbulent models. We also validate the sensor, using inhalation and exhalation tests and a reference method.

  3. [On evaluating the robot-based experimental system for biomechanical experiment of human knee].

    PubMed

    Deng, Guoyong; Tian, Lianfang; Bai, Bo; Sun, Hui

    2010-02-01

    This is a report on how we use the hybrid force-displacement control method to load the human knee and analyze the effect and value of our robot experimental system through the biomechanical experiments of total meniscal resection of human knee. The whole robot control system can load continuously on the specimens, thus overcoming the shortcomings of the traditional loading methods which can only load discretely. In the meantime, by using the robot-based testing system, the force (torque) of the specimens and the spatial position under the force can be measured in real-time, which overcomes the shortcomings caused by the separation of force (torque) measurement from displacement measurement and so greatly improves the measurement accuracy.

  4. Experimental Models of Vaginal Candidiasis and Their Relevance to Human Candidiasis

    PubMed Central

    Sobel, Jack D.

    2016-01-01

    Vulvovaginal candidiasis (VVC) is a high-incidence disease seriously affecting the quality of life of women worldwide, particularly in its chronic, recurrent forms (RVVC), and with no definitive cure or preventive measure. Experimental studies in currently used rat and mouse models of vaginal candidiasis have generated a large mass of data on pathogenicity determinants and inflammation and immune responses of potential importance for the control of human pathology. However, reflection is necessary about the relevance of these rodent models to RVVC. Here we examine the chemical, biochemical, and biological factors that determine or contrast the forms of the disease in rodent models and in women and highlight the differences between them. We also appeal for approaches to improve or replace the current models in order to enhance their relevance to human infection. PMID:26883592

  5. The institutional review board and beyond: future challenges to the ethics of human experimentation.

    PubMed

    Edgar, H; Rothman, D J

    1995-01-01

    Over the past two decades, institutional review boards (IRBs) have transformed the conduct of clinical research, in the process protecting human subjects and setting an admirable standard for monitoring the ethics of science. Nevertheless, the very proliferation of these committees, in addition to changing the character and sponsorship of new research, suggests that a ¿one size fits all¿ approach to the governance of human experimentation may have outlived its usefulness. It may be time to remove the ¿I¿ from the IRB and create a system with greater national oversight. Whether such a change can be accomplished within the current political climate is debatable. But the need for such a shift is becoming increasingly apparent.

  6. Experimental Models of Vaginal Candidiasis and Their Relevance to Human Candidiasis.

    PubMed

    Cassone, Antonio; Sobel, Jack D

    2016-05-01

    Vulvovaginal candidiasis (VVC) is a high-incidence disease seriously affecting the quality of life of women worldwide, particularly in its chronic, recurrent forms (RVVC), and with no definitive cure or preventive measure. Experimental studies in currently used rat and mouse models of vaginal candidiasis have generated a large mass of data on pathogenicity determinants and inflammation and immune responses of potential importance for the control of human pathology. However, reflection is necessary about the relevance of these rodent models to RVVC. Here we examine the chemical, biochemical, and biological factors that determine or contrast the forms of the disease in rodent models and in women and highlight the differences between them. We also appeal for approaches to improve or replace the current models in order to enhance their relevance to human infection.

  7. Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.

    PubMed

    Goldberg, Y P; MacFarlane, J; MacDonald, M L; Thompson, J; Dube, M-P; Mattice, M; Fraser, R; Young, C; Hossain, S; Pape, T; Payne, B; Radomski, C; Donaldson, G; Ives, E; Cox, J; Younghusband, H B; Green, R; Duff, A; Boltshauser, E; Grinspan, G A; Dimon, J H; Sibley, B G; Andria, G; Toscano, E; Kerdraon, J; Bowsher, D; Pimstone, S N; Samuels, M E; Sherrington, R; Hayden, M R

    2007-04-01

    Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

  8. Social laughter is correlated with an elevated pain threshold

    PubMed Central

    Dunbar, R. I. M.; Baron, Rebecca; Frangou, Anna; Pearce, Eiluned; van Leeuwen, Edwin J. C.; Stow, Julie; Partridge, Giselle; MacDonald, Ian; Barra, Vincent; van Vugt, Mark

    2012-01-01

    Although laughter forms an important part of human non-verbal communication, it has received rather less attention than it deserves in both the experimental and the observational literatures. Relaxed social (Duchenne) laughter is associated with feelings of wellbeing and heightened affect, a proximate explanation for which might be the release of endorphins. We tested this hypothesis in a series of six experimental studies in both the laboratory (watching videos) and naturalistic contexts (watching stage performances), using change in pain threshold as an assay for endorphin release. The results show that pain thresholds are significantly higher after laughter than in the control condition. This pain-tolerance effect is due to laughter itself and not simply due to a change in positive affect. We suggest that laughter, through an endorphin-mediated opiate effect, may play a crucial role in social bonding. PMID:21920973

  9. Social laughter is correlated with an elevated pain threshold.

    PubMed

    Dunbar, R I M; Baron, Rebecca; Frangou, Anna; Pearce, Eiluned; van Leeuwen, Edwin J C; Stow, Julie; Partridge, Giselle; MacDonald, Ian; Barra, Vincent; van Vugt, Mark

    2012-03-22

    Although laughter forms an important part of human non-verbal communication, it has received rather less attention than it deserves in both the experimental and the observational literatures. Relaxed social (Duchenne) laughter is associated with feelings of wellbeing and heightened affect, a proximate explanation for which might be the release of endorphins. We tested this hypothesis in a series of six experimental studies in both the laboratory (watching videos) and naturalistic contexts (watching stage performances), using change in pain threshold as an assay for endorphin release. The results show that pain thresholds are significantly higher after laughter than in the control condition. This pain-tolerance effect is due to laughter itself and not simply due to a change in positive affect. We suggest that laughter, through an endorphin-mediated opiate effect, may play a crucial role in social bonding.

  10. Neuropathic pain

    PubMed Central

    Colloca, Luana; Ludman, Taylor; Bouhassira, Didier; Baron, Ralf; Dickenson, Anthony H.; Yarnitsky, David; Freeman, Roy; Truini, Andrea; Attal, Nadine; Finnerup, Nanna B.; Eccleston, Christopher; Kalso, Eija; Bennett, David L.; Dworkin, Robert H.; Raja, Srinivasa N.

    2017-01-01

    Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7–10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain. PMID:28205574

  11. Central pain.

    PubMed

    Singh, Supreet

    2014-12-01

    Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topic addressed in this issue is central pain, a neuropathic pain syndrome caused by a lesion in the brain or spinal cord that sensitizes one's perception of pain. It is a debilitating condition caused by various diseases such as multiple sclerosis, strokes, spinal cord injuries, or brain tumors. Varied symptoms and the use of pharmacological medicines and nonpharmacological therapies will be addressed.

  12. Dystrophin Distribution and Expression in Human and Experimental Temporal Lobe Epilepsy

    PubMed Central

    Hendriksen, Ruben G. F.; Schipper, Sandra; Hoogland, Govert; Schijns, Olaf E. M. G.; Dings, Jim T. A.; Aalbers, Marlien W.; Vles, Johan S. H.

    2016-01-01

    Objective: Dystrophin is part of a protein complex that connects the cytoskeleton to the extracellular matrix. In addition to its role in muscle tissue, it functions as an anchoring protein within the central nervous system such as in hippocampus and cerebellum. Its presence in the latter regions is illustrated by the cognitive problems seen in Duchenne Muscular Dystrophy (DMD). Since epilepsy is also supposed to constitute a comorbidity of DMD, it is hypothesized that dystrophin plays a role in neuronal excitability. Here, we aimed to study brain dystrophin distribution and expression in both, human and experimental temporal lobe epilepsy (TLE). Method: Regional and cellular dystrophin distribution was evaluated in both human and rat hippocampi and in rat cerebellar tissue by immunofluorescent colocalization with neuronal (NeuN and calbindin) and glial (GFAP) markers. In addition, hippocampal dystrophin levels were estimated by Western blot analysis in biopsies from TLE patients, post-mortem controls, amygdala kindled (AK)-, and control rats. Results: Dystrophin was expressed in all hippocampal pyramidal subfields and in the molecular-, Purkinje-, and granular cell layer of the cerebellum. In these regions it colocalized with GFAP, suggesting expression in astrocytes such as Bergmann glia (BG) and velate protoplasmic astrocytes. In rat hippocampus and cerebellum there were neither differences in dystrophin positive cell types, nor in the regional dystrophin distribution between AK and control animals. Quantitatively, hippocampal full-length dystrophin (Dp427) levels were about 60% higher in human TLE patients than in post-mortem controls (p < 0.05), whereas the level of the shorter Dp71 isoform did not differ. In contrast, AK animals showed similar dystrophin levels as controls. Conclusion: Dystrophin is ubiquitously expressed by astrocytes in the human and rat hippocampus and in the rat cerebellum. Hippocampal full-length dystrophin (Dp427) levels are upregulated

  13. CD133(+) human umbilical cord blood stem cells enhance angiogenesis in experimental chronic hepatic fibrosis.

    PubMed

    Elkhafif, Nagwa; El Baz, Hanan; Hammam, Olfat; Hassan, Salwa; Salah, Faten; Mansour, Wafaa; Mansy, Soheir; Yehia, Hoda; Zaki, Ahmed; Magdy, Ranya

    2011-01-01

    The in vivo angiogenic potential of transplanted human umbilical cord blood (UCB) CD133(+) stem cells in experimental chronic hepatic fibrosis induced by murine schistosomiasis was studied. Enriched cord blood-derived CD133(+) cells were cultured in primary medium for 3 weeks. Twenty-two weeks post-Schistosomiasis infection in mice, after reaching the chronic hepatic fibrotic stage, transplantation of stem cells was performed and mice were sacrificed 3 weeks later. Histopathology and electron microscopy showed an increase in newly formed blood vessels and a decrease in the fibrosis known for this stage of the disease. By immunohistochemical analysis the newly formed blood vessels showed positive expression of the human-specific angiogenic markers CD31, CD34 and von Willebrand factor. Few hepatocyte-like polygonal cells showed positive expression of human vascular endothelial growth factor and inducible nitric oxide synthase. The transplanted CD133(+) human stem cells primarily enhanced hepatic angiogenesis and neovascularization and contributed to repair in a paracrine manner by creating a permissive environment that enabled proliferation and survival of damaged cells rather than by direct differentiation to hepatocytes. A dual advantage of CD133(+) cell therapy in hepatic disease is suggested based on its capability of hematopoietic and endothelial differentiation.

  14. Pathophysiology of Post Amputation Pain

    DTIC Science & Technology

    2014-12-01

    nociception and pain : analysis through imaging. Proc Natl Acad Sci U S A 1999;96:7668-74. 44. Casey KL, Minoshima S, Morrow TJ, Koeppe RA. Comparison of...trials. Eur J Pain 2006;10:77-88. 95. Dotson RM. Clinical neurophysiology laboratory tests to assess the nociceptive system in humans. J Clin...Award Number: W81XWH-11-1-0815 TITLE: Pathophysiology of Post Amputation Pain PRINCIPAL INVESTIGATOR: Dr. R. Norman Harden CONTRACTING

  15. Multimodal nociceptive mechanisms underlying chronic pelvic pain

    PubMed Central

    HELLMAN, Kevin M.; PATANWALA, Insiyyah Y.; POZOLO, Kristen E.; TU, Frank F.

    2015-01-01

    Objective To evaluate candidate mechanisms underlying the pelvic floor dysfunction in women with chronic pelvic pain and/or painful bladder syndrome/interstitial cystitis. Notably, prior studies have not consistently controlled for potential confounding by psychological or anatomical factors. Study Design As part of a larger study on pelvic floor pain dysfunction and bladder pain sensitivity, we compared a measure of mechanical pain sensitivity, pressure pain thresholds, between women with pelvic pain and pain-free controls. We also assessed a novel pain measure using degree and duration of post-exam pain aftersensation, and conducted structural and functional assessments of the pelvic floor to account for any potential confounding. Phenotypic specificity of pelvic floor measures was assessed with receiver-operator characteristic curves adjusted for prevalence. Results A total of 23 women with chronic pelvic pain, 23 painful bladder syndrome, and 42 pain-free controls completed the study. Women with chronic pelvic pain or painful bladder syndrome exhibited enhanced pain sensitivity with lower pressure pain thresholds (1.18 [interquartile range: 0.87–1.41] kg/cm2) than pain-free participants (1.48 [1.11–1.76] kg/cm2; p<0.001) and prolonged pain aftersensation (3.5 [0–9] vs 0 [0–1] minutes; p< 0.001). Although genital hiatus (p<0.01) was wider in women with chronic pelvic pain there were no consistently observed group differences in pelvic floor anatomy, muscle tone or strength. The combination of pressure pain thresholds and aftersensation duration correlated with severity of pelvic floor tenderness (R2 =41–51, p’s< 0.01). Even after adjustment for prevalence, the combined metrics discriminated pain-free controls from women with chronic pelvic pain or painful bladder syndrome (area under the curve=0.87). Conclusion Both experimental assessment of pelvic floor pain thresholds and measurement of sustained pain are independently associated with pelvic pain

  16. Doubling Your Payoff: Winning Pain Relief Engages Endogenous Pain Inhibition1,2,3

    PubMed Central

    Gandhi, Wiebke; Kwan, Saskia; Ahmed, Alysha-Karima; Schweinhardt, Petra

    2015-01-01

    Abstract When in pain, pain relief is much sought after, particularly for individuals with chronic pain. In analogy to augmentation of the hedonic experience (“liking”) of a reward by the motivation to obtain a reward (“wanting”), the seeking of pain relief in a motivated state might increase the experience of pain relief when obtained. We tested this hypothesis in a psychophysical experiment in healthy human subjects, by assessing potential pain-inhibitory effects of pain relief “won” in a wheel of fortune game compared with pain relief without winning, exploiting the fact that the mere chance of winning induces a motivated state. The results show pain-inhibitory effects of pain relief obtained by winning in behaviorally assessed pain perception and ratings of pain intensity. Further, the higher participants scored on the personality trait novelty seeking, the more pain inhibition was induced. These results provide evidence that pain relief, when obtained in a motivated state, engages endogenous pain-inhibitory systems beyond the pain reduction that underlies the relief in the first place. Consequently, such pain relief might be used to improve behavioral pain therapy, inducing a positive, perhaps self-amplifying feedback loop of reduced pain and improved functionality. PMID:26464995

  17. Characterising the mucosal and systemic immune responses to experimental human hookworm infection.

    PubMed

    Gaze, Soraya; McSorley, Henry J; Daveson, James; Jones, Di; Bethony, Jeffrey M; Oliveira, Luciana M; Speare, Richard; McCarthy, James S; Engwerda, Christian R; Croese, John; Loukas, Alex

    2012-02-01

    The mucosal cytokine response of healthy humans to parasitic helminths has never been reported. We investigated the systemic and mucosal cytokine responses to hookworm infection in experimentally infected, previously hookworm naive individuals from non-endemic areas. We collected both peripheral blood and duodenal biopsies to assess the systemic immune response, as well as the response at the site of adult worm establishment. Our results show that experimental hookworm infection leads to a strong systemic and mucosal Th2 (IL-4, IL-5, IL-9 and IL-13) and regulatory (IL-10 and TGF-β) response, with some evidence of a Th1 (IFN-γ and IL-2) response. Despite upregulation after patency of both IL-15 and ALDH1A2, a known Th17-inducing combination in inflammatory diseases, we saw no evidence of a Th17 (IL-17) response. Moreover, we observed strong suppression of mucosal IL-23 and upregulation of IL-22 during established hookworm infection, suggesting a potential mechanism by which Th17 responses are suppressed, and highlighting the potential that hookworms and their secreted proteins offer as therapeutics for human inflammatory diseases.

  18. Interleukin 34: a new modulator of human and experimental inflammatory bowel disease.

    PubMed

    Zwicker, Stephanie; Martinez, Gisele L; Bosma, Madeleen; Gerling, Marco; Clark, Reuben; Majster, Mirjam; Söderman, Jan; Almer, Sven; Boström, Elisabeth A

    2015-08-01

    IBD (inflammatory bowel disease), where CD (Crohn's disease) and UC (ulcerative colitis) represent the two main forms, are chronic inflammatory conditions of the intestine. Macrophages play a central role in IBD pathogenesis and are regulated by major differentiation factors such as CSF-1 (colony-stimulating factor 1) in homoeostasis and inflammation. IL (interleukin)-34 has recently been discovered as a second ligand for CSF-1R (CSF-1 receptor). However, expression and involvement of IL-34 in IBD remain unknown. In the present paper, we investigated the expression of IL34, CSF1 and their shared receptor CSF1R in normal human ileum and colon, in inflamed and non-inflamed tissues of CD and UC patients, and in a mouse model of experimental colitis. We found distinct expression patterns of IL34 and CSF1 in ileum and colon, with higher IL34 in ileum and, in contrast, higher CSF1 in colon. Furthermore, IL34 and CSF1 expression was increased with inflammation in IBD patients and in experimental colitis. In humans, infiltrating cells of the lamina propria and intestinal epithelial cells expressed IL-34, and TNF-α (tumour necrosis factor α) regulated IL-34 expression in intestinal epithelial cells through the NF-κB (nuclear factor κB) pathway. These data demonstrate the expression pattern of IL-34 in ileum and colon and suggest IL-34 as a new modulator of inflammation in IBD.

  19. An experimental and theoretical approach to a simplified model of human birth

    NASA Astrophysics Data System (ADS)

    Baumer, Alexa; Lehn, Andrea; Grotberg, James; Leftwich, Megan C.

    2014-11-01

    his study investigates the effects of amniotic fluid and vernix caseosa, as well as the uterine contraction wave dynamics, on the forces associated with human birth. An experimental model of the fetus passing through the birth canal is represented as concentric cylinders with a fluid filled gap. The rigid inner cylinder moves through the highly flexible outer cylinder while stabilized on a track. The inner cylinder is pulled through the system with constant velocity. As it moves, the rigid cylinder's position is recorded with a high-speed camera and the force is simultaneously measured. A perturbation solution considers the upper boundary as the uterine wall with a peristaltic wave. The lower boundary is the fetus traveling at constant velocity. Assuming lubrication theory and a small Reynolds number, the Navier-Stokes Equations and conservation of mass are solved for an expression for shear stress at the wall. This solution, and the experimental results, are compared to the exact Couette flow solution for constant gap width. This model can be used as the foundation for predicting the force needed to deliver a fetus in the final stages of parturition. From the concentric cylinders representation of human delivery, more complex and geometrically accurate models can be generated. NSF CBET-1437611.

  20. The relationship of the audible pop to hypoalgesia associated with high velocity, low amplitude thrust manipulation: A secondary analysis of an experimental study in pain free participants

    PubMed Central

    Bishop, Mark D; Robinson, Michael E; George, Steven Z

    2010-01-01

    Objective High velocity, low amplitude (HVLA) manipulation is an effective treatment for low back pain (LBP); however, the corresponding mechanisms are undetermined. Hypoalgesia is associated with HVLA manipulation and suggests specific mechanisms of action. An audible pop (AP) is also associated with HVLA manipulation; however, the influence of the AP on the hypoalgesia associated with HVLA manipulation is not established. The purpose of the current study was to observe the influence of the AP on hypoalgesia associated with HVLA manipulation. Methods The current study represents a secondary analysis of 40 participants. All participants underwent thermal pain sensitivity testing to their leg and low back using protocols specific to Aδ fiber mediated pain and temporal summation. Next, participants received HVLA manipulation to their low back and the examiner recorded whether or not an AP was perceived. Finally, participants underwent immediate follow up thermal pain sensitivity testing using the same protocols. Separate repeated measure ANOVAs were used to observe changes in pain sensitivity prior to and immediately following HVLA manipulation. Results Hypoalgesia of Aδ fiber mediated pain was observed in the low back following HVLA (p< 0.05) and this was independent of whether an AP was perceived (p> 0.05). Hypoalgesia of temporal summation was observed in the lower extremity following HVLA (p< 0.05) and this was independent of whether an AP was perceived (p= 0.08). However, a moderate effect size for temporal summation was observed favoring participants in whom an AP was perceived. Conclusion The current study suggests hypoalgesia is associated with HVLA manipulation and occurs independently of a perceived AP. Inhibition of lower extremity temporal summation may be larger in individuals in whom an AP is perceived, but further study is necessary to confirm this finding. PMID:20170777

  1. Modelling of the binding site of the human m1 muscarinic receptor: Experimental validation and refinement

    NASA Astrophysics Data System (ADS)

    Bourdon, Hélène; Trumpp-Kallmeyer, Susanne; Schreuder, Herman; Hoflack, , Jan; Hibert, Marcel; Wermuth, Camille-Georges

    1997-07-01

    Our model of the human m1 muscarinic receptor has been refined on the basis of the recently published projection map of bovine rhodopsin. The refined model has a slightly different helix arrangement, which reveals the presence of an extra hydrophobic pocket located between helices 3, 4 and 5. The interaction of series of agonists and antagonists with the m1 muscarinic receptor has been studied experimentally by site-directed mutagenesis. In order to account for the observed results, three-dimensional models of m1 ligands docked in the target receptor are proposed. Qualitatively, the obtained models are in good agreement with the experimental observations. Agonists and partial agonists have a relatively small size. They can bind to the same region of the receptor using, however, different anchoring receptor residues. Antagonists are usually larger molecules, filling almost completely the same pocket as agonists. They can usually produce much stronger interactions with aromatic residues. Experimental data combined with molecular modelling studies highlight how subtle and diverse receptor-ligand interactions could be.

  2. [Methodological approaches to the experimental study of the impact of environmental pollution on the human body].

    PubMed

    Sosedova, L M

    2014-01-01

    In the materials there are presented features of methodological approaches in the performing of experimental studies concerning of the investigation of the impacts of environmental factors on the human body. There were shown the results of our experiments performed at the Institute, in the modeling of biological effects of antimicrobial nanobiocomposites with nanosilver particles, toxic encephalopathy, in the study of the combined effect of the factors of biological and chemical nature. There was proved the importance of intracellular of proteomics in the assessment of the effects of the action of nanoparticles and nanomaterials on the body. There were revealed key parts of progredient course of mercury poisoning in the long-term. The special section is presented by the study of long-term effects of anthropogenic environmental factors on subsequent generations. There are presented results witnessing to a deterioration of the functional state of the central nervous system in rats in the first and second generations, whose parents were exposed to neurotoxicants. There was proved the aggravating role of prenatal hypoxia in the development of toxicity in rats in sexually mature age. Experimental biomodeling is aimed at sighting of pathogenetically substantiated treatment and preventive measures: initially, in experimental conditions, and in the future in the rehabilitation of sick or injured patients.

  3. Experimental verification of a computational technique for determining ground reactions in human bipedal stance.

    PubMed

    Audu, Musa L; Kirsch, Robert F; Triolo, Ronald J

    2007-01-01

    We have developed a three-dimensional (3D) biomechanical model of human standing that enables us to study the mechanisms of posture and balance simultaneously in various directions in space. Since the two feet are on the ground, the system defines a kinematically closed-chain which has redundancy problems that cannot be resolved using the laws of mechanics alone. We have developed a computational (optimization) technique that avoids the problems with the closed-chain formulation thus giving users of such models the ability to make predictions of joint moments, and potentially, muscle activations using more sophisticated musculoskeletal models. This paper describes the experimental verification of the computational technique that is used to estimate the ground reaction vector acting on an unconstrained foot while the other foot is attached to the ground, thus allowing human bipedal standing to be analyzed as an open-chain system. The computational approach was verified in terms of its ability to predict lower extre