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  • 1.
    Agalave, Nilesh M
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Max
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Abdelmoaty, Sally
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Su, Jie
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Baharpoor, Azar
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Lundbäck, Peter
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Palmblad, Karin
    Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Ulf
    Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Harris, Helena
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Svensson, Camilla I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis.2014In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 155, no 9, p. 1802-1813Article in journal (Refereed)
    Abstract [en]

    Extracellular high mobility group box-1 protein (HMGB1) plays important roles in the pathogenesis of nerve injury- and cancer-induced pain. However, the involvement of spinal HMGB1 in arthritis-induced pain has not been examined previously and is the focus of this study. Immunohistochemistry showed that HMGB1 is expressed in neurons and glial cells in the spinal cord. Subsequent to induction of collagen antibody-induced arthritis (CAIA), Hmgb1 mRNA and extranuclear protein levels were significantly increased in the lumbar spinal cord. Intrathecal (i.t.) injection of a neutralizing anti-HMGB1 monoclonal antibody or recombinant HMGB1 box A peptide (Abox), which each prevent extracellular HMGB1 activities, reversed CAIA-induced mechanical hypersensitivity. This occurred during ongoing joint inflammation as well as during the postinflammatory phase, indicating that spinal HMGB1 has an important function in nociception persisting beyond episodes of joint inflammation. Importantly, only HMGB1 in its partially oxidized isoform (disulfide HMGB1), which activates toll-like receptor 4 (TLR4), but not in its fully reduced or fully oxidized isoforms, evoked mechanical hypersensitivity upon i.t. injection. Interestingly, although both male and female mice developed mechanical hypersensitivity in response to i.t. HMGB1, female mice recovered faster. Furthermore, the pro-nociceptive effect of i.t. injection of HMGB1 persisted in Tlr2- and Rage-, but was absent in Tlr4-deficient mice. The same pattern was observed for HMGB1-induced spinal microglia and astrocyte activation and cytokine induction. These results demonstrate that spinal HMGB1 contributes to nociceptive signal transmission via activation of TLR4 and point to disulfide HMGB1 inhibition as a potential therapeutic strategy in treatment of chronic inflammatory pain.

  • 2.
    Amandusson, Åsa
    et al.
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Hermanson, Ola
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Estrogen-induced alterations of spinal cord enkephalin gene expression1999In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 83, no 2, p. 243-248Article in journal (Refereed)
    Abstract [en]

    Enkephalin-synthesizing neurons in the super®cial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P , 0:05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P , 0:05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.

  • 3.
    Bednarska, Olga
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Icenhour, Adriane
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
    Tapper, Sofie
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Witt, Suzanne Tyson
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Tisell, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Elsenbruch, Sigrid
    Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Walter, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Reduced excitatory neurotransmitter levels in anterior insulae are associated with abdominal pain in irritable bowel syndrome2019In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 160, no 9, p. 2004-2012Article in journal (Refereed)
    Abstract [en]

    Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstratealtered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However,alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changesremain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthycontrols [HC]) with respect to aINS glutamate 1 glutamine (Glx) and g-aminobutyric acid (GABA1) concentrations and addressedpossible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonancespectroscopy of bilateral aINS to assess Glx and GABA1 concentrations. Questionnaire data from all participants and prospectivesymptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related andpsychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P , 0.05, right aINS P , 0.001),whereas no group differences were detected for GABA1concentrations. Lower right-lateralized Glx concentrations in patients weresubstantially predicted by longer pain duration, while less frequent use of adaptive pain‐coping predicted lower Glx in left aINS. Ourfindings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results alsoindicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and ofthe left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.

  • 4.
    Bendtsen, Preben
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Division of Preventive and Social Medicine and Public Health Science. Östergötlands Läns Landsting, Centre for Public Health Sciences, Centre for Public Health Sciences.
    Hensing, G
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Division of Preventive and Social Medicine and Public Health Science.
    Ebeling, C
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Division of Preventive and Social Medicine and Public Health Science.
    Schedin, A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Division of Preventive and Social Medicine and Public Health Science.
    What are the qualities of dilemmas experienced when prescribing opioids in general practice? 1999In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 82, p. 89-96Article in journal (Refereed)
  • 5.
    Bernfort, Lars
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Gerdle, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Rahmqvist, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Levin, Lars-Åke
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Severity of chronic pain in an elderly population in Sweden-impact on costs and quality of life2015In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 156, no 3, p. 521-527Article in journal (Refereed)
    Abstract [en]

    Chronic pain is associated with large societal costs, but few studies have investigated the total costs of chronic pain with respect to elderly subjects. The elderly usually require informal care, care performed by municipalities, and care for chronic diseases, all factors that can result in extensive financial burdens on elderly patients, their families, and the social services provided by the state. This study aims to quantify the societal cost of chronic pain in people of age 65 years and older and to assess the impact of chronic pain on quality of life. This study collected data from 3 registers concerning health care, drugs, and municipal services and from 2 surveys. A postal questionnaire was used to collect data from a stratified sample of the population 65 years and older in southeastern Sweden. The questionnaire addressed pain intensity and quality of life variables (EQ-5D). A second postal questionnaire was used to collect data from relatives of the elderly patients suffering from chronic pain. A total of 66.5% valid responses of the 10,000 subjects was achieved; 76.9% were categorized as having no or mild chronic pain, 18.9% as having moderate chronic pain, and 4.2% as having severe chronic pain. Consumed resources increased with the severity of chronic pain. Clear differences in EQ-5D were found with respect to the severity of pain. This study found an association between resource use and severity of chronic pain in elderly subjects: the more severe the chronic pain, the more extensive (and expensive) the use of resources.

  • 6.
    Boersma, Katja
    et al.
    Orebro Univ, Sweden.
    Södermark, Martin
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hesser, Hugo
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology.
    Flink, Ida K.
    Orebro Univ, Sweden.
    Gerdle, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Linton, Steven J.
    Orebro Univ, Sweden.
    Efficacy of a transdiagnostic emotion-focused exposure treatment for chronic pain patients with comorbid anxiety and depression: a randomized controlled trial2019In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 160, no 8, p. 1708-1718Article in journal (Refereed)
    Abstract [en]

    The comorbidity between chronic pain and emotional problems has proven difficult to address with current treatment options. This study addresses the efficacy of a transdiagnostic emotion-focused exposure treatment ("hybrid") for chronic pain patients with comorbid emotional problems. Adults (n = 115) with chronic musculoskeletal pain and functional and emotional problems were included in a 2-centre, parallel randomized controlled, open-label trial comparing this treatment to an active control condition receiving a guided Internet-delivered pain management treatment based on CBT principles (iCBT). The hybrid treatment (n = 58, 10-16 sessions) integrates exposure in vivo for chronic pain based on the fear-avoidance model with an emotion-regulation approach informed by procedures in Dialectical Behavior Therapy. The iCBT (n = 57; 8 treatment modules) addresses topics such as pain education, coping strategies, relaxation, problem solving, stress, and sleep management using standard CBT techniques. Patient-reported outcomes were assessed before and after treatment as well as at a 9-month primary end point. Across conditions, 78% participants completed post-treatment and 81% follow-up assessment. Intent-to-treat analyses showed that the hybrid had a significantly better post-treatment outcome on pain catastrophizing (d = 0.39) and pain interference (d = 0.63) and significantly better follow-up outcomes on depression (d = 0.43) and pain interference (d = 0.51). There were no differences on anxiety and pain intensity. Observed proportions of clinically significant improvement favoured the hybrid on all but one comparison, but no statistically significant differences were observed. We conclude that the hybrid emotion-focused treatment may be considered an acceptable, credible, and efficacious treatment option for chronic pain patients with comorbid emotional problems.

  • 7. Buhrman, Monica
    et al.
    Fältenhag, Sofia
    Ström, Lars
    Andersson, Gerhard
    Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Behavioural Sciences, Clinical and Social Psychology.
    Controlled trial of Internet-based treatment with telephone support for chronic back pain2004In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 111, no 3, p. 368-377Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the effects of an Internet-based cognitive-behavioral intervention with telephone support for chronic back pain. Participants who met the criteria for chronic back pain (N=56) were randomly assigned to either an Internet-based cognitive behavioral self-help treatment or to a waiting-list control condition. The study period lasted 8 weeks and consisted of 1 week of self-monitoring prior to the intervention, 6 weeks of intervention, and 1 week of post-intervention assessment. Treatment consisted of education, cognitive skill acquisition, behavioral rehearsal, generalization and maintenance. The dropout rate was 9% (N=5). Results showed statistically significant improvements in catastrophizing, control over pain and ability to decrease pain. Some improvement was found in both the control group and the treatment group. A follow-up of 3 months after treatment termination was completed in 92% (N=47) of the participants who completed the treatment intervention. Follow-up results showed that some improvement was maintained. Findings indicate that Internet-based self-help with telephone support, based on established psychological treatment methods, holds promise as an effective approach for treating disability in association with pain.

  • 8.
    Bäckryd, Emmanuel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Lind, Anne-Li
    Uppsala University, Sweden.
    Thulin, Mans
    Uppsala University, Sweden.
    Larsson, Anders
    Uppsala University, Sweden.
    Gerdle, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Gordh, Torsten
    Uppsala University, Sweden.
    High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls2017In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 12, p. 2487-2495Article in journal (Refereed)
    Abstract [en]

    Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n 5 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

  • 9. Craig, AD
    et al.
    Zhang, ET
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Association of spinothalamic lamina I neurons and their ascending axons with calbindin-immunoreactivity in monkey and human2002In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 97, no 1-2, p. 105-115Article in journal (Refereed)
    Abstract [en]

    The calbindin-immunoreactivity of spinothalamic (STT) lamina I neurons and their ascending axons was examined in two experiments. In the first experiment, lamina I STT neurons in macaque monkeys were double-labeled for calbindin and for retrogradely transported WGA*HRP following large (n=2) or small (n=1) injections that included the posterior thalamus. Most, but not all (78%) of the contralateral retrogradely labeled lamina I STT cells were positive for calbindin. Calbindin-immunoreactivity was not selectively associated with any particular anatomical type of lamina I STT cell, 82% of the fusiform cells, 78% of the pyramidal cells and 67% of the multipolar cells were double-labeled. In the second experiment, oblique transverse sections from upper cervical spinal segments of three macaque monkeys, one squirrel monkey and five humans were stained for calbindin-immunoreactivity. In each case, a distinct bundle of fibers was densely stained in the middle of the lateral funiculus. This matches the location of anterogradely labeled ascending lamina I axons observed in prior work in cats and monkeys, and it matches the location of the classically described 'lateral spinothalamic tract' in humans. This bundle had variable shape across cases, an observation that might have clinical significance. These findings support the view that lamina I STT neurons are involved in spinal cordotomies that reduce pain, temperature and itch sensations. ⌐ 2002 International Association for the study of Pain. Published by Elsevier Science B.V. All rights reserved.

  • 10.
    Enthoven, Paul
    et al.
    Linköping University, Department of Department of Health and Society, Division of Physiotherapy. Linköping University, Faculty of Health Sciences.
    Skargren, Elisabeth
    Linköping University, Department of Department of Health and Society, Division of Physiotherapy. Linköping University, Faculty of Health Sciences.
    Carstensen, John
    Linköping University, Department of Department of Health and Society, Tema Health and Society. Linköping University, Faculty of Health Sciences.
    Öberg, Birgitta
    Linköping University, Department of Department of Health and Society, Division of Physiotherapy. Linköping University, Faculty of Health Sciences.
    Predictive factors for 1-year and 5-year outcome for disability in a working population of patients with low back pain treated in primary care2006In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 122, no 1-2, p. 137-144Article in journal (Refereed)
    Abstract [en]

    Many patients seeking primary care for low back pain continue to report disability several years after their initial visit. The aims of this study were to assess the independent predictive value of a number of potential predictive factors for disability at the 1-year and 5-year follow-ups, and to examine whether prediction models were improved by replacing baseline health-state-related variables with corresponding variables after treatment. A further aim was to describe possible differences between those on sick leave, early retirement or disability pension, and those who were not. Baseline factors were age, gender, self-reported physical-activity-related and work-related factors, expectations of treatment, similar problems previously, duration of episode, more than one localization, sick leave, pain frequency, disability, and well-being. The study sample comprised 148 participants in a previous randomized trial who were eligible for sick-leave benefits. Multiple logistic regression was used to identify predictive factors. At the 5-year follow-up, 37% (n = 19/52) of the patients with disability were on sick leave or were receiving early retirement or disability pension. For those without disability the corresponding figure was 9% (n = 8/92). Being a woman, duration of the current episode, similar problems during the previous 5 years, exercise level before the current episode, pain frequency at baseline, and disability after treatment emerged as predictive factors for disability at the 5-year follow-up. Replacing baseline health-state-related measures with corresponding measures after the treatment period, and adding physical-activity-related and possibly work-related factors might improve the likelihood of predicting future disability.

  • 11.
    Ghafouri, Nazdar
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Larsson, Britt
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Stensson, Niclas
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Fowler, Christopher J.
    Umeå University, Sweden .
    Gerdle, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity2013In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 154, no 9, p. 1649-1658Article in journal (Refereed)
    Abstract [en]

    Chronic widespread pain (CWP) is a complex condition characterized by central hyperexcitability and altered descending control of nociception. However, nociceptive input from deep tissues is suggested to be an important drive. N-Acylethanolamines (NAEs) are endogenous lipid mediators involved in regulation of inflammation and pain. Previously we have reported elevated levels of the 2 NAEs, the peroxisome proliferator-activated receptor type-alpha ligand N-palmitoylethanolamine (PEA) and N-stearoylethanolamine (SEA) in chronic neck/shoulder pain (CNSP). In the present study, the levels of PEA and SEA in women with CWP (n = 18), CNSP (n = 34) and healthy controls (CON, n = 24) were investigated. All subjects went through clinical examination, pressure pain threshold measurements and induction of experimental pain in the tibialis anterior muscle. Microdialysis dialysate of the trapezius was collected before and after subjects performed a repetitive low-force exercise and analyzed by mass spectrometry. The levels of PEA and SEA in CNSP were significantly higher post exercise compared with CWP, and both pre and post exercise compared with CON. Levels of both NAEs decreased significantly pre to post exercise in CWP. Intercorrelations existed between aspects of pain intensity and sensitivity and the level of the 2 NAEs in CWP and CNSP. This is the first study demonstrating that CNSP and CWP differ in levels of NAEs in response to a low-force exercise which induces pain. Increases in pain intensity as a consequence of low-force exercise were associated with low levels of PEA and SEA in CNSP and CWP. These results indicate that PEA and SEA have antinociceptive roles in humans.

  • 12.
    Gordh, T.E.
    et al.
    Multidisciplinary Pain Center, Uppsala University Hospital, S-751 85 Uppsala, Sweden.
    Stubhaug, A.
    Department of Anaesthesiology, University of Oslo, Rikshospitalet University Hospital, 0027 Oslo, Norway.
    Jensen, T.S.
    Department of Neurology, Danish Pain Research Centre, Aarhus University Hospital, Aarhus, 8000, Denmark.
    Arner, S.
    Arnèr, S., Pain Clinic, Department of Anaesthesiology, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden.
    Biber, B.
    Department of Anaestesiology, Umeå University Hospital, S-901 85 Umeå, Sweden.
    Boivie, Jörgen
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Neurology . Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Mannheimer, C.
    Multidisciplinary Pain Center, Department of Medicine, Sahlgrenska University Hospital, Östra, 41685 Göteborg, Sweden.
    Kalliomaki, J.
    Kalliomäki, J., Department of Rehabilitation, Lund University Hospital, S-221 85 Lund, Sweden.
    Kalso, E.
    Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Haartmaninkatu 2A, 00029 HUS, Finland.
    Gabapentin in traumatic nerve injury pain: A randomized, double-blind, placebo-controlled, cross-over, multi-center study2008In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 138, no 2, p. 255-266Article in journal (Refereed)
    Abstract [en]

    A double-blind, randomized, placebo-controlled cross-over multi-center study was conducted to evaluate the efficacy and safety of gabapentin in the treatment of neuropathic pain caused by traumatic or postsurgical peripheral nerve injury, using doses up to 2400 mg/day. The study comprised a run-in period of two weeks, two treatment periods of five weeks separated by a three weeks' washout period. The primary efficacy variable was the change in the mean pain intensity score from baseline to the last week of treatment. Other variables included pain relief, health related quality of life (SF-36), interference of sleep by pain, Clinician and Patient Global Impression of Change, and adverse effects. Nine centers randomized a total of 120 patients, 22 of whom withdrew. There was no statistically significant difference between the treatments for the primary outcome efficacy variable. However, gabapentin provided significantly better pain relief (p = 0.015) compared with placebo. More patients had at least a 30% pain reduction with gabapentin compared with placebo (p = 0.040) and pain interfered significantly less with sleep during gabapentin treatment compared with placebo (p = 0.0016). Both the Patient (p = 0.023) and Clinician (p = 0.037) Global Impression of Change indicated a better response with gabapentin compared with placebo. Gabapentin was well tolerated. The most common adverse effects were dizziness and tiredness. © 2007 International Association for the Study of Pain.

  • 13. Graven-Nilsen, T
    et al.
    Aspegren Kendall, Sally
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine/Pain Clinic. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Henriksson, Karl-Gösta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine/Pain Clinic. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Bengtsson, M
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Anaesthesiology. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, Anestesi.
    Sörensen, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Anaesthesiology. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, Anestesi.
    Johnson, A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Anaesthesiology. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, Anestesi.
    Gerdle, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine/Pain Clinic. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Arendt-Nielsen, L
    Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients2000In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 85, no 3, p. 483-491Article in journal (Refereed)
    Abstract [en]

    Central mechanisms related to referred muscle pain and temporal summation of muscular nociceptive activity are facilitated in fibromyalgia syndrome (FMS) patients. The present study assessed the effects of an NMDA-antagonist (ketamine) on these central mechanisms. FMS patients received either i.v. placebo or ketamine (0.3 mg/kg, Ketalar(«)) given over 30 min on two separate occasions. Habitual pain intensity was assessed on a visual analogue scale (VAS). Initially, 29 FMS patients received ketamine or isotonic saline to determine which patients were ketamine responders (>50% decrease in pain intensity at rest by active drug on two consecutive VAS assessments). Fifteen out of 17 ketamine-responders were included in the second part of the study. Before and after ketamine or placebo, experimental local and referred pain was induced by intramuscular (i.m.) infusion of hypertonic saline (0.7 ml, 5%) into the tibialis anterior (TA) muscle. The saline-induced pain intensity was assessed on an electronic VAS, and the distribution of pain drawn by the subject. In addition, the pain threshold (PT) to i.m. electrical stimulation was determined for single stimulus and five repeated (2 Hz, temporal summation) stimuli. The pressure PT of the TA muscle was determined, and the pressure PT and pressure pain tolerance threshold were determined at three bilaterally located tenderpoints (knee, epicondyle, and mid upper trapezius). VAS scores of pain at rest were progressively reduced during ketamine infusion compared with placebo infusion. Pain intensity (area under the VAS curve) to the post-drug infusion of hypertonic saline was reduced by ketamine (-18.4▒0.3% of pre-drug VAS area) compared with placebo (29.9▒18.8%, P<0.02). Local and referred pain areas were reduced by ketamine (-12.0▒14.6% of pre-drug pain areas) compared with placebo (126.3▒83.2%, P<0.03). Ketamine had no significant effect on the PT to single i.m. electrical stimulation. However, the span between the PT to single and repeated i.m. stimuli was significantly decreased by the ketamine (-42.3▒15.0% of pre-drug PT) compared with placebo (50.5▒49.2%, P<0.03) indicating a predominant effect on temporal summation. Mean pressure pain tolerance from the three paired tenderpoints was increased by ketamine (16.6▒6.2% of pre-drug thresholds) compared with placebo (-2.3▒4.9%, P<0.009). The pressure PT at the TA muscle was increased after ketamine (42.4▒9.2% of pre-drug PT) compared with placebo (7.0▒6.6%, P<0.011). The present study showed that mechanisms involved in referred pain, temporal summation, muscular hyperalgesia, and muscle pain at rest were attenuated by the NMDA-antagonist in FMS patients. It suggested a link between central hyperexcitability and the mechanisms for facilitated referred pain and temporal summation in a sub-group of the fibromyalgia syndrome patients. Whether this is specific for FMS patients or a general phenomena in painful musculoskeletal disorders is not known. Copyright (C) 2000 International Association for the Study of Pain. Published by Elsevier Science B.V.

  • 14.
    Larsson, Barbro
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine/Pain Clinic.
    Björk, J
    Henriksson, Karl-Gösta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine/Pain Clinic. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Gerdle, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine/Pain Clinic. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Lindman, R.
    The prevalences of cytochrome c oxidase negative and superpositive fibres and ragged-red fibres in the trapezius muscle of female cleaners with and without myalgia and of female healthy controls2000In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 84, no 2-3, p. 379-387Article in journal (Refereed)
    Abstract [en]

    The association of cytochrome c oxidase negative fibres (COX-negative) and ragged-red fibres (RR-fibres) with work related trapezius myalgia has been proposed. Hitherto studies have been small or without control groups. The aim of the present study was to investigate the prevalences of RR-fibres and COX-negative fibres in female cleaners with (n=25) and without (n=23) trapezius myalgia and in clinically healthy female teachers (n=21). The cleaners did mainly floor cleaning requiring monotonous loading on the trapezius muscle. A questionnaire covering background data and aspects of pain (prevalence, duration, intensity and influence on daily living) was answered. Biopsies were obtained from the trapezius muscle by an open surgical technique. The three groups did not differ in prevalence of COX-negative or COX-superpositive (i.e. type-I fibres with extremely strong brownish reaction in both the COX and SDH/COX stainings) fibres. The prevalence of COX-negative fibres was age dependent. Two subgroups of RR-fibres were present when stained for COX, COX-negative (73%) and COX-superpositive (26%) fibres. Forty-two percent of the COX-negative fibres were RR-fibres and 79% of the COX-superpositive were RR-fibres. A significantly (P=0.002) higher proportion of the COX-superpositive fibres in the cleaners were RR-fibres compared to the teachers. Multivariate regression analysis revealed that age, occupation as cleaner and a tender point in the trapezius were significantly associated with increased prevalences of RR-fibres, a cleaner with a tender point had a 4.35 higher prevalence of RR-fibres compared to a teacher without a tender point. No correlations between other pain related variables and prevalence of RR-fibres were noted. In conclusion, RR-fibres but not COX-negative or COX-superpositive fibres were correlated with cleaning work tasks and with a tender point in the trapezius.

  • 15.
    Larsson, Britt
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Rosendal, L
    DanTrials AS, Denmark.
    Kristiansen, J
    Denmark.
    Sjogaard, G
    Denmark.
    Sogaard, K
    Denmark.
    Ghafouri, Bijar
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Abdiu, Avni
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Kjaer, M
    Bispebjerg Hospital.
    Gerdle, Björn
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Responses of algesic and metabolic substances to 8 h of repetitive manual work in myalgic human trapezius muscle2008In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 140, no 3, p. 479-490Article in journal (Refereed)
    Abstract [en]

    The trapezius muscle often develops pain as the result of repetitive and stressful work tasks although it is unclear to what extent this pain is due to alterations in muscle concentrations of algesic/nociceptive substances. Twenty women with chronic neck- and shoulder pain (TM) whose work required highly repetitive work tasks and 20 pain-free female colleagues (CON) were studied during and after a full 8-hour workday. We collected microdialysates from their dominant/most painful trapezius muscle; concentrations of serotonin, glutamate, lactate, pyruvate, potassium, bradykinin, and cytokines and blood flow were determined. In addition, we measured surface electromyogram, task exposure level, pain intensity, perceived mental stress, and urine-cortisol. In connection to the clinical neck and Shoulder examination, we determined pressure pain thresholds (PPTs) over the trapezius and tibialis muscles. TM had higher concentrations Of glutamate (71 +/- 42 vs. 36 +/- 15 mu mol l(-1)) and pyruvate (187 +/- 89 vs. 125 +/- 63 mu mol l(-1)) than CON. Interstitial serotonin was higher ill TM (before work: 10.6 +/- 10.8 vs. 2.2 +/- 1.2 nM; after work: 9.2 +/- 8.3 vs. 1.5 +/- 2.9 nM). The trapezius blood flow during the working day was higher in TM than in CON. TM had lower PPT and higher pain intensity throughout the working day. No differences in EMG, task exposure level, Mental Stress, Or Urine-cortisol in the groups were found. These findings Support the idea that peripheral nociceptive processes are activated ill Occupationally active Subjects, who are diagnosed with trapezius myalgia. In contrast, no sign of low blood flow or increased stress or muscle activity markers were found in TM.

  • 16.
    Liljencrantz, Jaquette
    et al.
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Björnsdotter, Malin
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Morrison, India
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Bergstrand, Simon
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Ceko, Marta
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
    Seminowicz, David A
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
    Cole, Jonathan
    Department of Clinical Neurophysiology, Poole Hospital and University of Bournemouth, Bournemouth, UK.
    Bushnell, Catherine M
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
    Olausson, Håkan
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Department of Integrative Physiology, School of Medicine, University of Western Sydney, Sydney, Australia.
    Altered C-tactile processing in human dynamic tactile allodynia.2013In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 154, no 2, p. 227-234Article in journal (Refereed)
    Abstract [en]

    Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aβ afferents to access pain pathways. However, a recent mouse knockout study demonstrates that C-tactile afferents are necessary for allodynia to develop, suggesting a role for not only Aβ but also C-tactile afferent signaling. To examine the contribution of C-tactile afferents to the allodynic condition in humans, we applied the heat/capsaicin model of tactile allodynia in 43 healthy subjects and in 2 sensory neuronopathy patients lacking Aβ afferents. Healthy subjects reported tactile-evoked pain, whereas the patients did not. Instead, patients reported their C-touch percept (faint sensation of pleasant touch) to be significantly weaker in the allodynic zone compared to untreated skin. Functional magnetic resonance imaging in 18 healthy subjects and in 1 scanned patient indicated that stroking in the allodynic and control zones evoked different responses in the primary cortical receiving area for thin fiber signaling, the posterior insular cortex. In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aβ signaling, at least under these experimental conditions.

  • 17. List, T.
    et al.
    Tegelberg, A.
    Department of Stomatognathic Physiology, Central Hospital, SE-721, 89 Västerås, Sweden.
    Haraldson, T.
    Department of Stomatognathic Physiology, Borås Hospital, SE-501, 82 Borås, Sweden.
    Isacsson, G.
    AstraZeneca Clinical RandD, SE-151, 85 Södertälje, Sweden.
    Intra-articular morphine as analgesic in temporomandibular joint arthralgia/osteoarthritis2001In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 94, no 3, p. 275-282Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine the analgesic efficacy of a single dose intra-articular injection (i.a.) of morphine in 53 patients with unilateral arthralgia/osteoarthritis of the temporomandibular joint (TMJ). This randomized, double-blind, parallel group, multicenter study included a screening visit, a treatment visit, and a follow-up visit 1 week after treatment. Recordings of visual analog scales (VAS) pain intensity scores at maximum mouth opening (main efficacy variable) and at jaw rest were made directly before a 1-ml i.a. injection into one TMJ of either 1.0 mg morphine-HCl, 0.1 mg morphine-HCl, or saline (placebo). The pain intensity was also recorded at the follow-up and in a diary 3 days before and 5 days after the injection. The VAS pain score at maximum mouth opening was considerably reduced 1-10 h after injection but without significant differences between groups. At the follow-up, the median VAS pain score at maximal mouth opening was significantly lower in the 0.1-mg morphine group than in the 1.0-mg morphine group (P < 0.043) or the saline group (P < 0.021). A significant increase in pain pressure threshold over the affected joint was seen in the 0.1-mg morphine group compared with the saline group at the follow-up but not 1 and 2 h post-injection. The incidence of adverse events was small and did not differ between the treatment groups. In conclusion, one i.a. injection of 0.1 mg morphine significantly increased the pain pressure threshold and mouth opening ability, but evidence for the analgesic property of the locally applied opioid was inconclusive. No dose-effect relation and no significant short-term analgesic property were seen. Although statistically significant, the magnitude of the reduced VAS pain intensity score was not clinically relevant at the 1-week follow-up. © 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.

  • 18. List, Thomas
    et al.
    Leijon, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Neurology. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Helkimo, Martti
    Öster, Anders
    Svensson, Peter
    Effect of local anesthesia on atypical odontalgia - A randomized controlled trial2006In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 122, no 3, p. 306-314Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to evaluate the analgesic effect of lidocaine in a double-blind, controlled multi-center study on patients with atypical odontalgia (AO) - a possible orofacial neuropathic pain condition. Thirty-five consecutive AO patients (range 31-81 years) with a mean pain duration of 7.2 years (range 1-30 years) were recruited from four different orofacial pain clinics in Sweden. In a randomized cross-over design, 1.5 ml local anesthesia (20 mg/ml lidocaine and 12.5 μg/ml adrenaline) or 1.5 ml saline (9 mg/ml NaCl solution) (placebo) was injected to block the painful area. The VAS pain scores showed an overall effect of time (ANOVA: P < 0.001) and treatment (ANOVA: P = 0.018) with a significant interaction between the factors (ANOVA: P < 0.001). Overall, VAS pain relief was significantly greater at 15-120 min following the lidocaine injections compared to the placebo injections (Tukey: P < 0.05). All patients demonstrated significant disturbances in somatosensory function on the painful side compared to the non-painful side as revealed by quantitative sensory tests, however, only one significant inverse correlation was found between percentage pain relief and the magnitude of brush-evoked allodynia (Spearman: P < 0.01). In conclusion, AO patients experienced significant, but not complete, pain relief from administration of local anesthetics compared with placebo. The findings indicate that the spontaneous pain in AO patients only to some extent is dependent on peripheral afferent inputs and that sensitization of higher order neurons may be involved in the pathophysiology of AO. © 2006 International Association for the Study of Pain.

  • 19.
    List, Thomas
    et al.
    Malmö University.
    Leijon, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Neurology . Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Svensson, Peter
    University of Aarhus.
    Somatosensory abnormalities in atypical odontalgia: A case-control study2008In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 139, no 2, p. 333-341Article in journal (Refereed)
    Abstract [en]

    Somatosensory function in patients with persistent idiopathic types of orofacial pain like atypical odontalgia (AO) is not well described. This study tested the hypothesis that AO patients have significantly more somatosensory abnormalities than age- and sex-matched controls. Forty-six AO patients and 35 controls participated. Inclusion criteria for AO were pain in it region where a tooth had been endodontically Or surgically treated, persistent pain >6 months, and kick of clinical and radiological findings. The examination included qualitative tests and a battery of intraoral quantitative sensory testing (QST). Most AO patients (85%) had qualitative somatosensory abnormality compared with few controls (14%). The most common qualitative abnormalities in AO patients were found with pin-prick 67.4%, cold 47.8%, and touch 46.5%, compared with 11.4%, 8.6%, and 2.9%, respectively. in the control group (P < 0.001). Between-group differences were seen for many intraoral QST: mechanical detection threshold, mechanical pain threshold (pinprick), dynamic mechanical allodynia (brush), dynamic mechanical allodynia (vibration), wind-up ratio. and pressure pain threshold (P < 0.01). In the trigeminal area, between-group differences in thermal thresholds were nonsignificant while differences in cold detection at the thenar eminence were significant. Individual somatosensory profiles revealed complex patterns with hyper- and hyposensitivity to intraoral QST. Between-group differences in pressure pain thresholds (P < 0.022) were observed at the thenar eminence. In conclusion, significant abnormalities in intraoral somatosensory function were observed in AO. which may reflect peripheral and central sensitization of trigerminal pathways. More generalized sensitization of the nociceptive system may also be part of AO pathophysiology.

  • 20.
    Pritchard, Rory A.
    et al.
    University of Calif San Diego, CA 92093 USA.
    Falk, Lovissa
    Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Mathilda
    Linköping University, Faculty of Medicine and Health Sciences.
    Leinders, Mathias
    University of Calif San Diego, CA 92093 USA; University of Wurzburg, Germany.
    Sorkin, Linda S.
    University of Calif San Diego, CA 92093 USA.
    Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation2016In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 157, no 1, p. 137-146Article in journal (Refereed)
    Abstract [en]

    Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1% DMSO vehicle or an isoform-specific antagonist to PI3K-alpha (compound 15-e), -beta (TGX221), -delta (Cal-101), or -gamma (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-gamma antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P amp;lt;= 0.01). In contrast, pretreatment with PI3K-alpha, -delta, and-gamma antagonists reduced early indices of inflammation. Plasma extravasation PI3K-alpha (P amp;lt;= 0.05), -delta (P amp;lt;= 0.05), and -gamma (P amp;lt;= 0.01), early (0-2 hour) edema -alpha (P amp;lt;= 0.05), -delta (P amp;lt;= 0.001), and -gamma (P amp;lt;= 0.05), and neutrophil infiltration (all P amp;lt;= 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P amp;lt;= 0.05) were reduced by only the PI3K-delta and -gamma isoform antagonists, with the PI3K-delta antagonist having a greater effect on edema. PI3K-beta antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.

  • 21.
    Rosendahl, Lars
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Larsson, Britt
    Kristiansen, Jesper
    Peolsson, Michael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine.
    Sögaard, Karen
    Kjaer, Michael
    Sörensen, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Gerdle, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Increase in muscle nociceptive substances and anaerobic metabolism in patients with trapezius myalgia: Microdialysis in rest and during exercise2004In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 112, no 3, p. 324-334Article in journal (Refereed)
    Abstract [en]

    Local metabolic changes are suggested to be involved in muscle pain development in humans. Nineteen women with chronic work-related trapezius myalgia (TM) and 20 healthy female controls (CON) were studied during baseline rest, 20 min repetitive low-force exercise, and 120 min recovery. Interstitial serotonin (5-HT), glutamate, lactate, pyruvate, and blood flow were determined by microdialysis in the trapezius muscle. Baseline pressure pain threshold (PPT) was lower (143±18 (TM) vs. 269±17 (CON) kPa) (mean±SEM), pain intensity (visual analogue scale, VAS) higher (33±5 vs. 2±1 mm), muscle 5-HT higher (22.9±6.7 vs. 3.8±1.3 nmol/l), and glutamate higher (47±3 vs. 36±4 μmol/l) in TM than in CON (all P<0.05), whereas muscle blood flow was similar in groups. Furthermore, muscle pyruvate was higher (180±15 vs. 135±12 μmol/l) and lactate higher (4.4±0.3 vs. 3.1±0.3 mmol/l) in TM than in CON (P<0.001). In response to exercise, VAS and glutamate increased in both TM and CON (all P<0.05). In TM only, lactate and pyruvate increased significantly (P<0.02), whereas blood flow increased to similar levels in both groups. During the initial 20 min recovery period, blood flow remained increased in TM (P<0.005) whereas it decreased to baseline levels in CON. In conclusion, patients with chronic work-related TM have increased levels of muscle 5-HT and glutamate that were correlated to pain intensity (r=0.55, P<0.001) and PPT (r=-0.47, P<0.001), respectively. In addition, TM was associated with increased anaerobic metabolism, whereas a normal rise in blood flow was seen with exercise. These findings indicate that peripheral nociceptive processes are active in work-related TM. © 2004 International Association for the Study of Pain.

  • 22.
    Rosendal, Lars
    et al.
    Arbetsmiljöinstitutet, Köpenhamn, Danmark.
    Kristiansen, Jesper
    Arbetsmiljöinstitutet, Köpenhamn, Danmark.
    Gerdle, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Sögaard, Karen
    Arbetsmiljöinstitutet, Köpenhamn, Danmark.
    Peolsson, Michael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine.
    Kjaer, Michael
    Bispebjerg sjukhus, Köpenhamn, Danmark.
    Sörensen, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Larsson, Britt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Increased levels of interstitial potassium but normal levels of muscle IL-6 and LDH in patients with trapezius myalgia2005In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 119, no 1-3, p. 201-209Article in journal (Refereed)
    Abstract [en]

    The mechanisms behind the development of work-related trapezius pain are suggested to involve both peripheral and central components, but the specific contribution of alterations in muscle nociceptive and other substances is not clear. Female patients with chronic trapezius myalgia (N=19, TM) and female controls (N=20, CON) were studied at rest, during 20 min repetitive low-force exercise and recovery, and had their interstitial concentrations of potassium (K+), lactate dehydrogenase (LDH), interleukin-6 (IL-6) and collagen turnover determined in the trapezius muscle by the microdialysis technique. K+ levels were at all time points higher in TM than in CON (P<0.0001). Baseline levels of LDH and IL-6 were similar in both groups. In response to exercise pain intensity, rated perceived exertion, and the concentrations of K+, LDH and IL-6 increased significantly in both groups. [K+] immediately decreased to baseline levels in CON but remained elevated during the first 20 min of recovery in TM (P<0.01) whereafter it returned to baseline level. In all subjects taken together mean [K+] correlated negatively with pressure pain threshold of trapezius (P<0.001), positively with mean pain intensity VAS (P<0.001) and mean perceived exertion (P<0.001). Rises in muscle LDH and IL-6 as well as the anabolic ratio for collagen type I was not significantly different between groups. In conclusion, patients with chronic pain in the trapezius muscle had increased levels of interstitial potassium. This finding could be causally related to myalgia or secondary to pain due to deconditioned muscle or altered muscle activity pattern. © 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  • 23.
    Svensson, P.
    et al.
    Center for Sensory-Motor Interaction, Orofacial Pain Laboratory, Aalborg University, Fredrik Bajers Vej 7, D-3, 9220 Aalborg S, Denmark, Department of Prosthetic Dentistry, Royal Dental College, University of Aarhus, Aarhus, Denmark, Department of Maxillofacial Surgery, Aalborg Hospital, Aalborg, Denmark.
    List, T.
    Hector, G.
    Analysis of stimulus-evoked pain in patients with myofascial temporomandibular pain disorders2001In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 92, no 3, p. 399-409Article in journal (Refereed)
    Abstract [en]

    The pathophysiological mechanisms of myofascial temporomandibular disorders (TMD) are still under investigation. The hypothesis that TMD pain is caused by a generalized sensitization of higher order neurons in the nociceptive pathways combined with a decreased efficacy of endogenous inhibitory systems has recently gained support in the literature. This study was designed to further investigate the somatosensory sensibility within and outside the craniofacial region. Twenty-two patients fulfilled the research diagnostic criteria for TMD for myofascial pain (Dworkin and LeResche, J Craniomandib Disord Facial Oral Pain 6 (1992) 301) and 21 age- and sex-matched subjects served as a control group. The somatosensory sensibility to a deep tonic input was tested by standardized infusions of hypertonic saline into the masseter and anterior tibialis muscle. Furthermore, pressure pain thresholds (PPTs) and heat pain thresholds (HPTs) were assessed with phasic stimuli at the same sites before and following the infusions. Myofascial TMD patients reported infusion of hypertonic saline to be more painful on 10 cm visual analogue scales (peak pain 8.8 ± 0.4 cm) than control subjects (6.8 ± 0.5 cm, t-test: P = 0.003) in the masseter but not in the anterior tibialis (7.4 ± 0.5 vs. 6.6 ± 0.5 cm, P = 0.181). The perceived area of experimental masseter pain measured on drawings was marginally larger in TMD patients (2.6 ± 0.5 arbitrary units (a.u.)) than in control subjects (1.4 ± 0.2 a.u., Mann-Whitney: P = 0.048) but no differences were observed for the anterior tibialis (P = 0.771). The PPTs were lower in the myofascial TMD patients compared to the control group, both in the masseter (analysis of variance (ANOVA): P = 0.002) and in the anterior tibialis (P = 0.005), whereas there were no significant differences in HPT (ANOVAs: P = 0.357, P = 0.101). There were no significant correlations between measures of somatosensory sensibility and measures of clinical pain intensity, pain duration, graded chronic pain scores or somatization or depression scores (Pearson: R < 0.304, P > 0.172). The present study in a well-defined group of myofascial TMD patients found that the responsiveness to both tonic and phasic deep stimuli, but not to phasic superficial inputs at the pain threshold level, in the craniofacial region was higher compared with a control group. These findings suggest that myofascial TMD pain is associated with a facilitation of stimulus-evoked pain primarily, but not exclusively related to the painful region. © 2001 International Association for the Study of Pain.

  • 24.
    Tour, Jeanette
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Löfgren, Monika
    Karolinska Institute, Sweden; Danderyd Hospital, Sweden.
    Mannerkorpi, Kaisa
    University of Gothenburg, Sweden.
    Gerdle, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Larsson, Anette
    University of Gothenburg, Sweden.
    Palstam, Annie
    University of Gothenburg, Sweden.
    Bileviciute-Ljungar, Indre
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Bjersing, Jan
    University of Gothenburg, Sweden.
    Martin, Ingvar
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Ernberg, Malin
    Karolinska Institute, Sweden.
    Schalling, Martin
    Karolinska University Hospital, Sweden.
    Kosek, Eva
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden; Lowenstromska Hospital, Sweden.
    Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes2017In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 7, p. 1194-1203Article in journal (Refereed)
    Abstract [en]

    Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.

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