Johannes Gjerstad

• Rajalingam, Dhaksshaginy; Nymoen, Ingeborg; Jacobsen, Daniel Pitz; Eriksen, Mina Baarnes; Dissen, Erik; Nielsen, Morten Birkeland; Einarsen, Ståle & Gjerstad, Johannes (2020). Repeated social defeat promotes persistent inflammatory changes in splenic myeloid cells; decreased expression of β-arrestin-2 (ARRB2) and increased expression of interleukin-6 (IL-6). BMC Neuroscience.  ISSN 1471-2202.  21 . doi: 10.1186/s12868-020-00574-4 Vis sammendrag

  Background Previous studies suggest that persistent exposure to social stress in mammals may be associated with multiple physiological effects. Here, we examine the effects of social stress in rats, i.e. repeated social defeat, on behavior, hypothalamic–pituitary–adrenal (HPA)-axis and immune system. Methods A resident-intruder paradigm, where an intruder rat was exposed to social stress by a dominant resident rat for 1 hour each day for 7 consecutive days was used. The day after the last stress exposure in the paradigm the data were analyzed. Variation in social interaction was observed manually, whereas locomotion was analyzed off-line by a purpose-made software. Gene expression in the pituitary gland, adrenal gland and myeloid cells isolated from the spleen was measured by qPCR. Results The exposure to social stress induced decreased weight gain and increased locomotion. An increased nuclear receptor subfamily group C number 1 (NR3C1) expression in the pituitary gland was also shown. In myeloid cells harvested from the spleen, we observed decreased expression of the β2-adrenergic receptor (ADRB2) and β-arrestin-2 (ARRB2), but increased expression of interleukin-6 (IL-6). Subsequent analyses in the same cells showed that ARRB2 was negatively correlated with IL-6 following the stress exposure. Conclusion Our results show that that the experience of social stress in the form of repeated social defeat in rats is a potent stressor that in myeloid cells in the spleen promotes persistent inflammatory changes. Future research is needed to examine whether similar inflammatory changes also can explain the impact of social stress, such as bullying and harassment, among humans.

• Nguyen, Chinh BKrong; Kumar, Surendra; Zucknick, Manuela; Kristensen, Vessela N.; Gjerstad, Johannes; Nilsen, Hilde Loge & Wyller, Vegard Bruun Bratholm (2019). Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome. Brain, behavior, and immunity.  ISSN 0889-1591.  76, s 82- 96 . doi: 10.1016/j.bbi.2018.11.008 Fulltekst i vitenarkiv. Vis sammendrag

  Background Chronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology. Methods We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients). Results A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score. Conclusion We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

• Bjorland, Siri; Gjerstad, Johannes; Schistad, Ellina Iordanova; Swanson, David & Røe, Cecilie (2019). Persistent lumbar radicular and low back pain; impact of genetic variability versus emotional distress. BMC Research Notes.  ISSN 1756-0500.  12(1) . doi: 10.1186/s13104-019-4592-6 Fulltekst i vitenarkiv. Vis sammendrag

  Objective: Earlier studies documenting the effect of candidate genes on recovery have seldom taken into consideration the impact of emotional distress. Thus, we aimed to assess the modifying effect of emotional distress on genetic variability as a predictor for pain recovery in lumbar radicular (LRP) and low back pain (LBP). Results: The study population comprised 201 patients and mean age was 41.7 years. The significant association between MMP9 rs17576 (B = 0.71, 95% CI 0.18 to 1.24, p = 0.009) and pain recovery remained statistically significant after adjusting for pain intensity at baseline, age, gender, smoking, body mass index, pain localization and emotional distress (B = 0.68, 95% CI 0.18 to 1.18, p = 0.008). In contrast, the association between OPRM1 (B = − 0.85, 95% CI − 1.66 to − 0.05, p = 0.038) and pain recovery was abolished in the multivariate analysis (B = − 0.72, 95% CI − 1.46 to 0.02, p = 0.058). Hence, MMP9 rs17576 and emotional distress independently seem to predict persistent back pain. The predictive effect of OPRM1 rs179971 with regard to the same outcome is probably dependent on other factors including emotional processing.

• Hasvik, Eivind Olay; Haugen, Anne Julsrud; Haukeland-Parker, Stacey Marie; Rimehaug, Stein Arne; Gjerstad, Johannes & Grøvle, Lars (2019). Cross-cultural Adaptation and Validation of the Norwegian short-form McGill Pain Questionnaire-2 in Low Back-related Leg Pain. Spine.  ISSN 0362-2436.  44(13), s E774- E781 . doi: 10.1097/BRS.0000000000002976 Vis sammendrag

  Study Design: A prospective observational study with translation and psychometric analyses of a questionnaire. Objective: Cross-cultural adaptation of the Short-Form McGill Pain Questionnaire-2 into Norwegian. Summary of Background Data: The different versions of the McGill Pain Questionnaire (MPQ) have been important and influential tools for pain assessment. To more reliably assess qualities of both neuropathic and non-neuropathic pain, the Short-Form MPQ was revised in 2009 (SF-MPQ-2), including seven additional descriptors. No Norwegian adaptation of the SF-MPQ-2 has been performed. Methods: A translation of the SF-MPQ-2 was performed based on established guidelines. Forward-translations were compared and discussed in an expert workgroup. A synthesis was achieved by consensus. A backward translation was reviewed and consolidated with the forward translations to confirm linguistic equivalence. A prefinal version was tested in eight patients, who were interviewed to evaluate acceptability and comprehension of the questionnaire. Minor changes were implemented. The questionnaire was externally proofread. The final Norwegian version (NSF-MPQ-2) was tested for content and construct validity and internal consistency reliability in a population with low back-related leg pain. Results: The backward translation was in good accordance with the original version. The prefinal version showed excellent acceptability and comprehension in initial patient-testing. The NSF-MPQ-2 showed satisfactory content and construct validity, including responsiveness to change, and acceptable internal consistency reliability as measured by Cronbach's alpha. A confirmatory factor analysis showed poor fit for the established four-factor structure, especially regarding the neuropathic subscale. Conclusion: The NSF-MPQ-2 showed excellent acceptability and comprehension, satisfactory content and construct validity, including responsiveness to change, and internal consistency reliability as measured by Cronbach's alpha. However, a confirmatory factor analysis raised concerns regarding the factor-structure in the present population. Until more evidence emerges for the four-factor solution we suggest the NSF-MPQ-2 should be used as a single measure. Level of Evidence: 3

• Hasvik, Eivind Olay; Schjølberg, Tiril; Jacobsen, Daniel Pitz; Haugen, Anne Julsrud; Grøvle, Lars; Schistad, Ellina Iordanova & Gjerstad, Johannes (2019). Up-regulation of circulating microRNA-17 is associated with lumbar radicular pain following disc herniation. Arthritis Research & Therapy.  ISSN 1478-6354.  21(1) . doi: 10.1186/s13075-019-1967-y Vis sammendrag

  Background: Previous studies suggest that regulatory microRNAs (miRs) may modulate neuro-inflammatory processes. The purpose of the present study was to examine the role of miR-17 following intervertebral disc herniation. Methods: In a cohort of 97 patients with leg pain and disc herniation verified on MRI, we investigated the association between circulating miR-17 and leg pain intensity. A rat model was used to examine possible changes in miR-17 expression in nucleus pulposus (NP) associated with leak of NP tissue out of the herniated disc. The functional role of miR-17 was addressed by transfection of miR-17 into THP-1 cells (human monocyte cell line). Results: An association between the level of miR-17 in serum and the intensity of lumbar radicular pain was shown. Up-regulation of miR-17 in the rat NP tissue when applied onto spinal nerve roots and increased release of TNF following transfection of miR-17 into THP-1 cells were also observed. Hence, our data suggest that miR-17 may be involved in the pathophysiology underlying lumbar radicular pain after disc herniation. Conclusions: We conclude that miR-17 may be associated with the intensity of lumbar radicular pain after disc herniation, possibly through a TNF-driven pro-inflammatory mechanism

• Jacobsen, Daniel Pitz; Eriksen, Mina Baarnes; Rajalingam, Dhaksshaginy; Nymoen, Ingeborg; Nielsen, Morten Birkeland; Einarsen, Ståle & Gjerstad, Johannes (2019). Exposure to workplace bullying, microRNAs and pain; evidence of a moderating effect of miR-30c rs928508 and miR-223 rs3848900. Stress.  ISSN 1025-3890.  23(1), s 77- 86 . doi: 10.1080/10253890.2019.1642320 Fulltekst i vitenarkiv. Vis sammendrag

  Prolonged exposure to bullying behaviors may give rise to symptoms such as anxiety, depression and chronic pain. Earlier data suggest that these symptoms often are associated with stress-induced low-grade systemic inflammation. Here, using data from both animals and humans, we examined the moderating role of microRNAs (miRNAs, miRs) in this process. In the present study, a resident-intruder paradigm, blood samples, tissue harvesting and subsequent qPCR analyses were used to screen for stress-induced changes in circulating miRNAs in rats. The negative acts questionnaire (NAQ), TaqMan assays and a numeric rating scale (NRS) for pain intensity were then used to examine the associations among bullying behaviors, relevant miRNA polymorphisms and pain in a probability sample of 996 Norwegian employees. In rats, inhibited weight gain, reduced pituitary POMC expression, adrenal Nr3c1 mRNA downregulation, as well as increased miR-146a, miR-30c and miR-223 in plasma were observed following 1 week of repeated exposure to social stress. When following up the miRNA findings from the animal study in the human working population, a stronger relationship between NAQ and NRS scores was observed in subjects with the miR-30c GG genotype (rs928508) compared to other subjects. A stronger relationship between NAQ and NRS scores was also seen in men with the miR-223 G genotype (rs3848900) as compared to other men. Our findings show that social stress may induce many physiological changes including changed expression of miRNAs. We conclude that the miR-30c GG genotype in men and women, and the miR-223 G genotype in men, amplify the association between exposure to bullying behaviors and pain.

• Kongstorp, Mette; Schjølberg, Tiril; Jacobsen, Daniel Pitz; Haugen, Fred & Gjerstad, Johannes (2019). Epiregulin is released from intervertebral disks and induces spontaneous activity in pain pathways. Pain.  ISSN 0304-3959.  4(2) . doi: 10.1097/PR9.0000000000000718 Vis sammendrag

  Introduction: Lumbar radicular pain after disk herniation is associated with local release of many inflammatory molecules from nucleus pulposus (NP) cells leaking out of the intervertebral disk. Here, we have used a rat model to investigate the role of epiregulin (EREG), a member of the epidermal growth factor (EGF) family, in this process. Methods: A protein immunoassay was chosen to confirm the release of EREG from the NP tissue. Single unit recordings were used to demonstrate the effect of recombinant EREG applied onto the dorsal nerve roots in vivo. Intracellular responses induced by recombinant EREG were studied in cultured dorsal root ganglion (DRG) cells by phosphoprotein assay. Changes in EGF receptor expression induced by NP in the DRG were examined by quantitative polymerase chain reaction. Results: The protein immunoassay showed that EREG was released from the NP tissue. Moreover, application of EREG onto the spinal dorsal nerve roots induced a decrease in the evoked responses, but an increase in spontaneous activity in the dorsal horn neurons. Interestingly, the EREG activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the DRG, a pathway previously linked to cellular growth, proliferation, and tissue regeneration. An NP-induced upregulation of the EGF receptor HER3 in the DRG was also revealed. Conclusion: Taken together, the present observations indicate that EREG may induce changes in the DRG and spontaneous activity in the pain pathways. We suggest that EREG signaling may be involved in the pathophysiological process leading to sensory deficits and neuropathic pain in patients after disk herniation.

• Nielsen, Morten Birkeland; Skogstad, Anders; Gjerstad, Johannes & Einarsen, Ståle (2019). Are transformational and laissez-faire leadership related to state anxiety among subordinates? A two-wave prospective study of forward and reverse associations. Work & Stress.  ISSN 0267-8373.  33(2), s 137- 155 . doi: 10.1080/02678373.2018.1528307 Vis sammendrag

  The aim of this study was to determine the direction of associations between perceived leadership styles of an immediate leader and state anxiety among subordinates using time-lagged data from a large and heterogeneous probability sample of Norwegian employees. It was hypothesised that high levels of transformational leadership would be associated with a decrease, whereas high levels of laissez-faire leadership would be associated with an increase, in subsequent levels of anxiety. Reciprocal associations were also expected in that higher levels of anxiety were hypothesised to be related to subsequent increase in reports of laissez-faire, and decrease in reported exposure to transformational leadership. The sample comprised 1149 Norwegian employees. The design was a two-wave full panel study with a six-month time interval between the baseline and follow-up assessments. Contrary to hypotheses, neither transformational nor laissez-faire leadership were significantly related to subsequent levels of state anxiety. In support of hypotheses, baseline low levels of state anxiety were associated with reporting the immediate leader as less transformational and more laissez-faire six months later. In conclusion, the findings challenge theoretical models that explain leadership as a one-way superior–subordinate influence process.

• Pallesen, Ståle; Jacobsen, Daniel Pitz; Nielsen, Morten Birkeland & Gjerstad, Johannes (2019). The 5-HTTLPR rs25531 LALA-genotype increases the risk of insomnia symptoms among shift workers. Sleep Medicine.  ISSN 1389-9457.  60, s 224- 229 . doi: 10.1016/j.sleep.2019.04.009 Fulltekst i vitenarkiv. Vis sammendrag

  Background Previous studies indicate that shift work tolerance may be associated with individual factors including genetic variability in the gene encoding the serotonin transporter 5-HTT (SLC6A4). The present study aimed to explore the interaction between work schedule (shift work versus non-shift work), genetic variability in SLC6A4 and insomnia symptoms. Methods The study was based on a national probability sample survey of 987 Norwegian employees drawn from The Norwegian Central Employee Register by Statistics Norway. Insomnia symptoms were assessed by three items reflecting problems with sleep onset, sleep maintenance, and early morning awakenings. Genotyping concerning SLC6A4 (the 5-HTTLPR S versus L and the SNP rs25531 A versus G) was carried out using a combination of gel-electrophoresis and TaqMan assay. Results Using the LALA genotype as a reference a main effect of the SS genotype (B = 0.179; 95% CI = 0.027–0.330) was found. In addition, a main effect of work schedule (0 = non shift, 1 = shift work) was found (B = 0.504; 95% CI = 0.185–0.823). The genotype x work schedule interaction was significant for all genotypes; SLA (B = −0.590; 95% CI = −0.954–0.216), LALG (B = −0.879; 95% CI = −1.342–0.415), SLG (B = −0.705; 95% CI = −1.293–0.117) and SS (B = −0.773; 95% CI = −1.177–0.369) indicating higher insomnia symptom scores among LALA-participants compared to participants with other genotypes when working shifts. Conclusions The ability to cope with shift work is associated with the combination of the SLC6A4 variants 5-HTTLPR and SNP rs25531. Our findings demonstrated that the LALA-genotype increases the risk of insomnia symptoms among shift workers.

• Rajalingam, Dhaksshaginy; Jacobsen, Daniel Pitz; Nielsen, Morten Birkeland; Einarsen, Ståle & Gjerstad, Johannes (2019). Exposure to workplace bullying, distress, and insomnia: The moderating role of the miR-146a genotype. Frontiers in Psychology.  ISSN 1664-1078.  10:1204(MAY), s 1- 7 . doi: 10.3389/fpsyg.2019.01204 Fulltekst i vitenarkiv. Vis sammendrag

  Several lines of evidence show that systematic exposure to negative social acts at the workplace i.e., workplace bullying, results in symptoms of depression and anxiety among those targeted. However, little is known about the association between bullying, inflammatory genes and sleep problems. In the present study, we examined the indirect association between exposure to negative social acts and sleep through distress, as moderated by the miR-146a genotype. The study was based on a nationally representative survey of 1179 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. Exposure to workplace bullying was measured with the 9-item version of Negative Acts Questionnaire – Revised (NAQ-R) inventory. Seventeen items from Hopkins Symptom Checklist (HSCL-25) was used to measure distress. Insomnia was assessed with three items reflecting problems with sleep onset, maintenance of sleep and early morning awakening. Genotyping with regard to miR146a rs2910164, previously linked to inflammatory processes, was carried out using Taqman assay. The data revealed that individuals systematically exposed to negative social acts at the workplace reported higher levels of sleep problems than non-exposed individuals. Moreover, the relationship between distress induced by exposure to negative social acts and insomnia was significantly stronger for individuals with the miR-146a GG genotype. Thus, the miR-146a genotype moderated the association between distress and insomnia among individuals exposed to negative social acts. The present report support the hypothesis that inflammation could play a role in stress-induced insomnia among individuals exposed to workplace bullying.

• Reknes, Iselin; Einarsen, Ståle; Gjerstad, Johannes & Nielsen, Morten Birkeland (2019). Dispositional affect as a moderator in the relationship between role conflict and exposure to bullying behaviors. Frontiers in Psychology.  ISSN 1664-1078.  10, s 1- 12 . doi: 10.3389/fpsyg.2019.00044 Fulltekst i vitenarkiv. Vis sammendrag

  Stressors in the work environment and individual dispositions among targets have been established separately as antecedents and risk factors of workplace bullying. However, few studies have examined these stressors in conjunction in order to determine personal dispositions among targets as possible moderators in the work stressor–bullying relationship. The aim of the present study was to examine multiple types of dispositional affect among targets as potential moderators in the relationship between role conflict and exposure to bullying behaviors, employing two independent cross-sectional samples. The first sample comprised 462 employees from a Norwegian sea transport organization, where trait anger and trait anxiety were included moderators. The second sample was a nationwide probability sample of the Norwegian working population and comprised 1,608 employees randomly drawn from The Norwegian Central Employee Register, where positive and negative affect were included moderators. The results showed that trait anger, trait anxiety, and negative affect strengthened the positive relationship between role conflict and reports of bullying behaviors. Positive affect did not moderate this relationship. We conclude that the association between role conflict and bullying is particularly strong for those scoring high on trait anger, trait anxiety, and negative affect.

• Aslaksen, Per M; Forsberg, June Thorvaldsen & Gjerstad, Johannes (2018). The Opioid Receptor Mu 1 (OPRM1) rs1799971 and Catechol-O-methyltransferase (COMT) rs4680 as genetic markers for placebo analgesia. Pain.  ISSN 0304-3959.  159(12), s 2585- 2592 . doi: 10.1097/j.pain.0000000000001370 Fulltekst i vitenarkiv. Vis sammendrag

  The placebo effect is considered the core example of mind–body interactions. However, individual differences produce large placebo response variability in both healthy volunteers and patients. The placebo response in pain, placebo analgesia, may be dependent on both the opioid system and the dopaminergic system. Previous studies suggest that genetic variability affects the function of these 2 systems. The aim of this study was therefore to address the interaction between the single nucleotide polymorphisms opioid receptor mu 1 (OPRM1) rs1799971 and catechol-O-methyltransferase (COMT) rs4680 on placebo analgesia. Two hundred ninety-six healthy volunteers participated in a repeated-measures experimental design where thermal heat pain stimuli were used as pain stimuli. Participants were randomized either to a placebo group receiving placebo cream together with information that the cream would reduce pain, or to a natural history group receiving the same pain stimuli as the placebo group without any application of cream or manipulation of expectation of pain levels. The results showed that the interaction between OPRM1 rs1799971 and COMT rs4680 was significantly associated with the placebo analgesic response. Participants with OPRM1 Asn/Asn combined with COMT Met/Met and Val/Met reported significant pain relief after placebo administration, whereas those with other combinations of the OPRM1 and COMT genotypes displayed no significant placebo effect. Neither OPRM1 nor COMT had any significant influence on affective changes after placebo administration. As shown in this study, genotyping with regard to OPRM1 and COMT may predict who will respond favorably to placebo analgesic treatment.

• Forsberg, June Thorvaldsen; Gjerstad, Johannes; Flaten, Magne & Aslaksen, Per M. (2018). Influence of catechol-O-methyltransferase Val158Met on fear of pain and placebo analgesia. Pain.  ISSN 0304-3959.  159(1), s 168- 174 . doi: 10.1097/j.pain.0000000000001081 Vis sammendrag

  Higher levels of fear have been shown to partly explain individual differences in placebo analgesic responding. The catechol-Omethyltransferase (COMT) rs4680 Val158Met polymorphism has been associated with both increased placebo analgesia and increased fear-related behavior, in what appears to be inconsistent findings in the literature. The aim of the study was therefore to investigate placebo analgesia and fear-related processes with regard to the COMT genotype, to sort out whether the Met-allele is associated with increased placebo analgesia or increased fear of pain (FOP). A 3 Group (Emla, placebo and natural history) by 5 Test (2 pretest, 3 posttests) mixed design was used (N 5 223). A contact heat-evoked stimulator was used to induce pain, and FOP was quantified with the Fear of Pain Questionnaire-III. Saliva was obtained for genotyping. As expected, we observed a significant interaction of test by group (P , 0.01), with lower pain report in the placebo group compared with the natural history group (P , 0.01). There was a main effect of the COMT genotype on fear of medical pain (P 5 0.032), and Met-allele carriers reported significantly higher fear of medical pain compared with the Val-allele (P 5 0.044). We observed no effect of the COMT genotype on mean pain-level report or placebo analgesia. Thus, we conclude that the Met-allele seems to be associated with the negative emotional process of fear, but not with placebo analgesia.

• Hasvik, Eivind Olay; Haugen, Anne Julsrud; Gjerstad, Johannes & Grøvle, Lars (2018). Assessing neuropathic pain in patients with low back-related leg pain: Comparing the painDETECT Questionnaire with the 2016 NeuPSIG grading system. European Journal of Pain.  ISSN 1090-3801.  22(6), s 1160- 1169 . doi: 10.1002/ejp.1204 Vis sammendrag

  Background: Low back‐related leg pain with nerve root involvement is conceptually regarded as a neuropathic condition. However, it is uncertain to what extent patients with this condition can be formally classified with neuropathic pain. Method: First, we used the 2016 revision of the IASP Special Interest Group on Neuropathic Pain (NeuPSIG) grading system for neuropathic pain to grade patients suffering from low back‐related leg pain and a corresponding disc herniation with either unlikely, possible, probable or definite neuropathic pain. Examination included bedside quantitative sensory testing. Next, we used the clinical classification based on the 2016 NeuPSIG grading system as a reference standard to assess the ability of the painDETECT Questionnaire to identify patients with neuropathic pain. Results: Of the 50 included patients, six (12%) fulfilled the clinical classification criteria for probable and 44 (88%) for definite neuropathic pain, while none were graded unlikely or possible. According to painDETECT, 23 patients (46%) were classified with unlikely neuropathic pain, 18 patients (36%) had an uncertain condition and in nine patients (18%) neuropathic pain was likely. Among the 44 patients graded as having definite neuropathic pain by the clinical classification, eight were classified as likely neuropathic pain by painDETECT, resulting in an agreement of 18%. Of these 44 patients graded with definite neuropathic pain, painDETECT classified 21 patients (48%) as unlikely and 15 (34%) as uncertain. Conclusion: Our results do not support the use of painDETECT as a screening tool to classify or grade neuropathic components in patients with low back‐related leg pain.

• Jacobsen, Daniel Pitz; Nielsen, Morten Birkeland; Einarsen, Ståle & Gjerstad, Johannes (2018). Negative social acts and pain. Evidence of a workplace bullying and 5-HTT genotype interaction. Scandinavian Journal of Work, Environment and Health.  ISSN 0355-3140.  44(3), s 283- 290 . doi: 10.5271/sjweh.3704 Vis sammendrag

  Objectives: Long-term exposure to systematic negative acts at work, usually labeled workplace bullying, is a prevalent problem at many workplaces. The adverse effects of such exposure may range from psychological symptoms, such as depression and anxiety to somatic ailments like cardiovascular disease and musculoskeletal complaints. In this study, we examined the relationships among exposure to negative acts, genetic variability in the 5-HTT gene SLC6A4 and pain. Methods: The study was based on a nationally representative survey of 987 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. Exposure to bullying in the workplace was measured with the 9-item version of the Negative Acts Questionnaire – Revised (NAQ-R) inventory. Pain was rated using an 11-point (0–10) numeric rating scale (NRS). Genotyping with regard to SLC6A4 was carried out using a combination of gel-electrophoresis and TaqMan assay. Results: The data revealed a significant interaction between exposure to negative acts and the SLC6A4 genotype with regard to pain (linear regression with 5000 resamples; age, sex, tobacco use and education were included as covariates). The relationship between negative acts and pain intensity was significantly stronger for subjects with the LALA genotype than for subjects with the SLA/LALG/SLG genotype. No significant difference between subjects with the LALA genotype and SS genotype was observed. Conclusions: Our data demonstrated that the relationship between bullying and pain was modified by the 5-HTT genotype, ie, genetic variation in SLC6A4. The association between negative acts and health among vulnerable individuals appeared more potent than previously reported.

• Mahmood, Aqsa; Moen, Aurora Lie; Stafne, Signe Nilssen; Robinson, Hilde Stendal; Vøllestad, Nina Køpke; Salvesen, Kjell Å; Mørkved, Siv & Gjerstad, Johannes (2018). The MMP9 rs17576 A>G polymorphism is associated with increased lumbopelvic pain-intensity in pregnant women. Scandinavian Journal of Pain.  ISSN 1877-8860.  18(1), s 93- 98 . doi: 10.1515/sjpain-2017-0168 Fulltekst i vitenarkiv. Vis sammendrag

  Background and aims: Matrix metalloproteinase 9 (MMP9) is an enzyme that may affect degradation of several extracellular matrix (ECM) components in the pelvic ligaments during pregnancy. Previous studies indicate that genetic variations in the gene encoding MMP9 may affect the enzymatic activity. One such genetic variant is a single nucleotide polymorphism (SNP), rs17576 A>G. In this study we investigated whether the MMP9 SNP rs17576 A>G may be associated with increased lumbopelvic pain in 838 pregnant woman. The study was registered with ClinicalTrials.gov (NCT 00476567) on May 21, 2007. Methods: Lumbopelvic pain-intensity was measured by visual analog scale (VAS) at two time points during pregnancy, T1 (18–22 weeks), T2 (32–36 weeks) and 3 months after delivery. Blood samples were collected at each point and SNP genotyping was carried out using predesigned TaqMan SNP genotyping assays. Results: The results showed a significant association between the number of G alleles and pain-intensity in the evening at T2. The pain among G/G carriers was higher than among A/G carriers, which in turn was higher than among the A/A carriers. The most pronounced association between the G allele and pain-intensity was observed in primiparae. Conclusions: We conclude that the MMP9 rs17576 A>G polymorphism is associated with increased lumbopelvic pain-intensity during pregnancy. The present data support the hypothesis that lumbopelvic pain during pregnancy may be related to a relaxin – MMP9 – tissue remodeling mechanism.

• Schistad, Ellina Iordanova; Bjorland, Siri; Røe, Cecilie; Gjerstad, Johannes; Vetti, Nils; Myhre, Kjersti & Espeland, Ansgar (2018). Five-year development of lumbar disc degeneration—a prospective study. Skeletal Radiology.  ISSN 0364-2348.  s 1- 9 . doi: 10.1007/s00256-018-3062-x Vis sammendrag

  Objective: To examine the impact of demographic, clinical, and genetic factors as well as herniated discs on 5-year development of disc degeneration in the lumbar spine, and to investigate associations between changes in lumbar degenerative findings and pain. Materials and methods: In 144 patients with lumbar radicular pain or low back pain, we scored disc degeneration, herniated discs, and high-intensity zones in the posterior annulus fibrosus on lumbar magnetic resonance imaging (MRI) at baseline and 5-year follow-up. Genotyping (TaqMan assay) was performed for genes encoding vitamin D receptor (VDR), collagen XIα (COL11A), matrix metalloproteinase 1/9 (MMP1/MMP9), and interleukin 1α/1RN (IL-1α/IL-1RN). Associations were analyzed using multivariate linear regression adjusted for age, sex, smoking, body mass index, and baseline scores for degenerated discs and herniated discs (when analyzing impact of baseline factors) or for pain (when analyzing associations with pain). Results: Progression of disc degeneration over 5 years was significantly (p < 0.001) related to higher age and less disc degeneration at baseline, but not to sex, smoking, body mass index, herniated discs, or variants in the studied genes. No associations were identified between changes in disc degeneration or high-intensity zones and pain at 5-year follow-up. However, increased number of herniated discs over 5 years was associated with pain at rest (p = 0.019). Conclusions: Age and disc degeneration at baseline, rather than genetic factors, influenced the 5-year development of disc degeneration in patients with lumbar radicular pain or low back pain. Development of herniated discs was related to pain at rest.

• Andreassen, Cecilie Schou; Nielsen, Morten Birkeland; Pallesen, Ståle & Gjerstad, Johannes (2017). The Relationship Between Psychosocial Work Variables and Workaholism: Findings From a Nationally Representative Survey. International Journal of Stress Management.  ISSN 1072-5245.  26(1), s 1- 10 . doi: 10.1037/str0000073 Vis sammendrag

  Research into “workaholism” has substantially increased over the last decade, but little effort has been put into assessing work-related correlates. In the present study, 1,608 employees (Mage = 45.2 years, range = 21–60) participated in a nationally representative cross-sectional survey in Norway examining whether job demands, job control, role ambiguity, role conflict, exposure to negative acts, and leadership styles could explain variance in workaholism. The independent variables explained 28% of the variance. Demands, role conflict, and negative acts contributed substantially. Workaholism increased more strongly with increasing demands for workers reporting high control than for those reporting low control. The prevalence of workaholism was 7.3%. Study implications, strengths, and limitations are discussed.

• Bjorland, Siri; Røe, Cecilie; Moen, Aurora Lie; Schistad, Ellina Iordanova; Aqsa, Mahmood & Gjerstad, Johannes (2017). Genetic predictors of recovery in low back and lumbar radicular pain. Pain.  ISSN 0304-3959.  158(8), s 1456- 1460 . doi: 10.1097/j.pain.0000000000000934 Fulltekst i vitenarkiv. Vis sammendrag

  Previous data suggest that persistent back pain may be associated with genetic variability. In this study, we assessed the correlation between 8 genetic polymorphisms (VDR, COL11, MMP1, MMP9, IL-1a, IL-1RN, OPRM1, COMT) and pain recovery in patients with low back pain (LBP) and lumbar radicular pain (LRP). In total, 296 patients with LBP or LRP were followed for 5 years. The patients underwent standardized clinical examination and completed pain and function questionnaires. Univariate linear regression associations with P values ,0.1 were included in the multivariable analysis, adjusting for pain intensity at baseline, age, sex, smoking, body mass index, and LBP or LRP. Pain intensity at 5-year follow-up was associated with VDR rs731236 (B 5 20.5, 95% confidence interval [CI] 20.9 to 20.1, P 5 0.017), MMP9 rs17576 (B 5 0.5, 95% CI 0.1-0.9, P 5 0.022), and OPRM1 rs1799971 (B 5 20.8, 95% CI 21.4 to 20.2, P 5 0.006) in the univariate analyses. MMP9 rs17576 and OPRM1 rs1799971 remained significant (B 5 0.4, 95% CI 0.05-0.8, P 5 0.026 and B 5 20.8, 95% CI 21.3 to 20.2, P 5 0.007) in the multivariable model. Thus, the data demonstrated that the rare allele of MMP9 rs17576 was associated with poor pain recovery, whereas the rare allele of OPRM1 rs1799971 was associated with better pain recovery at 5-year follow-up in the LBP and LRP patients. In particular, the present study suggested that the OPRM1 rs179971 A.G in men was associated with better long-term pain recovery. In men, the OPRM1 rs1799971 explained 4.7% of the variance of pain intensity. We conclude that the MMP9 rs17576 and OPRM1 rs1799971 genotypes may affect 5-year recovery in patients with LBP and LRP.

• Moen, Aurora Lie; Jacobsen, Daniel; Phuyal, Santosh; Legfeldt, Anna; Haugen, Fred; Røe, Cecilie & Gjerstad, Johannes (2017). MicroRNA-223 demonstrated experimentally in exosome-like vesicles is associated with decreased risk of persistent pain after lumbar disc herniation. Journal of Translational Medicine.  ISSN 1479-5876.  15(89), s 1- 11 . doi: 10.1186/s12967-017-1194-8 Fulltekst i vitenarkiv. Vis sammendrag

  Background: Previous findings have demonstrated that lumbar radicular pain after disc herniation may be associated with up-regulation of inflammatory mediators. In the present study we examined the possible role of extracellular microRNAs (miRs) in this process. Methods: Single unit recordings, isolation of exosome-like vesicles, electron microscopy, nanoparticle tracking analysis, western blot analysis and qPCR were used in rats to demonstrate the effect of nucleus pulposus (NP) applied onto the dorsal nerve roots. ELISA and qPCR were used to measure the level of circulating IL-6 and miRs in a 1-year observational study in patients after disc herniation. Results: In the rats, enhanced spinal cord nociceptive responses were displayed after NP applied onto the dorsal nerve roots. An increased release of small non-coding RNAs, including miR-223, miR-760 and miR-145, from NP in exosome-like vesicles was demonstrated. In particular, the NP expression of miR-223, which inhibited the nociceptive spinal signalling, was increased. In the patients, increased extracellular miR-223 was also verified in the acute phase after disc herniation. The increased miR-223 expression was, however, only observed in those who recovered (sex, age and smoking were included as covariates). Conclusions: Our findings suggest that miR-223, which can be released from the NP after disc herniation, attenuates the neuronal activity in the pain pathways. Dysregulation of miR-223 may predict chronic lumbar radicular pain.

• Moen, Gunn-Helen Øiseth; Moen, Aurora Lie; Schistad, Ellina Iordanova & Gjerstad, Johannes (2017). Local up-regulation of interferon-γ (IFN-γ) following disc herniation is involved in the inflammatory response underlying acute lumbar radicular pain. Cytokine.  ISSN 1043-4666.  97, s 181- 186 . doi: 10.1016/j.cyto.2017.06.005 Vis sammendrag

  Lumbar radicular pain after disc herniation may be associated with release of pro-inflammatory cytokines from nucleus pulposus (NP) tissue. In the present study we examined the role of interferon-γ (IFN-γ) and cluster of differentiation 68 (CD68) in the acute phase of this process. First, in an animal model mimicking the clinical situation after disc herniation, the role of IFN-γ close to the dorsal nerve roots was studied. Next, in patients with lumbar radicular pain due to disc herniation, we examined how two single nucleotide polymorphisms (SNPs; rs2069705 and rs2069718) are important for the IFN-γ expression influenced the pain behavior. The animal data demonstrated a significant increase in the nociceptive activity at the spinal level after local application of NP and IFN-γ onto the dorsal nerve roots. A positive correlation between IFN-γ and CD68 in the NP tissue was also demonstrated. In the patients, a significant increase in Oswestry Disability Index (ODI) score was observed in carriers of the IFN-γ SNPs; rs2069705 A and rs2069718 G alleles. The present data suggest that IFN-γ close to the dorsal nerve roots may contribute to the pathogenesis, the nociceptive activity and the pain behavior following lumbar disc herniation.

• Nielsen, Morten Birkeland; Gjerstad, Johannes & Frone, Michael (2017). Alcohol use and psychosocial stressors in the Norwegian workforce. Substance Use & Misuse.  ISSN 1082-6084.  53(4), s 574- 584 . doi: 10.1080/10826084.2017.1349797 Vis sammendrag

  Background: Although alcohol use can have detrimental effects for employees, little is known about the prevalence, distribution, and correlates in the Norwegian workforce. Aims: To determine the overall and the work-related prevalence of weekly alcohol use, and to establish associations between psychosocial work stressors and alcohol use among Norwegian employees. Methods: Data were from a 2015 national probability sample of 1,608 Norwegian employees (response rate 32%). Job demands, lack of job control, role expectations, workplace bullying, and leadership were examined as correlates of several dimensions of alcohol use. Results: Average weekly alcohol consumption was 4.28 units (SD = 7.91). Male workers reported significantly higher consumption than female workers. Also, 2.6% of male and 2.0% of female workers reported problematic alcohol use. Only 0.1% of workers reported weekly alcohol use before the workday, 0.4% reported weekly use during the workday, 20.1% reported weekly use after ending the work day, and 80% reported use during weekends/days off. Alcohol intake increased with age, but was not related to marital status, educational level, work schedule, or leadership position. Problematic alcohol use was related to job demands and workplace bullying. Alcohol use after work was positively related to lack of job control and role ambiguity and negatively related to bullying. Conclusions/importance: Weekly alcohol use before and during the workday is not prevalent among Norwegian workers. Interventions to reduce job demands and workplace bullying may reduce problematic alcohol intake, whereas increasing job control and reducing role ambiguity may reduce after work use.

• Nielsen, Morten Birkeland; Gjerstad, Johannes; Jacobsen, Daniel Pitz & Einarsen, Ståle Valvatne (2017). Does ability to defend moderate the association between exposure to bullying and symptoms of anxiety?. Frontiers in Psychology.  ISSN 1664-1078.  8:1953, s 1- 11 . doi: 10.3389/fpsyg.2017.01953 Fulltekst i vitenarkiv. Vis sammendrag

  In the context of workplace bullying, the ability to defend refers to whether or not a target feels able to deal with those negative behaviors that typically constitute bullying. The aim of this study was to determine whether the perceived ability to defend oneself moderates the association between exposure to bullying behaviors at work and symptoms of anxiety as predicted by the definition of workplace bullying. It was hypothesized that exposure to bullying behaviors would be more strongly related to symptoms of anxiety among targets feeling unable to defend oneself than among targets who do feel that they are able to defend themselves in the actual situation. This survey study was based on a probability sample of 1,608 Norwegian employees (response rate 32%). Only respondents exposed to at least one bullying behavior were included (N = 739). In contrast to hypothesis, the findings showed that ability to defend only had a protective effect on the relationship between exposure to bullying behaviors and anxiety in cases of low exposure. In cases of high exposure, there was a stronger increase in anxiety among employees able to defend themselves than among those who generally felt unable to defend. Hence, the ability to defend against exposure to bullying behaviors does not seem to protect high-exposed targets against symptoms of anxiety. Organization should therefore intervene against bullying in early stages rather than relying on the individual resilience of those exposed.

• Bjorland, Siri; Moen, Aurora Lie; Schistad, Ellina Iordanova; Gjerstad, Johannes & Røe, Cecilie (2016). Genes associated with persistent lumbar radicular pain; a systematic review. BMC Musculoskeletal Disorders.  ISSN 1471-2474.  17(1), s 1- 10 . doi: 10.1186/s12891-016-1356-5 Fulltekst i vitenarkiv. Vis sammendrag

  Background: The aim of the present study was to provide an overview of the literature addressing the role of genetic factors and biomarkers predicting pain recovery in newly diagnosed lumbar radicular pain (LRP) patients. Methods: The search was performed in Medline OVID, Embase, PsycInfo and Web of Science (2004 to 2015). Only prospective studies of patients with LRP addressing the role of genetic factors (genetic susceptibility) and pain biomarkers (proteins in serum) were included. Two independent reviewers extracted the data and assessed methodological quality. Results: The search identified 880 citations of which 15 fulfilled the inclusion criteria. Five genetic variants; i.e., OPRM1 rs1799971 G allele, COMT rs4680 G allele, MMP1 rs1799750 2G allele, IL1α rs1800587 T allele, IL1RN rs2234677 A allele, were associated with reduced recovery of LRP. Three biomarkers; i.e., TNFα, IL6 and IFNα, were associated with persistent LRP. Conclusion: The present results indicate that several genetic factors and biomarkers may predict slow recovery in LRP. Still, there is a need for replication of the findings. A stricter use of nomenclature is also highly necessary.

• Eikemo, Marie Helene; Løseth, Guro Engvig; Johnstone, Tom; Gjerstad, Johannes; Willoch, Frode & Leknes, Siri (2016). Sweet taste pleasantness is modulated by morphine and naltrexone. Psychopharmacology.  ISSN 0033-3158.  233(21), s 13711- 3723 . doi: 10.1007/s00213-016-4403-x Vis sammendrag

  Background: Rodent models highlight the key role of μ-opioid receptor (MOR) signaling in palatable food consumption. In humans, however, the effects of MOR stimulation on eating and food liking remain unclear. Objectives Here, we tested sweet pleasantness experience in humans following MOR drug manipulations. We hypothesized that behaviors regulated by the endogenous MOR system would be enhanced by MOR agonism and decreased by antagonism. In line with rodent findings, we expected the strongest drug effects for the sweetest (high-calorie) sucrose stimuli. As very sweet stimuli are considered aversive by many people (called sweet dislikers), we also assessed whether MOR manipulations affect pleasantness ratings of sucrose-water stimuli differently depending on subjective and objective value. Methods: In a bidirectional psychopharmacological cross-over study, 49 healthy men underwent a sweet taste paradigm following double-blind administration of the MOR agonist morphine, placebo, and the opioid antagonist naltrexone. Results: As hypothesized, MOR stimulation with morphine increased pleasantness of the sweetest of five sucrose solutions, without enhancing pleasantness of the lower-sucrose solutions. For opioid antagonism, an opposite pattern was observed for the sweetest drink only. The observed drug effects on pleasantness of the sweetest drink did not differ between sweet likers and dislikers. Conclusions: The bidirectional effect of agonist and antagonist treatment aligns with rodent findings showing that MOR manipulations most strongly affect the highest-calorie foods. We speculate that the MOR system promotes survival in part by increasing concordance between the objective (caloric) and subjective (hedonic) value of food stimuli, so that feeding behavior becomes more focused on the richest food available.

• Hall, Karhryn T.; Kossowsky, Joe; Oberlander, Tim F.; Kaptchuk, Ted J.; Saul, J. Philip; Wyller, Vegard Bruun; Fagermoen, Frode Even; Sulheim, Dag; Gjerstad, Johannes; Winger, Anette & Mukamal, Kenneth Jay (2016). Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome. The Pharmacogenomics Journal.  ISSN 1470-269X.  16(5), s 454- 460 . doi: 10.1038/tpj.2016.53 Fulltekst i vitenarkiv. Vis sammendrag

  Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene–drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine–COMT interaction effects in other conditions.

• Jacobsen, Daniel Pitz; Moen, Aurora Lie; Haugen, Fred & Gjerstad, Johannes (2016). Hyperexcitability in spinal WDR neurons following experimental disc herniation is associated with upregulation of fractalkine and its receptor in nucleus pulposus and the dorsal root ganglion. International Journal of Inflammation.  ISSN 2042-0099. . doi: 10.1155/2016/6519408 Vis sammendrag

  Introduction: Lumbar radicular pain following intervertebral disc herniation may be associated with a local inflammatory response induced by nucleus pulposus (NP) cells. Methods. In anaesthetized Lewis rats, extracellular single unit recordings of wide dynamic range (WDR) neurons in the dorsal horn and qPCR were used to explore the effect of NP application onto the dorsal nerve roots (L3–L5). Results. A clear increase in C-fiber response was observed following NP conditioning. In the NP tissue, the expression of interleukin-1β (IL-1β), colony stimulating factor 1 (Csf1), fractalkine (CX3CL1), and the fractalkine receptor CX3CR1 was increased. Minocycline, an inhibitor of microglial activation, inhibited the increase in neuronal activity and attenuated the increase in IL-1β, Csf1, CX3L1, and CX3CR1 expression in NP tissue. In addition, the results demonstrated an increase in the expression of TNF, CX3CL1, and CX3CR1 in the dorsal root ganglions (DRGs). Conclusion. Hyperexcitability in the pain pathways and the local inflammation after disc herniation may involve upregulation of CX3CL1 signaling in both the NP and the DRG.

• Moen, Aurora Lie; Lind, Anne-Li; Thulin, Måns; Kamali-Moghaddam, Masood; Røe, Cecilie; Gjerstad, Johannes & Gordh, Torsten (2016). Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation. International Journal of Inflammation.  ISSN 2042-0099.  2016 . doi: 10.1155/2016/3874964 Fulltekst i vitenarkiv. Vis sammendrag

  Earlier studies suggest that lumbar radicular pain following disc herniation may be associated with a local or systemic inflammatory process. In the present study, we investigated the serum inflammatory protein profile of such patients. All 45 patients were recruited from Oslo University Hospital, Ullevål, Norway, during the period 2007–2009. The new multiplex proximity extension assay (PEA) technology was used to analyze the levels of 92 proteins. Interestingly, the present data showed that patients with radicular pain 12 months after disc herniation may be different from other patients with regard to many measurable serum cytokines. Given a false discovery rate (FDR) of 0.10 and 0.05, we identified 41 and 13 proteins, respectively, which were significantly upregulated in the patients with severe pain one year after disc herniation. On the top of the list ranked by estimated increase we found C-X-C motif chemokine 5 (CXCM5; 217% increase), epidermal growth factor (EGF; 142% increase), and monocyte chemotactic protein 4 (MCP-4; 70% increase). Moreover, a clear overall difference in the serum cytokine profile between the chronic and the recovered patients was demonstrated. Thus, the present results may be important for future protein serum profiling of lumbar radicular pain patients with regard to prognosis and choice of treatment. We conclude that serum proteins may be measurable molecular markers of persistent pain after disc herniation.

• Fagermoen, Frode Even; Sulheim, Dag; Winger, Anette; Andersen, Anders Mikal; Gjerstad, Johannes; Godang, Kristin; Rowe, Peter C; Saul, Philip J.; Skovlund, Eva & Wyller, Vegard Bruun (2015). Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: A randomized controlled trial. BMC Pediatrics.  ISSN 1471-2431.  15 . doi: 10.1186/s12887-015-0428-2 Fulltekst i vitenarkiv. Vis sammendrag

  Background: Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A–adrenoceptor agonist clonidine. Methods: A total of 176 adolescent CFS patients (12–18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 μg or 50 μg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model. Results: A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period. Conclusions: Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance.

• Meyer, Benedicte; Nguyen, Chinh Bkrong Thi Thuy; Moen, Aurora; Fagermoen, Frode Even; Sulheim, Dag; Nilsen, Hilde; Wyller, Vegard Bruun & Gjerstad, Johannes (2015). Maintenance of Chronic Fatigue Syndrome (CFS) in young CFS patients is associated with the 5-HTTLPR and SNP rs25531 A > G Genotype. PLOS ONE.  ISSN 1932-6203.  10(10) . doi: 10.1371/journal.pone.0140883 Vis sammendrag

  Earlier studies have shown that genetic variability in the SLC6A4 gene encoding the serotonin transporter (5-HTT) may be important for the re-uptake of serotonin (5-HT) in the central nervous system. In the present study we investigated how the 5-HTT genotype i.e. the short (S) versus long (L) 5-HTTLPR allele and the SNP rs25531 A > G affect the physical and psychosocial functioning in patients with chronic fatigue syndrome (CFS). All 120 patients were recruited from The Department of Paediatrics at Oslo University Hospital, Norway, a national referral center for young CFS patients (12–18 years). Main outcomes were number of steps per day obtained by an accelerometer and disability scored by the Functional Disability Inventory (FDI). Patients with the 5-HTT SS or SLG genotype had a significantly lower number of steps per day than patients with the 5-HTT LALG, SLA or LALA genotype. Patients with the 5-HTT SS or SLG genotype also had a significantly higher FDI score than patients with the 5-HTT LALG, SLA or LALA genotype. Thus, CFS patients with the 5-HTT SS or SLG genotype had worse 30 weeks outcome than CFS patients with the 5-HTT LALG, SLA or LALA genotype. The present study suggests that the 5-HTT genotype may be a factor that contributes to maintenance of CFS.

• Pedersen, Linda Margareth; Schistad, Ellina Iordanova; Jacobsen, Line Melå; Røe, Cecilie & Gjerstad, Johannes (2015). Serum levels of the pro-inflammatory interleukins 6 (IL-6) and -8 (IL-8) in patients with lumbar radicular pain due to disc herniation: A 12-month prospective study. Brain, behavior, and immunity.  ISSN 0889-1591.  46, s 132- 136 . doi: 10.1016/j.bbi.2015.01.008 Vis sammendrag

  Earlier studies indicate that lumbar radicular pain after disc herniation may be associated with a local inflammation induced by leakage of nucleus pulposus (NP) into the spinal canal and neuroforamen. In the present study we addressed the role of two interleukins, IL-6 and IL-8 in such long-lasting lumbar radicular pain. All 127 patients were recruited from Oslo University Hospital, Ullevål, Norway. At inclusion, 6 weeks and 12 months, serum concentrations of IL-6 and IL-8 were analyzed by enzyme-linked immunosorbent assay (ELISA) and pain intensity was reported on a 0–10 cm visual analog scale (VAS). Significantly higher levels of IL-6 and IL-8 in serum were found in patients with VAS ⩾3 at 12 months, than in patient with VAS <3 at 12 months (p ⩽ 0.01, test of between-subjects effect, repeated measures ANOVA, covariates for IL-6: age, smoking; covariates for IL-8: smoking, treatment). For the first time we show that chronic lumbar radicular pain may be associated with a persistent increase of the pro-inflammatory substances IL-6 and IL-8 in serum after disc herniation.

• Hasvik, Eivind Olay; Schistad, Elina Iordanova; Grøvle, Lars; Haugen, Anne Julsrud; Røe, Cecilie & Gjerstad, Johannes (2014). Subjective health complaints in patients with lumbar radicular pain and disc herniation are associated with a sex - OPRM1 A118G polymorphism interaction: A prospective 1-year observational study. BMC Musculoskeletal Disorders.  ISSN 1471-2474.  15(1) . doi: 10.1186/1471-2474-15-161 Vis sammendrag

  Background: Earlier observations show that development of persistent pain may be associated with the genetic variability in the gene encoding for the μ-opioid receptor 1, the OPRM1 A118G (rs1799971). The aim of this study was to investigate the association between OPRM1 genotype and subjective health complaints in patients with radicular pain and disc herniation. Methods: A prospective, 1-year observational study was conducted at a hospital back clinic, including 118 Caucasian patients with lumbar radicular pain and MRI confirmed disc herniation. Single nucleotide polymorphism genotyping regarding the OPRM1 A118G was performed. The data of individuals with AA versus AG or GG were analysed separately by linear mixed models. The Subjective Health Complaints Inventory (0-81) including 27 common complaints experienced the previous month on a scale from not at all (0) to severe (3) was used as outcome. Pain, prior duration of leg pain, age, smoking status, and lumbar disc surgery were considered as covariates. Results: In total 23 of 118 patients were carriers of the OPRM1 G-allele. All patients except female carriers of the G-allele reported a decrease in pain from baseline to 1 year. Female carriers of the G-allele reported significantly higher subjective health complaints score during the study time span than male carriers of the G-allele when controlling for pain and pain duration. Conclusion: The present data indicate that, when controlling for pain intensity and duration, subjective health complaints are associated with a sex - OPRM1 A118G polymorphism interaction in patients with radicular pain.

• Iordanova, Ellina; Espeland, Ansgar; Pedersen, Lars Martin; Sandvik, Leiv; Gjerstad, Johannes & Røe, Cecilie (2014). Association between baseline IL-6 and 1-year recovery in lumbar radicular pain. European Journal of Pain.  ISSN 1090-3801.  18(10), s 1394- 1401 . doi: 10.1002/j.1532-2149.2014.502.x Vis sammendrag

  Background: In the present study, the influence of cytokines on 1‐year recovery in lumbar radicular pain was examined. Methods: In total, 110 patients with symptomatic lumbar disc herniation were followed for 1 year. Uni‐ and multivariate linear regression was used to assess the influence of interleukin (IL)‐6, IL‐8, disc degeneration and endplate changes (Modic changes) on the changes in the Oswestry Disability Index (ODI change; primary outcome) and visual analogue scale (VAS) for low back pain (LBP) and leg pain (secondary outcomes). Results: Less favourable ODI outcome correlated with higher serum IL‐6 levels (B = −3.41, 95% CI −5.52 to −1.30, p = 0.002), non‐surgical treatment (B = −7.03, 95% CI 1.21 to 12.84, p = 0.018), higher baseline back pain intensity (B = −2.28, 95% CI −3.21 to −1.35, p < 0.001) and low educational level (B = −5.57, 95% CI 0.66 to 10.47, p = 0.027). High VAS for LBP and leg pain at 1 year was associated with high levels of serum IL‐6, higher back pain intensity and longer duration of lumbar radicular pain at baseline. Conclusions: High serum IL‐6 levels, but not disc degeneration or Modic changes, were associated with less favourable recovery in patients with lumbar radicular pain. Intense initial back pain, non‐surgical treatment, lower educational level and longer duration of radicular pain before treatment also correlated with a slower recovery the first year after disc herniation.

• Moen, Aurora Lie; Schistad, Elina Iordanova; Rygh, Lars Jørgen; Røe, Cecilie & Gjerstad, Johannes (2014). Role of IL1A rs1800587, IL1B rs1143627 and IL1RN rs2234677 genotype regarding development of chronic lumbar radicular pain; A prospective one-year study. PLOS ONE.  ISSN 1932-6203.  9(9) . doi: 10.1371/journal.pone.0107301 Vis sammendrag

  Previous studies indicate that lumbar radicular pain following disc herniation may be associated with release of several pro-inflammatory mediators, including interleukin-1 (IL1). In the present study, we examined how genetic variability in IL1A (rs1800587 C>T), IL1B (rs1143627 T>C) and IL1RN (rs2234677 G>A) influenced the clinical outcome the first year after disc herniation. Patients (n = 258) with lumbar radicular pain due to disc herniation were recruited from two hospitals in Norway. Pain and disability were measured by visual analogue scale (VAS) and Oswestry Disability Index (ODI) over a 12 month period. The result showed that patients with the IL1A T allele, in combination with the IL1RN A allele had more pain and a slower recovery than other patients (VAS p = 0.049, ODI p = 0.059 rmANOVA; VAS p = 0.003, ODI p = 0.050 one-way ANOVA at 12 months). However, regarding the IL1B/IL1RN genotype, no clear effect on recovery was observed (VAS p = 0.175, ODI p = 0.055 rmANOVA; VAS p = 0.105, ODI p = 0.214 one-way ANOVA at 12 months). The data suggest that the IL1A T/IL1RN A genotype, but not the IL1B T/IL1RN A genotype, may increase the risk of a chronic outcome in patients following disc herniation.

• Nielsen, Morten Birkeland; Magerøy, Nils; Gjerstad, Johannes & Einarsen, Ståle (2014). Mobbing i arbeidslivet og senere helseplager. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  134(12/13), s 1233- 1238 . doi: 10.4045/tidsskr.13.0880 Vis sammendrag

  BAKGRUNN: Tverrsnittsstudier viser at eksponering for mobbing i arbeidslivet er positivt relatert til selvopplevde helseplager. Studiene gir imidlertid ikke grunnlag for å konkludere om hvorvidt mobbing fører til økte helseplager eller om helseplager øker risikoen for å bli mobbet. For å gi bedre indikasjoner på årsak-virkning-forhold oppsummeres derfor kunnskap fra prospektive studier på sammenhenger mellom mobbing i arbeidslivet og helseutfall. MATERIALE OG METODE: Vi har gjort en systematisk litteraturgjennomgang av originalartikler fra sentrale litteraturdatabaser om longitudinelle sammenhenger mellom mobbing i arbeidslivet og helse. Gjennomsnittsammenhenger mellom mobbing og helseutfall er beregnet ved bruk av metaanalyse. RESULTATER: Et konsistent funn på tvers av de gjennomgåtte studier er at eksponering for mobbing er signifikant positivt relatert til psykiske (OR =1,68; 95 % KI 1,35 – 2,09) og somatiske plager (OR = 1,77; 95 % KI 1,41 – 2,22) over tid. Psykiske plager er også forbundet med senere eksponering for mobbing (OR = 1,74; 95 % KI 1,44 – 2,12). FORTOLKNING: Mobbing er positivt relatert til psykiske og somatiske helseplager. Assosiasjonen mellom psykiske plager og senere mobbing indikerer en selvforsterkende prosess mellom mobbing og psykisk helse. De gjennomgåtte studier er av relativt god metodisk kvalitet. Med utgangspunkt i eksisterende kunnskapsgrunnlag er det imidlertid ikke grunnlag for konklusjoner om entydige årsak-virkning-forhold mellom mobbing og helse.

• Schistad, Ellina Iordanova; Espeland, Ansgar; Rygh, Lars Jørgen; Røe, Cecilie & Gjerstad, Johannes (2014). The association between Modic changes and pain during 1-year follow-up in patients with lumbar radicular pain. Skeletal Radiology.  ISSN 0364-2348.  43(9), s 1271- 1279 . doi: 10.1007/s00256-014-1928-0 Vis sammendrag

  Objective: To examine whether Modic changes influence pain during a 1-year follow-up in patients with lumbar radicular pain. Materials and Methods: A total of 243 patients with lumbar radicular pain due to disc herniation were recruited from two hospitals in Norway and followed up at 6 weeks, 6 months, and 12 months. On baseline lumbar magnetic resonance images, two observers independently evaluated Modic changes (types I–III; craniocaudal size 0–3). Outcomes were sensory pain (McGill Pain Questionnaire), back and leg pain (visual analogue scale, VAS). Association between Modic type and outcomes was explored with a mixed model and then by two-way analysis of variance (ANOVA) at each time point with Modic and treatment groups (surgical, n = 126; nonsurgical, n = 117) as fixed factors, adjusted for disc degeneration, age, sex, smoking, and duration of radicular pain. Modic size was also analyzed using ANOVA. Results: Pain scores had decreased significantly at 1-year follow-up. Modic type was significantly related to McGill sensory scores (mixed model: p = 0.014–0.026; ANOVA: p = 0.007 at 6 weeks), but not to VAS back pain or VAS leg pain scores. At 6 weeks, the mean McGill sensory score was higher in Modic I than in Modic II–III patients (p = 0.003) and in patients without Modic changes (p = 0.018). Modic size L1–S1 was not associated with pain outcomes. Conclusion: Patients with lumbar radicular pain have a substantial pain reduction during 1-year follow-up, but Modic type I changes may imply a slower initial decrease in sensory pain.

• Schistad, Ellina Iordanova; Jacobsen, Line Melå; Røe, Cecilie & Gjerstad, Johannes (2014). The Interleukin-1[alpha] Gene C>T Polymorphism rs1800587 is associated with increased pain intensity and decreased pressure pain thresholds in patients with lumbar radicular pain. The Clinical Journal of Pain.  ISSN 0749-8047.  30(10), s 869- 874 . doi: 10.1097/AJP.0000000000000048 Vis sammendrag

  Objectives: Previous studies have suggested that many inflammatory cytokines, including interleukin (IL)-1a, may be associated with lumbar radicular pain after disk herniation. In the present study, we examined how variability of the IL-1a gene affects pain intensity and the pressure pain threshold (PPT) in patients with symptomatic disk herniation. Materials and Methods: A total of 121 patients with lumbar radicular pain due to disk herniation were recruited from Oslo University Hospital, Norway, and followed up at 6 weeks and 12 months. The primary outcome measures were pain intensity scores for the lower back and legs using a visual analog pain scale (VAS) and PPT for the gluteal muscles. Genotyping was carried out using a predesigned TaqMan assay for IL-1a rs1800587. The effect of the IL-1a genotype on the VAS and PPT was analyzed by repeated measure analyses of variance. Results: The IL-1a gene C> T polymorphism rs1800587 affected VAS and PPT scores in patients with symptomatic disk herniation. Patients with the CT/TT genotype reported a higher VAS leg pain intensity (P= 0.002) and also a lower PPT in the gluteal muscles (left P= 0.016; right P= 0.016) compared with patients with the CC genotype during 1 year of follow-up. Discussion: The present data show that the IL-1a CT/TT genotype rs1800587 may be associated with increased pain intensity and corresponding reduced PPT during the first year after disk herniation.

• Dominguez, Cecilia A.; Kalliomäki, Maija; Gunnarsson, Ulf; Moen, Aurora; Sandblom, Gabriel; Kockum, Ingrid; Lavant, Ewa; Olsson, Tomas; Nyberg, Fred; Rygh, Lars Jørgen; Røe, Cecilie; Gjerstad, Johannes; Gordh, Torsten & Piehl, Fredrik (2013). The DQB1*03:02 HLA haplotype is associated with increased risk of chronic pain after inguinal hernia surgery and lumbar disc herniation. Pain.  ISSN 0304-3959.  154(3), s 427- 433 . doi: 10.1016/j.pain.2012.12.003 Vis sammendrag

  Neuropathic pain conditions are common after nerve injuries and are suggested to be regulated in part by genetic factors. We have previously demonstrated a strong genetic influence of the rat major histocompatibility complex on development of neuropathic pain behavior after peripheral nerve injury. In order to study if the corresponding human leukocyte antigen complex (HLA) also influences susceptibility to pain, we performed an association study in patients that had undergone surgery for inguinal hernia (n = 189). One group had developed a chronic pain state following the surgical procedure, while the control group had undergone the same type of operation, without any persistent pain. HLA DRB1genotyping revealed a significantly increased proportion of patients in the pain group carrying DRB1⁄ 04 compared to patients in the pain-free group. Additional typing of the DQB1 gene further strengthened the association; carriers of the DQB1⁄ 03:02 allele together with DRB1⁄ 04 displayed an increased risk of postsurgery pain with an odds risk of 3.16 (1.61-6.22) compared to noncarriers. This finding was subsequently replicated in the clinical material of patients with lumbar disc herniation (n = 258), where carriers of the DQB1⁄ 03:02 allele displayed a slower recovery and increased pain. In conclusion, we here for the first time demonstrate that there is an HLA-dependent risk of developing pain after surgery or lumbar disc herniation; mediated by the DRB1⁄ 04 – DQB1⁄ 03:02 haplotype. Further experimental and clinical studies are needed to fine-map the HLA effect and to address underlying mechanisms.

• Egeland, Nina Gran; Moen, Aurora; Pedersen, Linda Margareth; Brisby, Helena & Gjerstad, Johannes (2013). Spinal nociceptive hyperexcitability induced by experimental disc herniation is associated with enhanced local expression of Csf1 and FasL. Pain.  ISSN 0304-3959.  154(9), s 1743- 1748 . doi: 10.1016/j.pain.2013.05.034 Vis sammendrag

  Sciatica after disc herniation may be associated with compression of spinal nerves, but also inflammatory substances released from the nucleus pulposus (NP) leaking into the spinal canal. Here, in an animal model mimicking clinical intervertebral disc herniation, we investigate the effect of NP on neuronal activity. In anaesthetized Lewis rats, extracellular single-unit recordings of spinal dorsal horn neurons were performed, and the C-fibre responses were examined. Moreover, quantitative polymerase chain reaction was used to explore the gene expression of proinflammatory cytokines in the NP tissue exposed to the spinal dorsal nerve roots L3–L5. In accordance with earlier studies, we showed a significant increase in the C-fibre response and an upregulation of the gene expression of interleukin 1b and tumour necrosis factor 180 minutes after application of NP onto the nerve roots. Moreover, based on a polymerase chain reaction array of 84 common inflammatory cytokines at the same time point, we demonstrated a highly significant upregulation of colony-stimulating factor 1 also termed macrophage colony-stimulating factor and Fas ligand. The pronounced upregulation of Csf1 and Fas ligand 180 minutes after application of NP onto the nerve roots suggests that macrophage activation and apoptosis may be involved in pain hypersensitivity and other sensory abnormalities after disc herniation

• Jacobsen, Line Melå; Schistad, Elina Iordanova; Storesund, Anette; Pedersen, Linda Margareth; Espeland, Ansgar; Rygh, Lars Jørgen; Røe, Cecilie & Gjerstad, Johannes (2013). The MMP1 rs1799750 2G allele is associated with increased low back pain, sciatica, and disability after lumbar disk herniation. The Clinical Journal of Pain.  ISSN 0749-8047.  29(11), s 967- 971 . doi: 10.1097/AJP.0b013e31827df7fd Vis sammendrag

  Objectives: Previous studies indicate that genetic variants in genes encoding proteins like matrix metalloproteinase (MMP) enzymes may affect degeneration of the intervertebral disk. One such genetic variant is a single nucleotide polymorphism insertion in the promoter region of the MMP1 gene, that is, the MMP1 rs1799750 2G allele, which increases the MMP1 expression in vitro. In this study, we examined whether the MMP1 rs1799750 2G allele might be associated with disk degeneration and clinical outcome after lumbar disk herniation. Materials and Methods: A total of 260 patients with lumbar disk herniation and sciatic pain were included in this study and genotyped for the MMP1 rs1799750 2G allele. Results: The present data showed no differences in the frequency of the MMP1 2G allele in patients recently diagnosed with disk herniation compared with pain-free controls. Moreover, in the patients, the MMP1 2G allele was not directly related to the disk degeneration. However, our data demonstrated that the MMP1 2G allele was associated with both pain and disability, that is, increased visual analog scale score, McGill Pain Questionnaire score, and Oswestry Disability Index score. Clearly, the patients homozygous for the 2G allele had more pain and reduced function compared with those carrying the 1G allele. Discussions: Our findings suggest that the MMP1 rs1799750 2G/2G genotype may contribute to low back pain, sciatica, and disability after lumbar disk herniation

• Matre, Dagfinn; Olsen, Maria Belland; Jacobsen, Line Melå; Klein, Thomas & Gjerstad, Johannes (2013). Induction of the perceptual correlate of human long-term potentiation (LTP) is associated with the 5-HTT genotype. Brain Research.  ISSN 0006-8993.  1491, s 54- 59 . doi: 10.1016/j.brainres.2012.10.045 Vis sammendrag

  The purpose of the present study was to examine how genetic variability in the promoter of the SLC6A4 gene encoding the serotonin transporter (5-HTT) may influence induction of long-term potentiation (LTP). The genotyping of the 53 healthy volunteers was performed by a combination of TaqMan assay and gel electrophoresis. Based on the transcription rates, the subjects were divided in 3 groups; 5-HTT SS, 5-HTT SLG/LALG/SLA and 5-HTT LALA. The intensity of pain to test stimuli was rated on a visual analog scale (VAS). High frequency stimulation (HFS) conditioning applied to one arm was used to induce LTP. Only a minor change in pain was observed following the HFS conditioning evoked by electrical test stimuli delivered through the conditioning electrode. Moreover, the change in pain evoked by test stimuli delivered through the conditioning electrode was not related to the 5-HTT genotype. However, we observed a clear increase in pain following the HFS conditioning evoked by mechanical pin-prick test stimuli delivered at the skin adjacent to the conditioning. Also, the 9 individuals with the 5-HTT SS genotype reported more pain than individuals with 5-HTT SLG/LALG/SLA genotype following HFS conditioning on mechanical pin-prick test stimuli. Thus, the present data show that induction of the perceptual correlate of human LTP is associated with the genetic variability in the gene encoding the 5-HTT. Taken together, this suggests that the expression of 5-HTT, may be important for induction of LTP in humans.

• Eriksen, Guro Søe; Jacobsen, Line Melå; Aqsa, Mahmood; Pedersen, Linda Margareth & Gjerstad, Johannes (2012). Inhibition of fatty acid amide hydrolase (FAAH) reduces spinal nociceptive responses and expression of spinal long-term potentiation (LTP). Brain Research Bulletin.  ISSN 0361-9230.  87(2-3), s 234- 237 . doi: 10.1016/j.brainresbull.2011.11.009 Vis sammendrag

  Fatty acid amide hydrolase (FAAH) is an enzyme that metabolizes endocannabinoids and fatty acid amides possibly linked to activation of the opioid system. To examine how this enzyme affects spinal signalling, electrophysiological recordings in the dorsal horn and qPCR on dorsal horn tissue following systemic administration of the FAAH inhibitor URB597 (0.3 and 1.0 mg/kg i.v.) and spinal administration of the opioid receptor antagonist naloxone (0.1 μg/μl i.th.), were performed. The present data showed that the suppressive effect of the FAAH inhibitor URB597 (1.0 mg/kg i.v.) on the spinal nociceptive responses was prevented by spinal administration of the opioid receptor antagonist naloxone (0.1 μg/μl i.th.). Moreover, the present findings demonstrated that the FAAH inhibitor URB597 (1.0 mg/kg i.v.) partly reversed expression of spinal long-term potentiation (LTP) and also attenuated the LTP-associated increased Zif expression. We conclude that pharmacological inactivation of FAAH may be a promising strategy to inhibit the development of central hyperalgesia; thereby reinforcing the role of FAAH as a potential therapeutic target.

• Jacobsen, Line Melå; Iordanova, Ellina; Storesund, Anette; Pedersen, Linda Margareth; Rygh, Lars Jørgen; Røe, Cecilie & Gjerstad, Johannes (2012). The COMT rs4680 met-allele contributes to long lasting low back pain, sciatica and disability after lumbar disc herniation. European Journal of Pain.  ISSN 1090-3801.  16(7), s 1064- 1069 . doi: 10.1002/j.1532-2149.2011.00102.x Vis sammendrag

  Background: The COMT enzyme metabolizes catecholamines and thus modulates adrenergic, noradrenergic and dopaminergic signaling. A functional polymorphism in the gene encoding this enzyme, i.e. the COMT Val158Met SNP that reduces enzyme activity, has previously been linked to pain sensitivity. Methods: We examined if the COMT Val158Met SNP could contribute to discogenic subacute low back pain and sciatica by comparing the frequency of the Val158Met genotypes of degenerative disc disease patients with healthy controls. Moreover, we examined if this SNP could predict the clinical outcome, i.e. the progression of pain and disability. Results: The present data demonstrated that there were no differences in COMT genotype frequencies between the newly diagnosed patients and controls. Analysis of pain and disability in the patients over time revealed, however, a significant or border‐line significant increase in McGill sensory score and Oswestry Disability Index (ODI) score for individuals with COMT Met/Met genotype. Furthermore, significant associations between the COMT Met‐allele and VAS activity score, McGill sensory score and ODI score were observed in the patients 6 months after inclusion. Discussion: Although the Val158Met SNP was not a risk factor for disc herniation, patients with Met/Met had more pain and slower recovery than those with Val/Met, which in turn also had more pain and slower recovery than those with Val/Val suggesting the SNP contributes to the progression of the symptoms of disc herniation. Conclusion: We conclude that the functional COMT Val158Met SNP contributes to long lasting low back pain, sciatica and disability after lumbar disc herniation.

• Olsen, Maria Belland; Jacobsen, Line Melå; Iordanova, Ellina; Pedersen, Linda Margareth; Rygh, Lars Jørgen; Røe, Cecilie & Gjerstad, Johannes (2012). Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor Mu 1 gene: evidence of a sex and genotype interaction. Journal of Neuroscience.  ISSN 0270-6474.  32(29), s 9831- 9834 . doi: 10.1523/JNEUROSCI.1742-12.2012 Vis sammendrag

  Earlier studies have shown that the single nucleotide polymorphism (SNP) A118G (rs1799971) in the opioid receptor mu 1 (OPRM1) gene may affect pain sensitivity. In the present study we investigated whether the A118G SNP could predict clinical outcome regarding progression of pain intensity and disability in patients with low back pain and sciatica after lumbar disc herniation. Patients (n = 258) with lumbar disc herniation and sciatic pain, all European-Caucasian, were recruited from two hospitals in Norway. Pain and disability were rated on a visual analog scale (VAS), by McGill Sensory Questionnaire and by Oswestry Disability Index (ODI) over a 12 months period. The data revealed a significant interaction between sex and A118G genotype regarding the pain intensity during the 12 months (VAS, p = 0.002; McGill, p = 0.021; ODI, p = 0.205, repeated-measures ANOVA). We found that */G women had a slower recovery rate than the */G men. Actually, the */G women had 2.3 times as much pain as the */G men 12 months after the disc herniation (VAS, p = 0.043, one-way ANOVA; p = 0.035, Tukey HSD). In contrast, the A/A women and A/A men seemed to have almost exactly the same recovery rate. The present data suggest that OPRM1 G allele increases the pain intensity in women, but has a protective effect in men the first year after disc herniation.

• Sommerfeldt, Line; Portilla, Helene; Jacobsen, Line Melå; Gjerstad, Johannes & Wyller, Vegard Bruun (2011). Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome. Acta Paediatrica.  ISSN 0803-5253.  100(2), s 293- 298 . doi: 10.1111/j.1651-2227.2010.02072.x Vis sammendrag

  Aim: To explore the frequency of polymorphisms in adrenergic cardiovascular control genes in adolescent with chronic fatigue syndrome (CFS) and the relation of such polymorphisms to cardiovascular variables. Methods: DNA from 53 patients with CFS, 12–18 years old, was analysed for five single nucleotide polymorphisms (SNPs) in the genes catechol‐O‐methyltransferase (COMT), the β2‐adrenergic receptor (two SNPs), the β1‐adrenergic receptor and the α2a‐adrenergic receptor. Frequencies were compared to a reference population constructed from the National Center for Biotechnology Information (NCBI) database, and associations between frequencies and autonomic cardiovascular responses during a 20° head‐uptilt‐test were explored. Results: For the COMT SNP Rs4680, patients with CFS had a higher frequency of the AA genotype and a lower frequency of the G containing genotypes (AG and GG), when compared to the reference sample (p = 0.046). Also, the AA genotype was associated with a smaller increase in LF/HF ratio (low‐frequency:high‐frequency heart rate variability ratio, an index of cardiac sympathovagal balance) during head‐up tilt when compared to the AG/GG genotypes. For the β2‐adrenergic receptor SNP Rs1042714, patients with CFS had a lower frequency of the GG genotype and a higher frequency of the genotypes containing C (CG and CC) (p = 0.044). Conclusions: CFS might be related to polymorphisms of COMT and the β2‐adrenergic receptor. More details of the molecular mechanisms remain to be investigated.

• Hjornevik, Trine; Schoultz, Bent Wilhelm; Marton, Janos; Gjerstad, Johannes; Drzezga, Alexander; Henriksen, Gjermund & Willoch, Frode (2010). Spinal long-term potentiation is associated with reduced opioid neurotransmission in the rat brain. Clinical Physiology and Functional Imaging.  ISSN 1475-0961.  30(4), s 285- 293 . doi: 10.1111/j.1475-097X.2010.00939.x Vis sammendrag

  Introduction: Neuronal events leading to development of long‐term potentiation (LTP) in the nociceptive pathways may be a cellular mechanism underlying hyperalgesia. In the present study, we examine if induction of spinal LTP may be associated with functional changes in the supraspinal opioidergic system. The opioid receptors (ORs) play a key role in nociceptive processing and controlling the descending modulatory system to the spinal cord. Methods: Spinal LTP was induced by electrical high‐frequency stimulation (HFS) conditioning applied to the sciatic nerve, and the excitability at spinal level was verified by spinal field potential recordings. To study supraspinal changes in opioid neurotransmission following the same HFS conditioning, we used small animal positron emission tomography (PET) and [11C]Phenethyl‐Orvinol ([11C]PEO). All rats included in the PET study were scanned at baseline and 150 min after HFS, and specific binding was calculated with a reference tissue model. Results: A clear C‐fibre LTP, i.e. increased C‐fibre response and reduced C‐fibre threshold, was observed 150 min after HFS conditioning (t‐test, P<0·05, n = 6). Moreover, increased OR binding, relative to baseline, was observed after the same type of HFS conditioning ipsilaterally in the amygdala, hippocampus, somatosensory cortex and superior colliculus, and bilaterally in the nucleus accumbens, caudate putamen and hypothalamus (paired t‐test, HFS>baseline, P<0·05, n = 8). Conclusions: HFS conditioning of the sciatic nerve resulted in both spinal LTP and functional changes in supraspinal opioidergic signalling. Our findings suggest that induction of spinal LTP may be associated with reduced opioid neurotransmission in brain regions involved in pain modulation and affective‐emotional responses.

• Iordanova, Ellina; Røe, Cecilie; Keller, Anne; Skouen, Jan Sture; Rygh, Lars Jørgen; Espeland, Ansgar & Gjerstad, Johannes (2010). Langvarige korsryggsmerter og MR-forandringer i ryggvirvlene :. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  130(22), s 2260- 2263 . doi: 10.4045/tidsskr.09.0122
• Jacobsen, Line Melå; Eriksen, Guro Søe; Pedersen, Linda Margareth & Gjerstad, Johannes (2010). Catechol-O-methyltransferase (COMT) inhibition reduces spinal nociceptive activity. Neuroscience Letters.  ISSN 0304-3940.  473(3), s 212- 215 . doi: 10.1016/j.neulet.2010.02.049 Vis sammendrag

  Several variants of the catechol-O-methyltransferase (COMT) gene have recently been linked to pain sensitivity. In the present study, electrophysiological field potential recordings from the dorsal horn in rats were used to examine the spinal effect of reduced COMT activity. The data demonstrated that 30 mg/kg of the COMT inhibitor OR 486 reduced spinal nociceptive responses to painful stimuli (p ≤ 0.01, OR 486 vs. vehicle) and attenuated the expression of spinal long-term potentiation (LTP), an often studied model for central sensitization (p ≤ 0.01, HFS vs. HFS + OR 486). Our findings suggest that low COMT activity may have an antinociceptive effect in the spinal cord.

• Pedersen, Linda Margareth; Jacobsen, Line Melå; Mollerup, Steen Kristen & Gjerstad, Johannes (2010). Spinal cord long-term potentiation (LTP) is associated with increased dorsal horn gene expression of IL-1 beta, GDNF and iNOS. European Journal of Pain.  ISSN 1090-3801.  14(3), s 255- 260 . doi: 10.1016/j.ejpain.2009.05.016 Vis sammendrag

  Previous data show that spinal cord long‐term potentiation (LTP) can be induced by electrical high‐frequency stimulation (HFS) conditioning applied to the sciatic nerve. It has been suggested that the cellular events leading to this form of plasticity may contribute to central hyperalgesia. In the present study, extracellular recordings from single dorsal horn neurons and quantitative real‐time reverse‐transcriptase polymerase chain reaction (RT‐PCR) on rat dorsal horn tissue were used to examine whether maintenance of spinal LTP is associated with changes in gene expression of the proinflammatory interleukin‐1β (IL‐1β), glial cell‐line derived neurotrophic factor (GDNF), inducible nitric oxide synthase (iNOS), p38 mitogen‐activated protein kinase (p38 MAPK), cyclooxygenase 2 (COX2) and tumor necrosis factor α (TNFα). The data demonstrated that the HFS conditioning induced a robust increase in the dorsal horn C‐fibre responses, which outlasted the duration of the experiments of 6 h (p < 0.05, HFS vs. control). Moreover, a significant increase in the expression of mRNA for IL‐1β, GDNF and iNOS were observed 6 h following the HFS conditioning (p < 0.05, HFS vs. control). For the first time we show that spinal cord LTP is associated with an increased dorsal horn expression of the genes for IL‐1β, GDNF and iNOS.

• Hjørnevik, Trine; Jacobsen, Line Melå; Qu, Hong; Bjaalie, Jan G.; Gjerstad, Johannes & Willoch, Frode (2008). Metabolic plasticity in the supraspinal pain modulating circuitry after noxious stimulus-induced spinal cord LTP. Pain.  ISSN 0304-3959.  140, s 456- 464 . doi: 10.1016/j.pain.2008.09.029 Vis sammendrag

  It has been suggested that spinal cord long-term potentiation (LTP) may contribute to hypersensitivity and hyperalgesia. We have investigated if noxious stimulus-induced spinal cord LTP might have a long lasting effect on supraspinal neuronal activity. First, we verified that spinal LTP was induced by electrical high frequency stimuli (HFS) conditioning applied to the sciatic nerve. The C-fibre response in the dorsal horn reached a twofold increase 150 min after HFS (t-test, p < 0.01, n = 6). Then, to study the metabolic supraspinal activity following the same stimulation protocol, we used small animal positron emission tomography (PET) and the glucose analog [18F]-fluorodeoxyglucose (FDG). With this combined approach we measured changes in regional supraspinal activity at two time points in HFS conditioned and in sham animals; acute (immediately after HFS/sham, n = 4) and late phase (150 min after HFS/sham, n = 10). Comparisons between HFS and sham groups revealed that induction of spinal LTP was followed by an acute metabolic response in the primary somatosensory cortex (S1), but also various slower metabolic adaptations in brain regions involved in modulation of nociceptive signaling and descending inhibition, i.e., amygdala, periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT) (t-test, p < 0.05). The study demonstrates that PET may be used as an in vivo method to study regional brain metabolic activity between different conditions. It is concluded that noxious sciatic stimuli which induce spinal cord LTP also affect supraspinal metabolic activity. We suggest that these changes might illustrate a supraspinal maladaptive dysfunction involved in pain hypersensitivity and hyperalgesia.

• Pedersen, Linda & Gjerstad, Johannes (2008). Spinal cord long-term potentiation is attenuated by the NMDA-2B receptor antagonist Ro 25-6981. Acta Physiologica Scandinavica.  ISSN 0001-6772.  192(3), s 421- 427

Se alle arbeider i Cristin

• Glambek, Mats; Gjerstad, Johannes; Einarsen, Ståle & Nielsen, Morten Birkeland (2019). The role of tenure and job satisfaction in the prospective relationship between workplace bullying and intention to leave: A moderated mediation model.
• Glambek, Mats; Nielsen, Morten Birkeland; Gjerstad, Johannes & Einarsen, Ståle (2018). Gender differences in the relationship between workplace bullying and subjective back and neck pain: A two-wave study in a Norwegian probability sample. Journal of Psychosomatic Research.  ISSN 0022-3999.  106, s 73- 75 . doi: 10.1016/j.jpsychores.2018.01.010
• Nielsen, Morten Birkeland; Gjerstad, Johannes & Frone, Michael (2018). Alcohol use among Norwegian workers: Associations with health and well-being. Occupational Medicine.  ISSN 0962-7480.  68(2), s 96- 98 . doi: 10.1093/occmed/kqy014 Fulltekst i vitenarkiv. Vis sammendrag

  Background: There is a lack of published data on the association between alcohol consumption and health and well-being in working populations. Aims: To determine how levels of alcohol consumption are associated with psychological distress, somatic complaints, sleep and job satisfaction in the Norwegian workforce. Methods: Survey questionnaire data from a probability sample comprising Norwegian employees. The association between alcohol consumption and health and well-being was assessed using analysis of covariance. Results: There were 1608 respondents (response rate 32%); 20% of the sample were abstainers, 72% were low- to moderate-alcohol users, 6% were moderate to high users and 2% were risky users. Adjusting for age, gender and tobacco use, employees with risky alcohol use reported significantly higher levels of psychological distress and lower job satisfaction when compared to employees who drank less. There were no differences between risky users and other employees with regard to sleep problems and somatic complaints, nor were there any gender differences. Conclusions: Our findings indicate that risky alcohol use in the Norwegian workforce is associated with impaired health and well-being, with no evidence of a gender differential. The findings support the thresholds for risky alcohol use as proposed by internationally recognized guidelines for alcohol consumption.

• Forsberg, June Thorvaldsen; Gjerstad, Johannes; Flaten, Magne & Aslaksen, Per M (2017). The genetic influence on fear of pain and placebo analgesia.
• Moen, Aurora Lie; Gjerstad, Johannes & Røe, Cecilie (2017). Disc herniation, inflammatory mediators and lumbar radicular pain.
• Reknes, Iselin; Einarsen, Ståle; Gjerstad, Johannes & Nielsen, Morten Birkeland (2017). Role conflict, personality, and exposure to bullying behaviors.
• Jacobsen, Line Melå; Gjerstad, Johannes & Bjaalie, Jan G. (2012). Spinal nociceptive signalling mechanisms to long-lasting low back pain and sciatica. Series of dissertations submitted to the Faculty of Medicine, University of Oslo. No.1387.
• Eriksen, Guro Søe; Jacobsen, Line Melå & Gjerstad, Johannes (2010). Spinal LTP is attenuated by the FAAH enzyme inhibitor URB597.
• Eriksen, Guro Søe; Jacobsen, Line Melå; Pedersen, Linda Margareth & Gjerstad, Johannes (2010). Inhibition of FAAH reverses spinal LTP.
• Eriksen, Guro Søe; Jacobsen, Line Melå; Pedersen, Linda Margareth & Gjerstad, Johannes (2010). Inhibition of FAAH reverses spinal LTP. Scandinavian Journal of Pain.  ISSN 1877-8860.  1(3), s 170- 170 . doi: 10.1016/j.sjpain.2010.05.010
• Eriksen, Guro Søe; Jacobsen, Line Melå; Pedersen, Linda Margareth & Gjerstad, Johannes (2009). Inhibition of FAHH reduces central sensitization after noxious stimulation.
• Hjornevik, Trine; Schoultz, Bent Wilhelm; Gjerstad, Johannes; Henriksen, Gjermund & Willoch, Frode (2009). C-fibre LTP is associated with dynamic changes in opioid neurotransmission in the brain. Journal of Cerebral Blood Flow and Metabolism.  ISSN 0271-678X.  29, s S369- S370
• Hjornevik, Trine; Schoultz, Bent Wilhelm; Gjerstad, Johannes; Henriksen, Gjermund & Willoch, Frode (2009). C-fibre LTP is associated with dynamic changes in opioid neurotransmission in the brain.
• Hjornevik, Trine; Schoultz, Bent Wilhelm; Marton, Janos; Gjerstad, Johannes; Drzezga, Alexander; Henriksen, Gjermund & Willoch, Frode (2009). Spinal LTP is associated with reduced opioid neurotransmission in the rat brain.
• Hjørnevik, Trine; Jacobsen, Line Melå; Qu, Hong; Bjaalie, Jan G.; Gjerstad, Johannes & Willoch, Frode (2008). Induction of spinal LTP results in activity-dependent plastic changes in pain modulatory of brain and brain stem.
• Hjørnevik, Trine; Qu, Hong; Gjerstad, Johannes; Jacobsen, Line Melå; Bjaalie, Jan G. & Willoch, Frode (2008). Rat model of pathological pain in the central nervous system.

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