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• Sommen, Silke Lauren; Segtnan, Sunniva; Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Stiansen-Sonerud, Tonje & Gjerstad, Johannes [Show all 11 contributors for this article] (2026). Long COVID: Deep single-cell immunophenotyping and machine learning reveal a general signature for fatigue. Journal of Translational Medicine. 24(1). doi: 10.1186/s12967-026-08149-3. Full text in Research Archive
• Gjerstad, Johannes; Solli, Kristin Klemmetsby; Tanum, Lars Håkon Reiestad; Weimand, Bente & Sannes, Ann-Christin (2026). The COMT rs4680 Met Allele Is Associated with High Impulsivity, Hyperactivity and Inattention in Patients with Opioid Use Disorder. Psychiatry International. 7(1), p. 1–10. doi: 10.3390/psychiatryint7010028. Full text in Research Archive Show summary

  Background: Previous research has linked opioid use disorder (OUD) to neuronal reward systems and impulsivity. The aim of this study was to examine the influence of COMT rs4680 Val158Met polymorphism on impulsivity, hyperactivity and inattention (IHI) in patients with OUD. Methods: Open-label, cross-sectional cohort study was conducted involving individuals, 18 to 65 years, with OUD who either were included in opioid agonist treatment (OAT)—or same group of individuals who were awaiting induction on extended-release naltrexone (XR-NTX). Adult ADHD Self-Report Scale 18-item version was used to score IHI, and saliva samples were collected for genotyping (TaqMan assays). Logistic regression models were used to analyze the data. Results: The data of the entire cohort (n = 206) showed that carriers of one or two Val alleles had a negative association with IHI compared to Met/Met carriers (Val/Met OR = 0.43, p-value = 0.017, and Val/Val OR = 0.29, p-value = 0.005). Individuals included in OAT not waiting for XR-NTX (n = 120) exhibited the same pattern as observed in the entire cohort (Val/Met OR = 0.33, p-value = 0.019, and Val/Val OR = 0.18, p-value = 0.004), but not those who chose XR-NTX (Val/Met OR = 0.60, p-value = 0.353, and Val/Val OR = 0.47, p-value = 2.779). Conclusions: The present study revealed that individuals with OUD carrying the COMT rs4680 Val allele had lower IHI scores than Met/Met carriers. Hence, in individuals with OUD, the COMT rs4680 Met allele is associated with higher IHI symptom burden.

• Sannes, Ann-Christin; Amjad, Imran; Duehr, Jenna; Ghani, Usman; Rice, David & Haavik, Heidi [Show all 9 contributors for this article] (2025). Unique RNA Gene Expression Profile Is Seen in Chronic Non-Specific Low Back Pain. International Journal of Molecular Sciences. ISSN 1661-6596. 27(1). doi: 10.3390/ijms27010287. Full text in Research Archive Show summary

  Previous reports suggest that the progression from subacute to chronic non-specific low back pain (nsLBP) involves functional changes in both the nervous and immune systems. The purpose of the present study was to characterize the gene expression profiles of circulating immune cells that affect the interaction between these two systems when subacute nsLBP turns into chronic nsLBP. Participants aged 18–55 were included based on the presence or duration of LBP, with peripheral blood mononuclear cells collected for RNA sequencing from 20 healthy controls (no nsLBP), 20 subclinical patients (intermittent nsLBP), and 19 chronic patients (long-term nsLBP). The data revealed that chronic nsLBP is linked to a distinct gene expression profile, with 139 uniquely differentially expressed genes (DEGs), differing from those in the subclinical and control groups. Interestingly, comparing chronic and subclinical groups showed minimal overlap in DEGs, indicating a clear inflammatory distinction between subclinical nsLBP and chronic nsLBP. The findings also indicated that patients with chronic nsLBP were different from other individuals regarding axon guidance, indicating neuroplastic changes when intermittent nsLBP turns into chronic nsLBP. Hence, early recognition of the transition from subclinical to chronic nsLBP using RNA profiling may pave the way for more precise therapeutic strategies targeting neuroplastic changes and inflammatory processes.

• Juya, Farid; Solli, Kristin Klemmetsby; Sannes, Ann-Christin; Weimand, Bente; Gjerstad, Johannes & Tanum, Lars Håkon Reiestad [Show all 7 contributors for this article] (2025). Genetic Influence on Extended-Release Naltrexone Treatment Outcomes in Patients with Opioid Use Disorder: An Exploratory Study. Brain Sciences. 16(1). doi: 10.3390/brainsci16010023. Full text in Research Archive Show summary

  Background/Objectives: The variation in the treatment outcomes of extended-release naltrexone (XR-NTX) including the potential role of genetic factors are poorly understood. This study aimed to explore the potential association between the catechol-O-methyltransferase (COMT) rs4680 and mu-opioid receptor (OPRM1) rs1799971 genotypes and XR-NTX treatment outcomes in patients with opioid use disorder (OUD) specifically focusing on treatment retention, relapse to opioids, number of days of opioid use, and opioid cravings. Methods: This was a 24-week, open-label clinical prospective, exploratory study involving patients with OUD who chose treatment with monthly injections of intramuscular XR-NTX. Men and women aged 18–65 years with OUD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were included. The participants were interviewed using the European Addiction Severity Index. Survival analyses and linear mixed models were used to analyze the data. Results: Of the 162 participants included in this study, 138 (21% female) initiated treatment with XR-NTX, with 88 genotyped for COMT rs4680 and 86 for OPRM1 rs1799971. Heterozygous Met/Val carriers of COMT rs4680 were less likely to relapse to opioids compared with those with the COMT rs4680 Met/Met genotype. No significant association was observed for the OPRM1 polymorphism. Conclusions: Patients with the COMT rs4680 Met/Val genotype exhibit a reduced risk of relapse to opioids and may therefore derive greater benefit from XR-NTX treatment compared with those with the COMT rs4680 Met/Met genotype. Future studies should be conducted with a larger number of participants and possibly include other genetic variants and treatment outcomes. The trial is registered at ClinicalTrials.gov (#NCT03647774) and the EU Clinical Trial Register (#2017-004706-18).

• Juya, Farid; Sannes, Ann-Christin; Solli, Kristin Klemmetsby; Weimand, Bente; Gjerstad, Johannes & Tanum, Lars Håkon Reiestad [Show all 7 contributors for this article] (2025). Pain Intensity in Patients with Opioid Use Disorder on Extended-Release Naltrexone or Opioid Agonists; The Role of COMT rs4680 and OPRM1 rs1799971: An Exploratory Study. Journal of Pain Research. 18, p. 827–836. doi: 10.2147/JPR.S500984. Full text in Research Archive
• Juya, Farid; Solli, Kristin Klemmetsby; Holtan, Line; Sannes, Ann-Christin; Weimand, Bente & Sagen, Anne Grete [Show all 10 contributors for this article] (2025). Pain intensity in patients using extended-release naltrexone or opioid agonists and its effect on extended-release naltrexone treatment outcomes. American Journal on Addictions. ISSN 1055-0496. 34(5), p. 528–535. doi: 10.1111/ajad.70035. Full text in Research Archive Show summary

  Background and Objectives Extended-release naltrexone (XR-NTX) is an opioid antagonist effective for treating opioid use disorder (OUD). However, concerns about inadequate pain management may limit its use. This study will examine changes in pain intensity in OUD patients choosing XR-NTX compared to opioid agonist treatment (OAT), identify subgroups with distinct pain intensity trajectories, and assess the effect of pain intensity on XR-NTX treatment outcomes (retention, relapse, opioid use, and cravings). Methods This 24-week study included OUD patients aged 18–65 years opting for XR-NTX (n = 160). Patients receiving OAT (n = 151) served as controls. Pain intensity was measured every 4 weeks for XR-NTX and at baseline and Week 24 for OAT using the numerical pain rating scale-11 (NPRS-11). Data were analyzed with linear mixed models and group-based trajectory modeling. Results Between baseline and Week 24, XR-NTX participants with low to moderate pain showed a significant reduction in pain intensity, while those with high pain did not. In the OAT group, no significant reduction in pain intensity was observed (from baseline to Week 24). Pain intensity was not associated with XR-NTX treatment outcomes. Discussion and Conclusions Contrary to perception, XR-NTX does not worsen pain intensity, nor did pain intensity affect XR-NTX treatment outcomes. Scientific Significance This study is the first to explore the association between changes in pain intensity and XR-NTX treatment outcomes in OUD patients over a 24-week period. The findings challenge the perception that XR-NTX is less suitable for treating OUD patients with pain.

• Sommen, Silke Lauren; Zhao, Zhi; Segtnan, Sunniva; Stiansen-Sonerud, Tonje; Selvakumar, Joel Pradeepkumar & Havdal, Lise Beier [Show all 9 contributors for this article] (2024). Bulk RNA sequencing for analysis of post COVID-19 condition in adolescents and young adults. Journal of Translational Medicine. 22(1). doi: 10.1186/s12967-024-05117-7. Full text in Research Archive Show summary

  Background Post COVID19 condition (PCC) is a complication of SARSCOV2 infection and can lead to longterm disability. Methods The present study was designed to analyse the gene expression patterns of PCC through bulk RNA sequencing of whole blood and to explore the potential molecular mechanisms of PCC. Whole blood was collected from 80 participants enrolled in a prospective cohort study following SARSCoV2 infected and non-infected individuals for 6 months after recruitment and was used for bulk RNA sequencing. Identification of differentially expressed genes (DEG), pathway enrichment and immune cell deconvolution was performed to explore potential biological pathways involved in PCC. Results We have found 13 differentially expressed genes associated with PCC. Enriched pathways were related to interferon - signalling and antiviral immune processes. Conclusion The PCC transcriptome is characterized by a modest overexpression of interferon-stimulated genes, pointing to a subtle ongoing inflammatory response.

• Sannes, Ann-Christin; Ghani, Usman; Niazi, Imran Khan; Moberget, Torgeir; Jonassen, Rune & Haavik, Heidi [Show all 7 contributors for this article] (2024). Investigating Whether a Combination of Electro-Encephalography and Gene Expression Profiling Can Predict the Risk of Chronic Pain: A Protocol for an Observational Prospective Cohort Study. Brain Sciences. 14(7). doi: 10.3390/brainsci14070641. Full text in Research Archive
• Zylla, Terese Elisabeth; Wang, Junbai & Gjerstad, Johannes (2024). Social stress in rats promotes transcriptional mitochondrial changes of the adrenal tissue. Endocrine and Metabolic Science. 16. doi: 10.1016/j.endmts.2024.100188. Full text in Research Archive Show summary

  Previous observations suggest that strong social stressors, that is, repeated social defeat, could initiate functional changes in the hypothalamic-pituitary-adrenal (HPA) axis in social mammals. Here, we examine whether exposure to such stress in rats causes persistent alterations in gene expression associated with hypo-and/or hyper-methylation in the adrenal tissue, i.e., the interface between the HPA axis and the circulating hormones. Our integrated analyses of RNA-sequencing (RNAseq) and whole genome bisulfite sequencing (WGBS), suggested that adrenal mitochondrial membrane transport necessary for corticosterone (CORT) synthesis, are affected by repeated social defeat. The increased CORT levels observed in blood in the stressed rats further suggested that corticosterone synthesis might be influenced by this form of social stress. The cellular mechanisms underlying these changes, i.e., the enriched gene ontology (GO)-terms and increased levels of circulating CORT, remain to be investigated.

• Aas, Monica; Andreassen, Ole; Gjerstad, Johannes; Rødevand, Linn; Hjell, Gabriela & Johansen, Ingrid Torp [Show all 12 contributors for this article] (2023). Expression of ANK3 moderates the association between childhood trauma and affective traits in severe mental disorders. Scientific Reports. 13:13845, p. 1–9. doi: 10.1038/s41598-023-40310-6. Full text in Research Archive Show summary

  Exposure to early life trauma increases the risk of psychopathology later in life. Here we investigated if ANK3 mRNA levels influence the relationship between childhood trauma experiences and clinical characteristics in mental disorders. A sample of 174 patients with bipolar disorder and 291 patients with schizophrenia spectrum disorder were included. Patients were diagnosed using the Structured Clinical Interview for DSM-IV, and childhood trauma was assessed using the childhood trauma questionnaire. Age at illness onset and number of psychotic and affective episodes were assessed from interview and medical records. Current depressive symptoms were measured using the calgary depression scale for schizophrenia and the inventory for depressive symptomatology. ANK3 expression was analyzed in whole blood using the Illumina HumanHT-12 v4 Expression BeadChip. Analyses were carried out with the Process adjusted for confounders. Within the total sample, patients with both high ANK3 expression and with the most severe childhood sexual abuse had more manic/hypomanic episodes and an earlier age at onset of the first episode. ANK3 mRNA levels also moderated the relationship between emotional neglect and manic/hypomanic episodes. Our results suggest that ANK3 expression levels moderate the association between specific types of childhood trauma and affective traits in mental disorders.

• Glambek, Mats; Einarsen, Ståle Valvatne; Gjerstad, Johannes & Nielsen, Morten Birkeland (2023). Last in, first out? Length of service as a moderator of the relationship between exposure to bullying behaviors and work-related outcomes. Current Psychology. ISSN 1046-1310. 43, p. 1296–1308. doi: 10.1007/s12144-022-04202-8. Full text in Research Archive Show summary

  In the present study, we proposed and tested a conceptual model of length of service in the organization as a moderator of the relationship between exposure to workplace bullying behaviors and turnover intention, as mediated through job dissatisfaction. Specifically, based on the conservation of resources theory and organizational socialization research, we hypothesized that bullying exposure would be more detrimental to employees relatively new to the organization, and less so to those with a long length of service. We employed a probability sample from the Norwegian workforce (N = 1003), with data collected at two time-points separated by six months. In line with previous research, we found that exposure to workplace bullying behaviors predicts increased levels of stability-adjusted turnover intentions, and, that job dissatisfaction mediates this association. Moreover, the mediation effect was dependent on length of service, such that it only was present at average (50th percentile; 8.5 years) and short employment length (16th percentile; 2.5 years), and was significantly stronger for the latter group. Additionally, a Johnson-Neyman test of significance regions revealed that the moderation effect became non-significant at the 69th percentile (14.6 years of length of service) in the present sample. This indicates that while short length of service represents a risk condition for work-related outcomes of bullying exposure, long length of service may represent a resource relating to individual resilience that accumulates over long time-spans.

• Nielsen, Morten Birkeland; Gjerstad, Johannes & Einarsen, Ståle Valvatne (2023). The Moderating Role of Transformational Leadership in the Relationships between Job Demands and Turnover Intentions. Scandinavian Journal of Work and Organizational Psychology. 8(1). doi: 10.16993/sjwop.193. Full text in Research Archive Show summary

  There is a shortage of knowledge about how different job demands influence turnover among employees. This study determines cross-sectional and prospective associations between challenge demands (quantitative demands), hindrance demands (role ambiguity and role conflict), and threat demands (workplace bullying), respectively, with turnover intentions and examine whether transformational leadership buffers the effects of the examined job demands on turnover intentions. Data were from a national probability survey comprising 1,149 Norwegian employees with two waves (response rate at baseline: 32%). Time-lag between baseline and follow-up was six months. Hindrance and threat demands, but not challenge demands, were associated with turnover intentions in multivariate analyses of the cross-sectional data, with workplace bullying as the strongest correlate. Workplace bullying emerged as the only predictor of changes in turnover intentions in the prospective data. High levels of transformational leadership buffered the association between challenge and hindrance demands with turnover intentions cross-sectionally but had no moderating effect on workplace bullying in neither the cross-sectional nor the prospective data. Turnover and related withdrawal behaviors are expensive for organizations, so discovering the factors that may lead to turnover is important for the organization’s ability to reduce levels of turnover intentions among employees. Our findings point to transformational leadership as beneficial regarding challenge and hindrance demands. However, other measures and interventions are necessary to reduce the negative impact of threat demands.

• Ågotnes, Kari Wik; Nielsen, Morten Birkeland; Skogstad, Anders; Gjerstad, Johannes & Einarsen, Ståle Valvatne (2023). The role of leadership practices in the relationship between role stressors and exposure to bullying behaviours–a longitudinal moderated mediation design. Work & Stress - An International Journal of Work, Health & Organisations. ISSN 0267-8373. 38(1), p. 44–72. doi: 10.1080/02678373.2023.2226635. Full text in Research Archive Show summary

  Role conflicts and role ambiguity have been identified as important risk factors for exposure to workplace bullying, particularly when combined with inadequate leadership practices. Even though role ambiguity theoretically can be considered a causal precursor to role conflicts, previous research has mainly examined these role stressors as concurrent predictors of workplace bullying. The present study provides a more nuanced analysis by investigating role conflicts as a mediator in the relationship between role ambiguity and exposure to bullying behaviours. Adding to the understanding of the bullying process we also considered the possible moderating roles of laissez-faire and transformational leadership in the role stressor–bullying relationship. Employing a national probability sample of 1,164 Norwegian workers, with three measurements across a 12-month period, the results showed an indirect effect of employees’ role ambiguity on subsequent exposure to bullying behaviours through employees’ experience of role conflicts. Moreover, laissez-faire leadership exacerbated, while transformational leadership attenuated, the indirect relationship between role ambiguity and exposure to bullying behaviours through role conflicts. In summary, the present data shows that when the management of organisations neglects its inherent responsibility to adequately address employees’ experiences of role ambiguity and role conflicts, the risk of exposure to workplace bullying is likely to increase.

• Olsen, Maria Belland; Sannes, Ann-Christin; Yang, Kuan; Nielsen, Morten Birkeland; Einarsen, Ståle Valvatne & Christensen, Jan Olav [Show all 9 contributors for this article] (2022). Mapping of pituitary stress-induced gene regulation connects Nrcam to negative emotions. iScience. 25(9). doi: 10.1016/j.isci.2022.104953. Full text in Research Archive Show summary

  Environmental stressors such as repeated social defeat may initiate powerful activation of subconscious parts of the brain. Here, we examine the consequences of such stress (induced by resident-intruder paradigm) on the pituitary gland. In male stressed vs. control rats, by RNA- and bisulfite DNA sequencing, we found regulation of genes involved in neuron morphogenesis and communication. Among these, Neuronal cell adhesion molecule (Nrcam) showed reduced transcription and reduced DNA methylation in a region corresponding to intron 1 in human NRCAM. Also, genetic variability in this area was associated with altered stress response in male humans exposed to repeated social defeat in the form of abusive supervision. Thus, our data show that the pituitary gene expression may be affected by social stress and that genetic variability in NRCAM intron 1 region influences stress-induced negative emotions. We hope our shared datasets will facilitate further exploration of the motions triggered by social stressors.

• Sannes, Ann-Christin; Christensen, Jan Olav; Nielsen, Morten Birkeland & Gjerstad, Johannes (2022). Stress-induced headache in the general working population is moderated by the NRCAM rs2300043 genotype. Scandinavian Journal of Pain. ISSN 1877-8860. doi: 10.1515/sjpain-2022-0094. Full text in Research Archive Show summary

  Earlier findings suggest that social stress such as abusive supervision may promote pain. In the present study we examine the possible moderating role of genetic variability in the NRCAM gene in this process. The data were collected through a national survey drawn from the National Central Employee Register by Statistics Norway. A total of 1,205 individuals returned both the questionnaire and the saliva kit. Abusive supervision was scored by a 5-item version of the Tepper's 2,000 scale. Headache was measured on a four-category scale; 'not bothered,' 'a little bothered,' 'considerably bothered', 'seriously bothered'. Genotyping with regards to NRCAM rs2300043 was carried out using Taqman assay. Ordinal logistic regression was used to analyse the data. For males exposed to abusive supervision, those carrying the rs2300043 CC genotype reported the highest levels of headache. Women showed a trend towards the opposite pattern. Women with the rs2300043 CC genotype seem to have a weaker effect of abusive supervision regarding reported headache than their male counterparts with the CC genotype when exposed to abusive supervision. The present results indicated that the association between abusive supervision and headache in men with the NRCAM rs2300043 C allele was stronger than in other men. This suggests that the NRCAM genotype in men is important for the tolerance of social stress e.g., repeated negative acts from a superior. In contrast, a trend, though non-significant, towards the opposite pattern was observed in women. Our result suggests that the NRCAM genotype in men manifestly affects stress-induced pain such as headache.

• Lie, Marie; Pedersen, Linda Margareth; Heuch, Ingrid; Winsvold, Bendik K S; Gjerstad, Johannes & Hasvik, Eivind Olay [Show all 11 contributors for this article] (2022). Low Back Pain With Persistent Radiculopathy; the Clinical Role of Genetic Variants in the Genes SOX5, CCDC26/GSDMC and DCC. Frontiers in Genetics. 12(12). doi: 10.3389/fgene.2021.757632. Full text in Research Archive Show summary

  In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; SOX5, CCDC26/GSDMC and DCC. This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months (n = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.

• Nielsen, Morten Birkeland; Hetland, Jørn; Harris, Anette Kristoffersen; Notelaers, Guy Louis Alice; Gjerstad, Johannes & Einarsen, Ståle Valvatne (2022). The impact of follower leadership position on transformational leadership as moderator of the association between work-related ambiguity and job satisfaction. Frontiers in Psychology. 13. doi: 10.3389/fpsyg.2022.970887. Full text in Research Archive Show summary

  This two-part study examined if the buffering effect of transformational leadership on the association between work-related ambiguity and job satisfaction is contingent upon whether a follower holds a formal leadership position him/herself. Data from two separate surveys were employed: Study 1: A sample of 845 respondents from Belgium. Study 2: A national probability sample of 1,608 Norwegian employees. Study 1 showed that task ambiguity had a significant negative relation with job satisfaction, but that transformational leadership did only buffer the association between task ambiguity and job satisfaction among employees holding a formal position as a supervisor or manager. Study 2 extended Study 1 by adjusting for age and job tenure of subordinates as a confounding variable. Study 2 confirmed that transformational leadership had a significantly stronger impact on the observed association between role ambiguity and job satisfaction among respondents holding a supervisor or manager position. In conclusion, when considering job satisfaction as an outcome of work-related ambiguity, transformational leadership is mainly beneficial for followers holding a formal supervisor or manager position themselves. Our findings thereby question assumptions about the general effectiveness of transformational leadership.

• Rajalingam, Dhaksshaginy; Nymoen, Ingeborg; Nyberg, Henriette; Nielsen, Morten Birkeland; Einarsen, Ståle Valvatne & Gjerstad, Johannes (2021). Workplace bullying increases the risk of anxiety through a stress-induced β2-adrenergic receptor mechanism: a multisource study employing an animal model, cell culture experiments and human data. International Archives of Occupational and Environmental Health. ISSN 0340-0131. 94, p. 1905–1915. doi: 10.1007/s00420-021-01718-7. Full text in Research Archive Show summary

  Objectives Several studies show that severe social stressors, e.g., in the form of exposure to workplace bullying in humans, is associated with negative mental health effects such as depression and anxiety among those targeted. However, the understanding of the underlying biological mechanisms that may explain the relationship between exposure to bullying and such negative health outcomes is scarce. The analyses presented here focus on understanding the role of the β2-adrenergic receptors (ADRB2) on this association. Methods First, a resident-intruder paradigm was used to investigate changes in circulating norepinephrine (NE) in rat serum induced by repeated social defeat and its relationship with subsequent social behavior. Second, the direct effects of the stress-hormones NE and cortisol, i.e., synthetic dexamethasone (DEX), on the ADRB2 expression (qPCR) and monocyte chemoattractant protein-1 (MCP-1) release (immunoassay) was examined in cultured EL-1 cells. Third, in a probability sample of 1052 Norwegian employees, the 9-item short version of the Negative Acts Questionnaire—Revised (S-NAQ) inventory, Hopkins Symptom Checklist and genotyping (SNP TaqMan assay) were used to examine the association between social stress in the form of workplace bullying and anxiety moderated by the ADRB2 genotype (rs1042714) in humans. Results The present study showed a clear association between reduced social interaction and increased level of circulating NE in rats previously exposed to repeated social defeat. Parallel cell culture work, which was performed to examine the direct effects of NE and DEX on ADRB2, demonstrated ADRB2 downregulation and MCP-1 upregulation in cultured EL-1 cells. Genotyping with regard to the ADRB2 genotype; rs1042714 CC vs CG/GG, on human saliva samples, showed that individuals with CC reported more anxiety following exposure to bullying behaviors as compared to the G carriers. Conclusion We conclude that workplace bullying promotes anxiety and threaten well-being through an ADRB2 associated mechanism.

• Nielsen, Morten Birkeland; Pallesen, Ståle; Einarsen, Ståle; Harris, Anette; Rajalingam, Dhaksshaginy & Gjerstad, Johannes (2021). Associations between exposure to workplace bullying and insomnia. A cross-lagged prospective study of causal directions. International Archives of Occupational and Environmental Health. ISSN 0340-0131. 94, p. 1003–1011. doi: 10.1007/s00420-020-01618-2. Full text in Research Archive Show summary

  Objective Workplace bullying has been established as a significant correlate of sleep problems. However, little is known regarding the causal direction between bullying and sleep. The aim of this study was to examine temporal relationships between bullying and symptoms of insomnia. Methods Reciprocal and prospective associations between exposure to workplace bullying and symptoms of insomnia were investigated in a national probability sample comprising 1149 Norwegian employees. Data stemmed from a two-wave full panel survey study with a 6-month time interval between the baseline and follow-up assessments. Models with stabilities, forward-, reverse-, and reciprocal associations were tested and compared using Structural Equation Modelling. Analyses were adjusted for age, gender, and the stability in the outcome variables over time. Workplace bullying was assessed with the nine-item Short Negative Acts Questionnaire. Insomnia was assessed with a previously validated three item scale reflecting problems with sleep onset, sleep maintenance, and early morning awakening. Results The forward association model, which showed that exposure to workplace bullying prospectively increased levels of insomnia (b = 0.08; p < 0.001), had best fit with the data [CFI = 0.94; TLI = 0.93; RMSEA = 0.049 (0.046–0.052)]. The reverse association model where insomnia influences risk of being subjected to bullying was not supported. Conclusion Workplace bullying is a risk factor for later insomnia. There is a need for further studies on moderating and mediating variables that can explain how and when bullying influence sleep.

• Hamre, Kristina Vaktskjold; Fauske, Margrethe Ringen; Reknes, Iselin; Nielsen, Morten Birkeland; Gjerstad, Johannes & Einarsen, Ståle Valvatne (2021). Preventing and Neutralizing the Escalation of Workplace Bullying. The Role of Conflict Management Climate. International Journal of Bullying Prevention. ISSN 2523-3653. doi: 10.1007/s42380-021-00100-y. Full text in Research Archive Show summary

  Workplace bullying is, by definition, a gradually escalating process, theorized to occur from psychosocial stressors when there is a lack of management intervention in escalating conflicts, and a lack of fair and robust conflict management procedures in the organization. Based on national probability survey data gathered in 2015–2016 from the official Norwegian employee-register, we investigated how a strong perceived climate for conflict management may buffer the escalation of workplace bullying over time. A total of 1197 respondents participated in the study at two measuring points. The average age at baseline was 45.20 years (SD = 9.98), and the sample consisted of 52.1% women and 47.9% men. Structural equation modelling in Mplus 7.4 was used to test the construct validity and the study’s hypothesis. As expected, the analyses showed that a strong conflict management climate buffered the escalation of workplace bullying. Exposure to bullying behaviour at T1 largely explained (47%) new and increased instances of bullying behaviour at T2, but only for those employees working in what they perceived as a weak conflict management climate. We conclude that a strong conflict management climate neutralizes the escalation and development of workplace bullying.

• Sannes, Ann-Christin; Christensen, Jan Olav; Matre, Dagfinn; Nielsen, Morten Birkeland & Gjerstad, Johannes (2021). Patterns of pain complaints and insomnia symptoms are associated with abusive supervision in the Norwegian working population: A latent class analysis. Scandinavian Journal of Pain. ISSN 1877-8860. 22(1), p. 118–124. doi: 10.1515/sjpain-2021-0124. Full text in Research Archive Show summary

  Objectives Previous findings suggest that abusive supervision, i.e., subordinates’ perceptions of their supervisor’s behaviours as hostile (excluding physical aggression), may increase the risk of health complaints. In addition, recent data suggest that the FKBP5 genotype rs9470080 important in the regulation of cortisol release, influences the same outcome. Adding to this complexity, different health complaints often co-occur. The present study aimed to (1) uncover patterns of pain complaints and insomnia symptoms by using latent class analysis, (2) determine whether abusive supervision or FKBP5 rs9470080 was associated with these patterns, and (3) examine the interaction between abusive supervision and FKBP5 genotype regarding pain and insomnia symptoms. Methods The data was collected through a national probability survey of 5,000 employees drawn from the National Central Employee Register by Statistics Norway. Abusive supervision was measured by a 5-item version of the Tepper’s 2000 scale. Pain and insomnia symptoms were measured by 5 items reflecting pain and 3 items reflecting insomnia. The FKBP5 rs9470080 genotyping was carried out using TaqMan assay. Results A total of 1,226 participants returned the questionnaire and the saliva kit sample. Based on these the latent class analyses revealed four classes based on response patterns of pain and insomnia symptoms. In the regression analysis, abusive supervision was a significant predictor for the response patterns. However, neither the FKBP5 nor the interaction between abusive supervision and FKBP5 showed significant contributions. Conclusions In conclusion, awareness of the association between abusive supervision and the revealed four pain- and insomnia subgroups, and what separates them, may be important for prognosis and an optimal follow-up for those affected.

• Sannes, Ann-Christin; Christensen, Jan Olav; Nielsen, Morten Birkeland & Gjerstad, Johannes (2021). The association between abusive supervision and anxiety in female employees is stronger in carriers of the CRHR1 TAT haplotype. Current Research in Behavioral Sciences (CRBS). 2. doi: 10.1016/j.crbeha.2021.100021. Full text in Research Archive Show summary

  Objective Previous findings suggest that exposure to social stress in the form of abusive supervision may increase the risk of anxiety disorders. In the present study, we examined the link between abusive supervision, the CRHR1 genotype and anxiety. Methods The data was collected through a national survey drawn from the National Central Employee Register by Statistics Norway. A total of 1225 individuals returned both the questionnaire and the saliva kit. Abusive supervision was assessed with 5 items from the Tepper's “Abusive Supervision Scale”. Anxiety was measured by 5 items of the “Hopkins Symptom checklist”. Genotyping with regard to CRHR1 rs7209436 C/T, rs110402 G/A and rs242924 G/T was carried out using Taqman assay, and Phase v.2.1.1 was used to define the CRHR1 haplotype TAT versus CGG. Results The analyses revealed that abusive supervision was associated with anxiety. In particular, we observed a strong effect of abusive supervision on anxiety in female TAT/TAT carriers (p = 0.000). Moreover, using TAT/TAT as a reference, TAT/CGG and CGG/CGG both showed protective effects (p = 0.015, p = 0.001, respectively). Thus, the association between abusive supervision and anxiety was strong among female TAT/TAT carriers was stronger than among female TAT/CGG and female CGG/CGG carriers. No such gene-environment interaction was seen in men. Conclusion Our data demonstrated that the CRHR1 TAT haplotype may exacerbate, whereas the CRHR1 CGG haplotype may reduce, the effect of abusive supervision on anxiety in female employees. Hence, the present study supports the theory that both gender and the CRHR1 genotype, moderate the responses to social stressors.

• Sannes, Ann-Christin; Risøy, Andrine; Christensen, Jan Olav; Nielsen, Morten Birkeland & Gjerstad, Johannes (2021). Spinal pain in employees exposed to abusive supervision: Evidence of a sex and CRHR1 CTC haplotype interaction. Molecular Pain. 17. doi: 10.1177/17448069211042123. Full text in Research Archive Show summary

  Previous findings suggest that exposure to social stress in the form of abusive supervision may increase the risk of musculoskeletal disorders. In the present study, we examined the link between abusive supervision, the CRHR1 genotype and spinal pain. The data were collected through a national survey drawn from the National Central Employee Register by Statistics Norway. A total of 1226 individuals returned both the questionnaire and the saliva kit. Abusive supervision was measured by a 5-item version of the Tepper’s 2000 scale. Spinal pain was measured by 3 items (neck-, upper and low back pain). Genotyping with regard to CRHR1 rs242941, rs242939 and rs1876828 was carried out using Taqman assay, and Phase v.2.1.1 was used to define the CRHR1 allele combinations. The analyses revealed that abusive supervision was associated with spinal pain. In particular, we observed a strong effect of abusive supervision on spinal pain in female +CTC/+CTC carriers (p = 0.002). Moreover, using +CTC/+CTC as a reference, +CTC/−CTC and −CTC/−CTC both showed protective effects (p = 0.024, p = 0.002, respectively). Also, our data demonstrated a clear sex and CRHR1 CTC haplotype interaction (p = 0.013). No such gene-environment interaction was seen in men. Our data demonstrated that the CRHR1 CTC haplotype may exacerbate the effect of abusive supervision on spinal pain in female employees. Hence, the present study supports the theory that both gender and the CRHR1 genotype, may moderate the pain responses to social stressors.

• Christensen, Jan Olav; Nielsen, Morten Birkeland; Sannes, Ann-Christin & Gjerstad, Johannes (2021). Leadership style, headache, and neck pain the moderating role of the catechol-o-methyltransferase (comt) genotype. Journal of Occupational and Environmental Medicine. ISSN 1076-2752. 63(2), p. 151–158. doi: 10.1097/JOM.0000000000002103. Full text in Research Archive Show summary

  Objective: Leadership styles can influence subordinates’ health. We investigated how the gene encoding the Catechol-O-Methyltransferase (COMT) enzyme (ie, COMT rs4680 Val158Met) influenced effects of abusive supervision and transformational leadership on subordinates’ headache and neck pain. Methods: Multiple group structural equation modeling (SEM) was employed to test associations of leadership with subordinates’ pain 6 months after in a representative sample of the Norwegian working population (n = 996). Genotyping was performed by TaqMan technology. Results: Abusive supervision was associated with increased risk, and transformational leadership with decreased risk, of headache and neck pain. Both leadership styles exhibited more pronounced effects in individuals with the Met/Met genotype. Conclusion: Met/Met employees were relatively vulnerable to adversity, but also relatively responsive to constructive leadership. Many workers may benefit more from constructive leadership than population-averaged associations might suggest.

• Lie, Marie; Winsvold, Bendik; Gjerstad, Johannes; Matre, Dagfinn; Pedersen, Linda Margareth & Heuch, Ingrid [Show all 8 contributors for this article] (2020). The association between selected genetic variants and individual differences in experimental pain. Scandinavian Journal of Pain. ISSN 1877-8860. 21(1), p. 163–173. doi: 10.1515/sjpain-2020-0091. Full text in Research Archive Show summary

  Objectives The underlying mechanisms for individual differences in experimental pain are not fully understood, but genetic susceptibility is hypothesized to explain some of these differences. In the present study we focus on three genetic variants important for modulating experimental pain related to serotonin (SLC6A4 5-HTTLPR/rs25531 A>G), catecholamine (COMT rs4680 Val158Met) and opioid (OPRM1 rs1799971 A118G) signaling. We aimed to investigate associations between each of the selected genetic variants and individual differences in experimental pain. Methods In total 356 subjects (232 low back pain patients and 124 healthy volunteers) were genotyped and assessed with tests of heat pain threshold, pressure pain thresholds, heat pain tolerance, conditioned pain modulation (CPM), offset analgesia, temporal summation and secondary hyperalgesia. Low back pain patients and healthy volunteers did not differ in regards to experimental test results or allelic frequencies, and were therefore analyzed as one group. The associations were tested using analysis of variance and the Kruskal-Wallis test. Results No significant associations were observed between the genetic variants (SLC6A4 5-HTTLPR/rs25531 A>G, COMT rs4680 Val158Met and OPRM1 rs1799971 A118G) and individual differences in experimental pain (heat pain threshold, pressure pain threshold, heat pain tolerance, CPM, offset analgesia, temporal summation and secondary hyperalgesia). Conclusions The selected pain-associated genetic variants were not associated with individual differences in experimental pain. Genetic variants well known for playing central roles in pain perception failed to explain individual differences in experimental pain in 356 subjects. The finding is an important contribution to the literature, which often consists of studies with lower sample size and one or few experimental pain assessments.

• Sannes, Ann-Christin; Christensen, Jan Olav; Nielsen, Morten Birkeland & Gjerstad, Johannes (2020). The influence of age, gender and the FKBP5 genotype on subjective health complaints in the Norwegian working population. Journal of Psychosomatic Research. ISSN 0022-3999. 139: 110264. doi: 10.1016/j.jpsychores.2020.110264. Full text in Research Archive Show summary

  Objective In the present study we examined the potential association between age, gender, the genetic variant FKBP5 rs9470080 and subjective health complaints. Methods The data were collected through a three-wave nationally representative survey of 1060 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. The follow-up period was six months. Subjective health complaints were scored by eight items reflecting; headache, neck pain, mid- and low back pain, stomach cramps or intestinal discomfort, problems with sleep onset or maintenance and early morning awakening. Genotyping with regard to FKBP5 rs9470080, previously linked to cortisol sensitivity, was carried out using Taqman assay. Results The baseline data showed that in women, levels of subjective health complaints were highest among those above 50 years of age. Moreover, in women the rs9470080 CC variant at baseline was associated with higher levels of subjective health complaints. However, the effect size was not large, and no relationships were demonstrated between age or genotype and subjective health complaints in men. Also, the study variables were not related to any changes in the levels of subjective health complaints during the follow-up period. Conclusion We conclude that our biology such as age and sex, but also single genetic variants found in non-sex chromosomes, may be important in understanding the mechanisms underlying subjective health complaints in the general working population.

• Rajalingam, Dhaksshaginy; Nymoen, Ingeborg; Jacobsen, Daniel Pitz; Eriksen, Mina Baarnes; Dissen, Erik & Nielsen, Morten Birkeland [Show all 8 contributors for this article] (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. 21:25. doi: 10.1186/s12868-020-00574-4. Full text in Research Archive Show summary

  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.

• 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. 10:1204(MAY), p. 1–7. doi: 10.3389/fpsyg.2019.01204. Full text in Research Archive Show summary

  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.

• Jacobsen, Daniel Pitz; Eriksen, Mina Baarnes; Rajalingam, Dhaksshaginy; Nymoen, Ingeborg; Nielsen, Morten Birkeland & Einarsen, Ståle [Show all 7 contributors for this article] (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), p. 77–86. doi: 10.1080/10253890.2019.1642320. Full text in Research Archive Show summary

  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.

• Nguyen, Chinh BKrong; Kumar, Surendra; Zucknick, Manuela; Kristensen, Vessela N.; Gjerstad, Johannes & Nilsen, Hilde Loge [Show all 7 contributors for this article] (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, p. 82–96. doi: 10.1016/j.bbi.2018.11.008. Full text in Research Archive Show summary

  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. 12(1). doi: 10.1186/s13104-019-4592-6. Full text in Research Archive Show summary

  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.

• 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. 10, p. 1–12. doi: 10.3389/fpsyg.2019.00044. Full text in Research Archive Show summary

  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.

• 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. Full text in Research Archive Show summary

  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.

• Hasvik, Eivind Olay; Schjølberg, Tiril; Jacobsen, Daniel Pitz; Haugen, Anne Julsrud; Grøvle, Lars & Schistad, Ellina Iordanova [Show all 7 contributors for this article] (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. Full text in Research Archive Show summary

  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

• 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, p. 224–229. doi: 10.1016/j.sleep.2019.04.009. Full text in Research Archive Show summary

  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.

• 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), p. E774–E781. doi: 10.1097/BRS.0000000000002976. Full text in Research Archive Show summary

  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

• 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 - An International Journal of Work, Health & Organisations. ISSN 0267-8373. 33(2), p. 137–155. doi: 10.1080/02678373.2018.1528307. Full text in Research Archive Show summary

  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.

• 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, p. 73–75. doi: 10.1016/j.jpsychores.2018.01.010. Full text in Research Archive Show summary

  Objective: The association between exposure to bullying at work and subsequent pain reports is relatively well-established, but few studies have examined possible moderators of this relationship. As gender is a known risk factor for pain, with women reporting pain levels of higher intensity and longer duration, a possible gender difference in the relationship between bullying and pain has been suggested, but not sufficiently tested. The objective of the present study was therefore to examine whether gender moderates the prospective relationship between exposure to workplace bullying behaviours and subsequent subjective back and neck pain. Methods: A national probability sample of Norwegian workers (N = 1003) was collected at two time points with a six-month time-lag. Assumptions were tested using regression and moderation analyses. Results: Exposure to bullying behaviours was associated with increased reports of subjective back and neck pain over time, and this relationship was moderated by gender. However, the interaction took a different form than expected, with back and neck pain increasing in response to bullying among men only, to a degree that nullified the baseline gender difference. Conclusion: The assumption that being female is a vulnerability factor for the development of pain in the aftermath of psychosocial stressors such as bullying was contradicted in the present study. Instead, women's relatively high baseline pain levels remain stable over time even after exposure to workplace bullying, while men's relatively low baseline pain levels increase in response to bullying, ultimately becoming tangent to the pain reported by women.

• 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), p. 2585–2592. doi: 10.1097/j.pain.0000000000001370. Full text in Research Archive Show summary

  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), p. 168–174. doi: 10.1097/j.pain.0000000000001081. Full text in Research Archive Show summary

  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.

• Schistad, Ellina Iordanova; Bjorland, Siri; Røe, Cecilie; Gjerstad, Johannes; Vetti, Nils & Myhre, Kjersti [Show all 7 contributors for this article] (2018). Five-year development of lumbar disc degeneration—a prospective study. Skeletal Radiology. ISSN 0364-2348. 48(6), p. 871–879. doi: 10.1007/s00256-018-3062-x. Full text in Research Archive Show summary

  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.

• 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), p. 96–98. doi: 10.1093/occmed/kqy014. Full text in Research Archive Show summary

  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.

• Mahmood, Aqsa; Moen, Aurora Lie; Stafne, Signe Nilssen; Robinson, Hilde Stendal; Vøllestad, Nina Køpke & Salvesen, Kjell Å [Show all 8 contributors for this article] (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), p. 93–98. doi: 10.1515/sjpain-2017-0168. Full text in Research Archive Show summary

  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.

• 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), p. 283–290. doi: 10.5271/sjweh.3704. Full text in Research Archive Show summary

  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.

• 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), p. 1160–1169. doi: 10.1002/ejp.1204. Full text in Research Archive Show summary

  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.

• Moen, Aurora Lie; Jacobsen, Daniel; Phuyal, Santosh; Legfeldt, Anna; Haugen, Fred & Røe, Cecilie [Show all 7 contributors for this article] (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. 15(89), p. 1–11. doi: 10.1186/s12967-017-1194-8. Full text in Research Archive Show summary

  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.

• 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), p. 574–584. doi: 10.1080/10826084.2017.1349797. Full text in Research Archive Show summary

  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. 8:1953, p. 1–11. doi: 10.3389/fpsyg.2017.01953. Full text in Research Archive Show summary

  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.

• 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, p. 181–186. doi: 10.1016/j.cyto.2017.06.005. Full text in Research Archive Show summary

  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.

• 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), p. 1–10. doi: 10.1037/str0000073. Full text in Research Archive Show summary

  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), p. 1456–1460. doi: 10.1097/j.pain.0000000000000934. Full text in Research Archive Show summary

  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; Lind, Anne-Li; Thulin, Måns; Kamali-Moghaddam, Masood; Røe, Cecilie & Gjerstad, Johannes [Show all 7 contributors for this article] (2016). Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation. International Journal of Inflammation. ISSN 2090-8040. 2016. doi: 10.1155/2016/3874964. Full text in Research Archive Show summary

  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.

• 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 2090-8040. doi: 10.1155/2016/6519408. Full text in Research Archive Show summary

  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.

• Hall, Karhryn T.; Kossowsky, Joe; Oberlander, Tim F.; Kaptchuk, Ted J.; Saul, J. Philip & Wyller, Vegard Bruun [Show all 11 contributors for this article] (2016). Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome. The Pharmacogenomics Journal. ISSN 1470-269X. 16(5), p. 454–460. doi: 10.1038/tpj.2016.53. Full text in Research Archive Show summary

  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.

• 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), p. 13711–3723. doi: 10.1007/s00213-016-4403-x. Full text in Research Archive Show summary

  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.

• 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. 17(1), p. 1–10. doi: 10.1186/s12891-016-1356-5. Full text in Research Archive Show summary

  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.

• Meyer, Benedicte; Nguyen, Chinh Bkrong Thi Thuy; Moen, Aurora; Fagermoen, Frode Even; Sulheim, Dag & Nilsen, Hilde [Show all 8 contributors for this article] (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. 10(10). doi: 10.1371/journal.pone.0140883. Full text in Research Archive Show summary

  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, p. 132–136. doi: 10.1016/j.bbi.2015.01.008. Full text in Research Archive Show summary

  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.

• Fagermoen, Frode Even; Sulheim, Dag; Winger, Anette; Andersen, Anders Mikal; Gjerstad, Johannes & Godang, Kristin [Show all 10 contributors for this article] (2015). Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: A randomized controlled trial. BMC Pediatrics. 15. doi: 10.1186/s12887-015-0428-2. Full text in Research Archive Show summary

  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.

• 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), p. 1394–1401. doi: 10.1002/j.1532-2149.2014.502.x. Full text in Research Archive Show summary

  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. 9(9). doi: 10.1371/journal.pone.0107301. Full text in Research Archive Show summary

  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.

• 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. 15(1). doi: 10.1186/1471-2474-15-161. Full text in Research Archive Show summary

  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.

• Nielsen, Morten Birkeland; Magerøy, Nils; Gjerstad, Johannes & Einarsen, Ståle (2014). Mobbing i arbeidslivet og senere helseplager. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 134(12/13), p. 1233–1238. doi: 10.4045/tidsskr.13.0880. Full text in Research Archive Show summary

  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; 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), p. 869–874. doi: 10.1097/AJP.0000000000000048. Full text in Research Archive Show summary

  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.

• 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), p. 1271–1279. doi: 10.1007/s00256-014-1928-0. Full text in Research Archive Show summary

  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.

• Dominguez, Cecilia A.; Kalliomäki, Maija; Gunnarsson, Ulf; Moen, Aurora; Sandblom, Gabriel & Kockum, Ingrid [Show all 14 contributors for this article] (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), p. 427–433. doi: 10.1016/j.pain.2012.12.003. Full text in Research Archive Show summary

  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.

• 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, p. 54–59. doi: 10.1016/j.brainres.2012.10.045. Full text in Research Archive Show summary

  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.

• Jacobsen, Line Melå; Schistad, Elina Iordanova; Storesund, Anette; Pedersen, Linda Margareth; Espeland, Ansgar & Rygh, Lars Jørgen [Show all 8 contributors for this article] (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), p. 967–971. doi: 10.1097/AJP.0b013e31827df7fd. Full text in Research Archive Show summary

  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

• 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), p. 1743–1748. doi: 10.1016/j.pain.2013.05.034. Full text in Research Archive Show summary

  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

• 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), p. 234–237. doi: 10.1016/j.brainresbull.2011.11.009. Full text in Research Archive Show summary

  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 [Show all 7 contributors for this article] (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), p. 1064–1069. doi: 10.1002/j.1532-2149.2011.00102.x. Full text in Research Archive Show summary

  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 [Show all 7 contributors for this article] (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), p. 9831–9834. doi: 10.1523/JNEUROSCI.1742-12.2012. Full text in Research Archive Show summary

  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), p. 293–298. doi: 10.1111/j.1651-2227.2010.02072.x. Full text in Research Archive Show summary

  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.

• 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), p. 255–260. doi: 10.1016/j.ejpain.2009.05.016. Full text in Research Archive Show summary

  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.

• Hjornevik, Trine; Schoultz, Bent Wilhelm; Marton, Janos; Gjerstad, Johannes; Drzezga, Alexander & Henriksen, Gjermund [Show all 7 contributors for this article] (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), p. 285–293. doi: 10.1111/j.1475-097X.2010.00939.x. Full text in Research Archive Show summary

  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 [Show all 7 contributors for this article] (2010). Langvarige korsryggsmerter og MR-forandringer i ryggvirvlene :. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 130(22), p. 2260–2263. doi: 10.4045/tidsskr.09.0122. Full text in Research Archive Show summary

  Bakgrunn: Selv om korsryggssmerter som oftest går over av seg selv, blir en del pasienter ikke bedre og trenger behandling. Det er derfor viktig å klargjøre hvilke forhold som bidrar til smertene. Vi gir her en oversikt over ny forskning omkring MR-funn og genetiske forhold som kan ha betydning for utviklingen av langvarige korsryggssmerter. Materiale og metode: Utgangspunkt for denne oversikten er et ikke-systematisk søk i PubMed og EMBASE. Forfatternes kjennskap til feltet er bakgrunn for valg av artikler. Resultater: Tradisjonelt har man antatt at korsryggssmerter ofte stammer fra mellomvirvelskiver, fasettledd og lumbale ryggmuskler. Men det har også lenge vært kjent at mange pasienter med fremtredende skivedegenerasjon har såkalte Modic-forandringer, dvs. MR-forandringer i beinmargen ved ryggvirvlenes endeplater. I flere nye studier er det påvist en sammenheng mellom slike forandringer og smerte. Det er også vist at pasienter med Modic-forandringer og korsryggssmerter ofte har en pågående lokal inflammasjonstilstand, med innvekst av smertefibre i endeplatene. I hvilken grad dette skjer, kan være delvis genetisk betinget. Fortolkning: Genetiske faktorer kan bidra til korsryggssmerter. Mer kunnskap om genetikk og Modic-forandringer kan danne grunnlag for bedre diagnostikk og mer spesifikk behandling av pasienter med langvarige korsryggssmerter.

• 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), p. 212–215. doi: 10.1016/j.neulet.2010.02.049. Full text in Research Archive Show summary

  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.

• 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, p. 456–464. doi: 10.1016/j.pain.2008.09.029. Full text in Research Archive Show summary

  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), p. 421–427. Full text in Research Archive
• Gjerstad, Johannes (2007). Genetic susceptibility and development of chronic non-malignant back pain. Reviews in the Neurosciences. ISSN 0334-1763. 18(1), p. 83–91. doi: 10.1515/revneuro.2007.18.1.83. Full text in Research Archive Show summary

  Previous data indicate that persistent pain states often involve sensitization within the central nervous system (CNS). Many recently described human genetic variants may affect these central processes. Genetic variability influences both synthesis and function of proteins affecting the plasticity of the CNS. Hence, individual genetic variability may be important to understand the development of many persistent pain conditions including chronic nonmalignant back pain. In this review we argue that genotyping of each patient may be a valuable complement to diagnosis of back disorders. This may be important for future prescription of medicine to individuals predisposed for persistent pain. Increased understanding of genetic variability may also improve multidisciplinary and cognitive-behavioral approaches to management of persistent pain. Translation of this information from the laboratory into clinical application will be important for future prevention as well as treatment of long-lasting non-malignant pain conditions.

• Gjerstad, Johannes; Valen, E.C.; Trotier, Didier & Døving, Kjell Bjarne (2003). Photolysis of caged inositol 1,4,5-triphosphate induces action potentials in frog vomeronasal microvillar receptor neurones. Neuroscience. ISSN 0306-4522. 119(1), p. 193–200. doi: 10.1016/S0306-4522(03)00115-5. Full text in Research Archive Show summary

  To study the effect of inositol 1,4,5-trisphosphate (IP3) in isolated frog vomeronasal microvillar receptor neurones, whole-cell recordings were performed with 0.5 μM caged IP3 dissolved in the pipette solution. IP3 was released by photolysis of caged IP3 initiated by a 0.8-ms ultraviolet flash from a xenon flash lamp 70 s after the start of dialysis of caged IP3 into the cell. Flash illuminating the whole receptor neurone with caged IP3 triggered action potentials when the current was clamped at zero and a series of transient inward currents of 12–55 pA at a holding potential of −70 mV. The average number of spikes during the first 40 s after release of IP3 was 7.2±2.5 (n=6, mean±S.E.M.). The average maximum current and the total inward transport of charge during the first 40 s after photolysis of caged IP3 were −24±8.0 pA and −1.7±0.8 pC, respectively (n=5, mean±S.E.M.). Inward membrane currents of 12–55 pA after release of IP3 were not observed with 50 μM La3+ in the bath. Notably, flash focused on the terminal vesicle also triggered action potentials. No action potentials were observed following flash focused on the soma or outside the dendrite. The average number of spikes during the first 40 s after release of IP3 initiated by flash spatially restricted to the terminal vesicle was 5.0±2.0 (n=4, mean±S.E.M.). The present study indicates that local release of IP3 in the terminal vesicle of the vomeronasal neurones triggers transient depolarizations and induces action potentials. We suggest that IP3 might be a second messenger in the vomeronasal microvillar receptor neurones.

• Gjerstad, Johannes; Tjølsen, Arne & Hole, Kjell (2001). Induction of long-term potentiation of single wide dynamic range neurones in the dorsal horn is inhibited by descending pathways. Pain. ISSN 0304-3959. 91(3), p. 263–268. doi: 10.1016/S0304-3959(00)00448-6. Full text in Research Archive Show summary

  Previous studies have shown that long-term potentiation (LTP) in the dorsal horn may be induced by noxious stimuli. In this study it is investigated whether induction of LTP in the dorsal horn may be affected by the descending pathways. Extracellular recordings of wide dynamic range (WDR) neurones in the lumbar dorsal horn in intact urethane-anaesthetized Sprague--Dawley rats were performed, and the electrically evoked neuronal responses in these neurones were defined as A-fibre and C-fibre responses according to latencies. Using a short-term cold block of the thoracic spinal cord, which produced a completely reversible increase of the A-fibre and C-fibre responses, the influence of the descending inhibitory system on the induction of LTP by electrical high-frequency conditioning applied to the sciatic nerve was examined. As previously shown the A-fibre responses were almost unchanged following the conditioning. In contrast, the C-fibre responses following the same conditioning were strongly increased. Thus, a clear LTP of the nociceptive transmission in the dorsal horn was observed following electrical high-frequency conditioning. Interestingly, we found that the LTP was more powerful when the effects of the descending pathways were temporarily eliminated during conditioning. It is concluded that induction of LTP by electrical high-frequency conditioning stimulation, which may be part of the wider term central sensitization, is inhibited by descending pathways.

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• Bull, Synne Tollerud; Lind, Pedro G. & Gjerstad, Johannes (2025). Modern AI and the possibility of an AI hub downtown in Oslo: The Why and the What. Full text in Research Archive
• Bjelkarøy, Maria Torheim; Siddiqui, Tahreem Ghazal; Simonsen, Tone Breines; Gjerstad, Johannes & Lundqvist, Anders Christofer (2024). Brief intervention as a general method to address prescription or non-prescription medication misuse. Full text in Research Archive
• 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. Full text in Research Archive
• Reknes, Iselin; Einarsen, Ståle; Gjerstad, Johannes & Nielsen, Morten Birkeland (2017). Role conflict, personality, and exposure to bullying behaviors. Full text in Research Archive
• Forsberg, June Thorvaldsen; Gjerstad, Johannes; Flaten, Magne & Aslaksen, Per M (2017). The genetic influence on fear of pain and placebo analgesia. Full text in Research Archive
• Kongstorp, Mette; Gjerstad, Johannes; Moen, Aurora Lie & Haugen, Fred (2016). Activation of epidermal growth factor receptors (EGRFs) following disc herniation induces hyperexcitability in the pain pathways. Full text in Research Archive
• Eriksen, Guro Søe; Jacobsen, Line Melå; Pedersen, Linda Margareth & Gjerstad, Johannes (2010). Inhibition of FAAH reverses spinal LTP. Full text in Research Archive
• 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), p. 170–170. doi: 10.1016/j.sjpain.2010.05.010. Full text in Research Archive
• Hjornevik, Trine; Schoultz, Bent Wilhelm; Marton, Janos; Gjerstad, Johannes; Drzezga, Alexander & Henriksen, Gjermund [Show all 7 contributors for this article] (2009). Spinal LTP is associated with reduced opioid neurotransmission in the rat brain. Full text in Research Archive
• Eriksen, Guro Søe; Jacobsen, Line Melå; Pedersen, Linda Margareth & Gjerstad, Johannes (2009). Inhibition of FAHH reduces central sensitization after noxious stimulation. Full text in Research Archive
• 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, p. S369–S370. Full text in Research Archive
• 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. Full text in Research Archive
• 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. Full text in Research Archive
• 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. Full text in Research Archive
• Sannes, Ann-Christin & Gjerstad, Johannes (2022). The influence of psychosocial stressors, genetic variability, and gender on subjective health complaints: Abusive supervision, genetics, and health complaints. Universitetet i Oslo. Full text in Research Archive Show summary

  Being exposed to psychosocial stress activates biological processes that is normally self-regulating. However, if this self-regulation fails it might have consequences. In this thesis it was shown that abusive supervision has an influence on patterns of subjective health complaints, spinal pain, and headache. Further, the influence of several genetic factors, age, and gender was proven to have an influence, thus important to consider when investigating health complaints. This knowledge provides further support for the biopsychosocial model and the importance of implementing this model in a treatment setting. Moreover, these results provide further understanding as to why different people in the same situation may respond differently. The results also provide an indication as to the importance of work environment, in particular a leader’s behaviour. By being conscious of the type of leadership style might help reduce sick-leave and/or absenteeism among employees.

• Rajalingam, Dhaksshaginy; Gjerstad, Johannes & Nielsen, Morten Birkeland (2020). The impact of workplace bullying and repeated social defeat on health and behavioral outcomes: A biopsychosocial perspective. Universitetet i Bergen. ISSN 9788230866467. Full text in Research Archive Show summary

  Workplace bullying is a severe problem that needs further investigation from a range of disciplines. Yet, during more than twenty years of research on workplace bullying, few studies have addressed the bullying phenomenon from a biological perspective. Hence, the purpose of this thesis was to learn more about how stressors such as workplace bullying in humans and repeated social defeat in rats affect the physiological and psychological mechanisms of the body, seeing the latter as an animal model of bullying among humans. The purpose of this thesis was, therefore, to advance our understanding of how workplace bullying leads to severe health problems in those targeted. As such, the present research addresses individual susceptibility when exposed to workplace bullying and examines causative effects and mechanisms on the relationship between exposure to workplace bullying and subsequent health outcomes. The first paper addressed the potential moderating effect of the miR-146a genotype on the association between exposure to workplace bullying and insomnia through psychological distress, using a nationally representative survey of Norwegian employees. The findings showed that the relationship between distress and insomnia induced by exposure to bullying was stronger among GG genotype individuals compared with GC/CC genotype individuals. The second paper addressed the neuro-immune changes initiated by exposure to prolonged social stressors. Thus, an animal model of repeated social defeat – the resident-intruder paradigm – was implemented. The animal data demonstrated stress-induced health effects, including reduced weight gain, hypothalamic-pituitary-adrenal (HPA) axis changes, and an increased inflammatory profile of the isolated splenic myeloid cells. The third paper addressed the changed expression of the β2-adrenergic receptor (ADRB2) during prolonged exposure to stressors and its role in the association between exposure to workplace bullying and anxiety. A moderating effect of the ADRB2 genotype on the workplace bullying-anxiety relationship in humans was also observed. Moreover, in vivo and in vitro experiments demonstrated reduced ADRB2 gene expression induced by the stress hormone norepinephrine (NE) and a stress-induced switch from an anti-inflammatory to a pro-inflammatory state of the immune cells. In conclusion, the findings of the present thesis indicate that persistent social stressors in the form of workplace bullying may lead to subjective health complaints such as insomnia and anxiety by promoting a state of low-grade systemic inflammation. Also, the findings from the animal model of repeated social defeat suggest that the systemic inflammation may be a consequence of the missing functioning of the “breaks” of the sympathetic nervous system (SNS) and HPA axis. The persistent inflammatory state following exposure to persistent social stressors, causing excess production of pro-inflammatory cytokines, seems to cause dysregulation and mal-adaptation of biological mechanisms central in the stress response system leading to physiological and psychological changes that may be damaging for overall health and well-being. Thus, the present thesis demonstrates a clear link between exposure to persistent social stressors, genetic factors, and severe health problems in targets of bullying.

• Eriksen, Guro Søe; Jacobsen, Line Melå & Gjerstad, Johannes (2010). Spinal LTP is attenuated by the FAAH enzyme inhibitor URB597. Universitetet i Oslo. Full text in Research Archive Show summary

  Fatty-acid amide hydrolase (FAAH) is an enzyme that metabolizes several endocannabinoids and fatty acid amides. A functional variant of the gene encoding FAAH, which reduces the enzymatic activity, has been associated with decreased human pain sensitivity. In addition, several preclinical studies suggest that increased activity in the endocannabinoid system by inactivating FAAH may be a promising strategy to promote antinociceptive effects. Spinal long-term potentiation (LTP) may represent a cellular memory of nociceptive information. In the present study spinal LTP was induced by high frequency stimulation (HFS) conditioning applied to the sciatic nerve of anaesthetized rats. Extracellular field potential recordings in the spinal dorsal horn were performed to observe the expression of spinal LTP, and to examine if maintenance of spinal LTP is affected by administration of the FAAH inhibitor URB597 (0.3 or 1.0 mg/kg i.v.). Quantitative real-time RT-PCR was used to explore if HFS conditioning alone, or in combination with URB597 (1.0 mg/kg i.v.), is associated with changes in spinal dorsal horn expression of the genes encoding Zif and iNOS. The field potential recording experiments confirmed the previous observations that sciatic HFS conditioning can induce a robust LTP. The maintenance of LTP was, however, attenuated by administration of URB597 (1.0 mg/kg i.v.). Moreover, an increase in ipsilateral dorsal horn expression of the genes encoding Zif and iNOS was observed following HFS conditioning. The dorsal horn expression of both genes was less pronounced after HFS conditioning in combination with URB597 (1.0 mg/kg i.v.). The present data suggest that inhibition of FAAH activity, and thereby possible accumulation of endocannabinoids, attenuates expression of spinal LTP and also diminish the increase of Zif and iNOS gene expression associated with spinal LTP.

• Knardahl, Stein; Veiersted, Kaj Bo; Medbø, Jon Ingulf; Matre, Dagfinn; Jensen, Jørgen & Pedersen, Linda M. [Show all 10 contributors for this article] (2008). Arbeid som årsak til muskel-skjelettlidelser. Kunnskapsstatus 2008. STAMI - Statens arbeidsmiljøinstitutt. Full text in Research Archive Show summary

  Denne rapporten er et resultat av prosjektet "Sammenstilling av kunnskap om utvikling av muskelskjelettlidelser og årsaksforhold knyttet til fysiske, psykologiske og organisatoriske forhold". Prosjektet er et samarbeid mellom Statens arbeidsmiljøinstitutt, Direktoratet for arbeidstilsynet og Petroleumstilsynet og kom i stand da Arbeids‐ og inkluderingsdepartementet (AID) våren 2007 ga tilsagn om midler. Prosjektet har pågått fra høsten 2007 og hele 2008. Arbeidstilsynet har hatt det overordnede informasjons‐ og koordineringsansvaret. Målet med rapporten er å systematisere og vurdere kunnskap for å skape et årsaksbilde om hva som bidrar til utvikling av muskelskjelettlidelser i dagens og morgendagens arbeidsliv. På denne måten ønsker vi å bidra til at myndighetenes strategi for rammesetting og tilsyn forankres i dokumenterte og relevante risikoforhold for muskelskjelettlidelser. Videre håper vi at denne kunnskapen skal bidra til at arbeidet med å forebygge muskelskjelettlidelser i bedriftene i større grad bygger på fakta om risiko og hvilke typer intervensjoner som bidrar til forbedring. Muskelskjelettlidelser er den hyppigste årsaken til sykefravær og uføretrygding i Norge. Det er også en av de vanligste årsakene til arbeidsbetinget sykdom. Utviklingen i samfunnet har bidratt til at belastninger i arbeidslivet stadig endres, og dermed endres også årsakene til utvikling av muskelskjelettlidelser. Tidligere ble utvikling av muskelskjelettlidelser i stor grad forbundet med mekaniske belastninger. Studier og undersøkelser som er gjort de siste årene viser at årsaksbildet er mer sammensatt enn tidligere antatt. Også psykologiske, sosiale og organisatoriske forhold i arbeidet bidrar til utviklingen av denne type plager. Det er viktig at ny kunnskap om årsaksbildet og hva som bidrar til utvikling av muskelskjelettlidelser blir systematisert og vurdert med tanke på utnyttelse i forbedring av myndighetsrollen. Likeledes er det viktig å utnytte kunnskap om effekt av ulike typer intervensjoner for å redusere risiko. Statens arbeidsmiljøinstitutt har gjennomført en systematisk kritisk gjennomgang av undersøkelser av risiko for utvikling av muskelskjelettlidelser både med tanke på fysiske, psykologiske, organisatoriske og 2 sosiale faktorer. Videre har instituttet innhentet kunnskap om effekt av ulike typer tiltak for å redusere risiko for muskelskjelettlidelser. Arbeidet skal bidra til en kompetanseheving både i Arbeidstilsynet og i Petroleumstilsynet om hvordan de ulike faktorer påvirker hverandre og dermed utgjør en risiko for muskelskjelettlidelser. Håpet er at det også skal bidra til en kompetanseheving i bedriftene. Videre er det tenkt at resultatene fra prosjektet skal brukes til å forbedre etatenes tilsyn og rådgiving. Tilsynene skal i størst mulig utstrekning være kunnskapsbaserte. For å formidle kunnskapen både internt og eksternt vil fagseminarer og ulike former for informasjon også være en del av prosjektet. Avdeling for Arbeidsrelaterte muskelskjelettlidelser ved Statens arbeidsmiljøinstitutt står faglig ansvarlig for innholdet i rapporten. Arbeidet har vært ledet av professor Stein Knardahl. Rapporten inneholder både en populærvitenskapelig del og en mer inngående diskusjonsdel der forskningsfunn og metoder diskuteres nærmere. Målgruppen for rapporten er både ansatte i de respektive tilsynsetatene og praktikere, samt forskere innen feltet.

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