Cellular mechanisms involved in the induction and maintenance of long-term potentiation (LTP) in the spinal dorsal horn

The cellular processes leading to spinal long-term potentiation (LTP) are regarded as underlying mechanisms of sensitization in the dorsal horn. In this study, spinal LTP was induced by high-frequency stimulation (HFS) conditioning of the sciatic nerve. Electrophysiological extracellular recordings from nociceptive single dorsal horn neurons were used in combination with quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) to examine the mechanisms for induction and maintenance of spinal LTP. Spinal administration of the N-methyl-D-aspartate-2B (NMDA-2B) receptor antagonist Ro 25-6981 showed an antinociceptive effect on spinal dorsal horn neuronal activity and clearly attenuated the magnitude of spinal LTP. Moreover, induction of LTP after HFS conditioning was not observed following pre-treatment of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. A transient increase in the expression of the gene for the transcription factor Zif268 was observed in the spinal cord 120 minutes after HFS conditioning. Further, the expression of the genes for interleukin-1β (IL-1β), glial cell linederived neurotrophic factor (GDNF) and inducible nitric oxide synthase (iNOS) increased significantly in the ipsilateral dorsal horn 360 minutes after HFS conditioning. These data demonstrate that activation of the spinal NMDA-2B receptor and the intracellular CaMKII enzyme may be important for the induction of spinal LTP. Moreover our results indicate that increased gene expression of Zif268, IL-1β, GDNF and iNOS following HFS might be associated with the maintenance of spinal LTP

Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes

Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.publishedVersio

Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement

Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.publishedVersio

Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100–12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation

Validation of the Norwegian pain sensitivity questionnaire

Background and purpose: There is a large variation in people’s reactions to painful stimuli. Although some conditions are more painful, the variation between people is larger than the reaction to pain across conditions. Induced experimental pain is one way to assess some aspects of these differences in pain perception. Experimental nociceptive testing is time consuming and not always feasible in a clinical setting. In order to overcome the obstacles of assessing pain sensitivity using experimental stimulation, the Pain Sensitivity Questionnaire (PSQ) was developed. The purpose of this study is to validate the Norwegian version of the PSQ. Methods: Construct validity was examined through an exploratory principal component factor analysis with varimax rotation. Internal consistency was measured by Cronbach’s alpha reliability for subscales and the total PSQ. As confounding variables such as age and gender may contribute to the experience of pain, a regression analysis was performed with demographic variables and PSQ scores as independent variables and the experimental measures of pain as the dependent variable. Results: The factor analysis yielded at two factor solution, with an eigenvalue greater than one, explain 58% of the variance. Cronbach’s alpha for the PSQ was 0.92. In the regression analysis, only PSQ scores contributed to explain the experimental pain intensity and tolerance. Gender only influenced the experimental pain threshold, as men had statistically significant higher heat pain threshold than women. Conclusion: This study shows that PSQ is a valid and reliable questionnaire and might be a promising instrument for assessing pain sensitivity in Norwegian clinical settings. Further studies are needed to examine whether the PSQ can be used in clinical settings to predict postoperative pain and the development of chronic pain

Validation of the Norwegian pain sensitivity questionnaire

Background and purpose: There is a large variation in people’s reactions to painful stimuli. Although some conditions are more painful, the variation between people is larger than the reaction to pain across conditions. Induced experimental pain is one way to assess some aspects of these differences in pain perception. Experimental nociceptive testing is time consuming and not always feasible in a clinical setting. In order to overcome the obstacles of assessing pain sensitivity using experimental stimulation, the Pain Sensitivity Questionnaire (PSQ) was developed. The purpose of this study is to validate the Norwegian version of the PSQ. Methods: Construct validity was examined through an exploratory principal component factor analysis with varimax rotation. Internal consistency was measured by Cronbach’s alpha reliability for subscales and the total PSQ. As confounding variables such as age and gender may contribute to the experience of pain, a regression analysis was performed with demographic variables and PSQ scores as independent variables and the experimental measures of pain as the dependent variable. Results: The factor analysis yielded at two factor solution, with an eigenvalue greater than one, explain 58% of the variance. Cronbach’s alpha for the PSQ was 0.92. In the regression analysis, only PSQ scores contributed to explain the experimental pain intensity and tolerance. Gender only influenced the experimental pain threshold, as men had statistically significant higher heat pain threshold than women. Conclusion: This study shows that PSQ is a valid and reliable questionnaire and might be a promising instrument for assessing pain sensitivity in Norwegian clinical settings. Further studies are needed to examine whether the PSQ can be used in clinical settings to predict postoperative pain and the development of chronic pain

Low Back Pain With Persistent Radiculopathy; the Clinical Role of Genetic Variants in the Genes SOX5, CCDC26/GSDMC and DCC

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

The causal role of smoking on the risk of headache. A Mendelian randomization analysis in the HUNT Study

Background and purpose: Headache has been associated with various lifestyle and psychosocial factors, one of which is smoking. The aim of the present study was to investigate whether the association between smoking intensity and headache is likely to be causal. Method: A total of 58 316 participants from the Nord‐Trøndelag Health (HUNT) study with information on headache status were genotyped for the rs1051730 C>T single‐nucleotide polymorphism (SNP). The SNP was used as an instrument for smoking intensity in a Mendelian randomization analysis. The association between rs1051730 T alleles and headache was estimated by odds ratios with 95% confidence intervals. Additionally, the association between the SNP and migraine or non‐migrainous headache versus no headache was investigated. All analyses were adjusted for age and sex. Results: There was no strong evidence that the rs1051730 T allele was associated with headache in ever smokers (odds ratio 0.99, 95% confidence interval 0.95–1.02). Similarly, there was no association between the rs1051730 T allele and migraine or non‐migrainous headache versus no headache. Conclusion: The findings from this study do not support that there is a strong causal relationship between smoking intensity and any type of headache. Larger Mendelian randomization studies are required to examine whether higher smoking quantity can lead to a moderate increase in the risk of headache subtypes

Low Back Pain With Persistent Radiculopathy; the Clinical Role of Genetic Variants in the Genes SOX5, CCDC26/GSDMC and DCC

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