Line M. Jacobsen

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

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.

Spinal cord long-term potentiation (LTP) is associated with increased dorsal horn gene expression of IL-1β, GDNF and iNOS

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.

The COMT rs4680 Met allele contributes to long-lasting low back pain, sciatica and disability after lumbar disc herniation.

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.

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

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, 6weeks and 12months, serum concentrations of IL-6 and IL-8 were analyzed by enzyme-linked immunosorbent assay (ELISA) and pain intensity was reported on a 0-10cm visual analog scale (VAS). Significantly higher levels of IL-6 and IL-8 in serum were found in patients with VAS ⩾3 at 12months, than in patient with VAS <3 at 12months (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.

Metabolic plasticity in the supraspinal pain modulating circuitry after noxious stimulus-induced spinal cord LTP

Abstract 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.

Catechol-O-methyltransferase (COMT) inhibition reduces spinal nociceptive activity.

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<or=0.01, OR 486 vs. vehicle) and attenuated the expression of spinal long-term potentiation (LTP), an often studied model for central sensitization (p<or=0.01, HFS vs. HFS+OR 486). Our findings suggest that low COMT activity may have an antinociceptive effect in the spinal cord.

The MMP1 rs1799750 2G allele is associated with increased low back pain, sciatica, and disability after lumbar disk herniation.

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.

Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome

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.

The interleukin-1α gene C>T polymorphism rs1800587 is associated with increased pain intensity and decreased pressure pain thresholds in patients with lumbar radicular pain.

Objectives:Previous studies have suggested that many inflammatory cytokines, including interleukin (IL)-1&agr;, may be associated with lumbar radicular pain after disk herniation. In the present study, we examined how variability of the IL-1&agr; 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-1&agr; rs1800587. The effect of the IL-1&agr; genotype on the VAS and PPT was analyzed by repeated measure analyses of variance. Results:The IL-1&agr; 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-1&agr; CT/TT genotype rs1800587 may be associated with increased pain intensity and corresponding reduced PPT during the first year after disk herniation.

Induction of the perceptual correlate of human long-term potentiation (LTP) is associated with the 5-HTT genotype

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 SL(G)/L(A)L(G)/SL(A) and 5-HTT L(A)L(A). 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 SL(G)/L(A)L(G)/SL(A) 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.