Johannes Gjerstad

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 substance P release in vivo during the induction of long-term potentiation in dorsal horn neurons

&NA; Long‐term potentiation (LTP) in wide dynamic range (WDR) neurons in the dorsal horn has been suggested to contribute to central sensitization and the development of chronic pain. Indirect experimental evidence indicates an involvement of substance P (SP), in this respect. The aim of the present study was to monitor the extracellular level of substance P‐like immunoreactivity (SP‐LI) in the dorsal horn of the rat during and after induction of LTP in WDR neurons in vivo. Electrophysiological recordings of single (WDR) neurons were performed in parallel with microdialysis in the dorsal horn under urethane‐anaesthesia. The amount of SP‐LI in the microdialysate was determined by radioimmunoassay. As previously shown, high frequency conditioning stimulation of the sciatic nerve induced an increased firing response of WDR neurons. An increased response to C‐fibre stimulation, but not A‐fibre stimulation, could be determined. A significant increase of the extracellular level of SP‐LI in the dorsal horn was detected during, but not after, induction of LTP. These data suggest that SP may be involved in the induction of LTP by high frequency stimulation. However, the maintenance of spinal LTP following high frequency peripheral nerve stimulation does not seem to depend on an increased release of SP.

Induction of long-term potentiation of single wide dynamic range neurones in the dorsal horn is inhibited by descending pathways

&NA; 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.

Workplace bullying and subsequent health problems

BACKGROUND Cross-sectional studies demonstrate that exposure to bullying in the workplace is positively correlated with self-reported health problems. However, these studies do not provide a basis to draw conclusions on the extent to which bullying leads to increased health problems or whether health problems increase the risk of being bullied. To provide better indications of a causal relationship, knowledge from prospective studies on the association between bullying in the workplace and health outcomes is therefore summarised. MATERIAL AND METHOD We conducted a systematic literature review of original articles from central literature databases on longitudinal associations between bullying in the workplace and health. Average associations between bullying and health outcomes are calculated using meta-analysis. RESULTS A consistent finding across the studies is that exposure to bullying is significantly positively related to mental health problems (OR =1.68; 95% KI 1.35-2.09) and somatic symptoms (OR = 1.77; 95% KI 1.41-2.22) over time. Mental health problems are also associated with subsequent exposure to bullying (OR = 1.74; 95% KI 1.44-2.12). INTERPRETATION Bullying is positively related to mental health problems and somatic symptoms. The association between mental health problems and subsequent bullying indicates a self-reinforcing process between mental health and bullying. The methodological quality of the studies that were conducted is relatively sound. However, based on the existing knowledge base there are no grounds for conclusions regarding an unambiguous causal relationship between bullying and health.

Long term potentiation of single WDR neurons in spinalized rats

We report long-term potentiation (LTP) in single spinal wide dynamic range (WDR) neurons in urethane-anaesthetized spinalized rats with a complete neuromuscular blockade. Peripheral influences were excluded by a complete lidocaine block distal to the stimulation site on the sciatic nerve. As previously shown A-beta fibre evoked responses were not increased by the tetanic stimulation when there was a neuromuscular blockade during the experiment. Spinalization, excluding influences from supraspinal structures, increased all firing responses, and the LTP of C-fibre evoked responses when calculated in number of action potentials compared to intact animals and to previous studies. Furthermore, an LTP of the post discharge was observed after spinalization. An LTP of the post discharge has previously not been reported. Therefore, we conclude that LTP in the dorsal horn normally seems to be inhibited by descending pathways.

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.

Spinal cord long-term potentiation is attenuated by the NMDA-2B receptor antagonist Ro 25-6981

Aim:  The NR2B‐containing N‐methyl‐d‐aspartate (NMDA) receptors may be involved in a variety of phenomena including synaptic plasticity, memory formation and pain perception. Here we used the NMDA‐2B receptor antagonist Ro 25‐6981 to investigate the role of the NR2B‐containing NMDA receptors in spinal nociception.

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.

Recording of long-term potentiation in single dorsal horn neurons in vivo in the rat

We have published several reports on long-term potentiation (LTP) in single spinal wide dynamic range (WDR) neurons (responding to both innocuous and noxious stimuli) in urethane-anaesthetised rats. The protocol presented here, with single unit recordings of dorsal horn neurons before and after a nociceptive conditioning stimulation, may be useful in many electrophysiological studies of plastic changes in the spinal cord, such as LTP. We invite others to use this protocol for the study of spinal plasticity. Findings using this technique may be relevant for the understanding of changes in nociceptive transmission, induction of central sensitisation and maybe even in mechanisms of pathological pain and chronic pain states. We describe modified and alternative protocols for the study of LTP mechanisms under different conditions in intact and in spinalised animals, and after natural noxious stimuli. We present a novel method minimising peripheral influence of afferent input induced by antidromic neurogenic inflammation or inflammatory changes following a natural noxious stimulation. This is made possible by dissection of the sciatic nerve at two separate locations and local anaesthetic block distal to the stimulation site.