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

Jacobsen, Daniel Pitz; Møen, Atle; Haugen, Fred; Gjerstad, Johannes

doi:10.1155/2016/6519408

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…The C-fiber responses were followed for 180 min after application of NP transplant covering 1–2 mm of the dorsal nerve roots, or 40 µL 0.6 mg/mL miR-223-3p in Invivofectamine (Invitrogen, Carlfbad, USA). In accordance with our earlier studies [ 30 , 31 ], NP was applied in absence of nerve root compression. Application of 40 µL 0,9% NaCl served as controls.…”

Section: Methodsmentioning

confidence: 62%

MicroRNA-223 demonstrated experimentally in exosome-like vesicles is associated with decreased risk of persistent pain after lumbar disc herniation

et al. 2017

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BackgroundPrevious 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.MethodsSingle 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.ResultsIn 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).ConclusionsOur 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. Trial registration/ethics REK 2014/1725Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1194-8) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 62%

MicroRNA-223 demonstrated experimentally in exosome-like vesicles is associated with decreased risk of persistent pain after lumbar disc herniation

et al. 2017

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“…In line with our findings, other studies have shown that CX3CL1 upregulation in rat DRG was involved in inflammatory pain 30 or disc herniation-induced pathological pain. 31 In addition, the result that neutralization of CX3CL1 activity prevented the increase of action potential firing in DRG neurons following oxaliplatin treatment suggested that DRG neuronal hyperexcitability mediated by CX3CL1 might be a major reason for oxaliplatin-induced chronic pain.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of CX3CL1 mediated by NF-κB activation in dorsal root ganglion contributes to peripheral sensitization and chronic pain induced by oxaliplatin administration

et al. 2017

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Painful peripheral neuropathy is a severe side effect in oxaliplatin therapy that compromises cancer patients' quality of life. However, its underlying pathogenic mechanisms remain largely unknown. Here, we found that intraperitoneal consecutive administration of oxaliplatin significantly increased excitability of small diameter dorsal root ganglion neurons and induced thermal hyperalgesia in rats. Furthermore, the CX3CL1 expression was significantly increased after oxaliplatin treatment, and intrathecal injection of a neutralizing antibody against CX3CL1 markedly attenuated the enhanced excitability of dorsal root ganglion neurons and thermal hyperalgesia. Importantly, the upregulated CX3CL1 is mediated by the NF-κB signaling pathway, as inhibition of NF-κB p65 activation with pyrrolidine dithiocarbamate or p65 siRNA inhibited the upregulation of CX3CL1, the enhanced excitability of dorsal root ganglion neurons, and thermal hyperalgesia induced by oxaliplatin. Further studies with chromatin immunoprecipitation found that oxaliplatin treatment increased the recruitment of NF-κB p65 to the CX3Cl1 promoter region. Our results suggest that upregulation of CX3CL1 in dorsal root ganglion mediated by NF-κB activation contributes to the peripheral sensitization and chronic pain induced by oxaliplatin administration.

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“…One NP graft from each donor rat plus a control (made by the bisection) was used in the analyses. As previously described [29, 30], one piece was immediately frozen (native), and the other piece was applied onto the spinal dorsal nerve roots for 180 min before frozen (exposed). All animal experiments were approved by the Norwegian Animal Research Authority and were handled in accordance with the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes.…”

Section: Methodsmentioning

confidence: 99%

Up-regulation of circulating microRNA-17 is associated with lumbar radicular pain following disc herniation

et al. 2019

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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. Electronic supplementary material The online version of this article (10.1186/s13075-019-1967-y) contains supplementary material, which is available to authorized users.

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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

Cited by 5 publications

References 42 publications

MicroRNA-223 demonstrated experimentally in exosome-like vesicles is associated with decreased risk of persistent pain after lumbar disc herniation

MicroRNA-223 demonstrated experimentally in exosome-like vesicles is associated with decreased risk of persistent pain after lumbar disc herniation

Upregulation of CX3CL1 mediated by NF-κB activation in dorsal root ganglion contributes to peripheral sensitization and chronic pain induced by oxaliplatin administration

Up-regulation of circulating microRNA-17 is associated with lumbar radicular pain following disc herniation

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