• High frequency stimulation
• Lumbar radiculopathy
• Neurostimulation
• Sciatica

• R01AR071431 NIAMS NIH HHS

• cytokines
• degeneration
• herniation
• immune
• inflammation
• intervertebral disc
• pain

• Natural Science Foundation of Guangdong Province
• Natural Science Foundation of Fujian Province by Fujian Science and Technology Department
• National Natural Science Foundation of China

• animal models
• epidermai growth factor receptor
• inflammation
• membrane traffic
• neuropathic pain
• receptor tyrosine kinase

Nerve root enlargement with increased contrast uptake has been reported in dogs and humans secondary to nerve root compression. In cats, nerve root enlargement and contrast uptake only have been reported in association with inflammatory and neoplastic diseases, but not as a sequela to nerve root compression. An 8‐year‐old oriental short hair cat was presented with acute neurologic deficits consistent with left‐sided sciatic nerve deficit and possible L6‐S1 myelopathy. Magnetic resonance imaging (MRI) was performed and identified compression of the cauda equina and L7 nerve root associated with intervertebral disc herniation (IVDH) at L6‐L7 as well as widespread sciatic nerve enlargement with moderate rim enhancement. A hemilaminectomy was performed to evacuate herniated disc material. The nerve root was biopsied and submitted for histological evaluation. Interstitial nerve edema was diagnosed. Follow‐up MRI 3 months postoperatively showed complete remission of the changes. Nerve root thickening together with contrast enhancement may represent nerve edema in cats secondary to IVDH.

• MRI
• feline
• rim enhancement
• sciatic nerve

• Autoimmunity
• Autoinmunidad
• Citoquinas proinflamatorias
• Dolor ciático
• Hernia del disco intervertebral
• Immunoglobulins
• Inflamación
• Inflammation
• Inmunoglobulinas
• Intervertebral disc herniation
• Proinflammatory cytokines
• Sciatic pain

Ischemia-related risk factors are consistently correlated with discogenic pain, but it remains unclear how the ischemia-associated hypoxia and acidosis influence the peripheral sensory nervous system, namely the dorsal root ganglion (DRG), either directly or indirectly via intervertebral disc (IVD) mediation.

Bovine tail IVD organ cultures were preconditioned in different hypoxic and/or acidic conditions for 3 days to collect the conditioned medium (CM). The DRG-derived ND7/23 cells were either treated by the IVD CM or directly stimulated by hypoxic and/or acidic conditions. Neuronal sensitization was evaluated using calcium imaging (Fluo-4) after 3 days.

We found that direct exposure of DRG cell line to hypoxia and acidosis increased both spontaneous and bradykinin-stimulated calcium response compared to normoxia-neutral pH cultures. Hypoxia and low pH in combination showed stronger effect than either parameter on its own. Indirect exposure of DRG to hypoxia-acidosis-stressed IVD CM also increased spontaneous and bradykinin-stimulated response, but to a lower extent than direct exposure. The impact of direct hypoxia and acidosis on DRG was validated in a primary sheep DRG cell culture, showing the same trend.

Our data suggest that targeting hypoxia and acidosis stresses both in IVD and DRG could be a relevant objective in discogenic pain treatment.

• Acidosis
• Calcium Imaging
• Dorsal root ganglion
• Hypoxia
• Intervertebral disc
• Low back pain

• Anatomy
• Innervation
• Meninges
• Pain
• Spine

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.

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.

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.

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.

• Disk herniation
• EREG
• Epiregulin
• Growth factors
• Inflammation

Lumbar radiculopathy (LR) is a term used to describe a pain syndrome caused by compression or irritation of nerve roots in the lower back. The surgery cost for LR increased by 23% annually during 1992-2003 in the developed country. Although it is one of most common complaints in clinical practice, the diagnosis for LR is still very challenging. Here we discuss the current tools of LR diagnosis and highlight the needs to develop new diagnosis tools for LR.

• Magnetic resonance imaging
• Nerve root
• Pain
• Lumbar radiculopathy
• Lateral stenosis

• Bone mesenchymal stem cell
• Inflammation
• Intervertebral disk herniation
• Microglia
• Radicular pain

• Animals
• Intervertebral Disc Degeneration/pathology
• Intervertebral Disc Degeneration/therapy
• Intervertebral Disc Displacement/pathology
• Intervertebral Disc Displacement/therapy
• Male
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Microglia/metabolism
• Rats
• Rats, Sprague-Dawley

• Grant no. 81472071 National Natural Science Foundation of China
• Grant no.81301537 National Natural Science Foundation of China
• Grant no. 2013AA032203 National HighTechnology Research and Development Program ("863"Program) of China

• low back pain
• lumbar disc herniation
• pulsed radio frequency
• radicular pain
• spinal nerve root
• transforaminal epidural steroid injection

The aim of this study was to investigate the clinicopathologic features of lumbar disc herniation (LDH) with endplate degeneration and the association between cartilaginous fragments and inflammatory response to the herniated disc.

LDH often involves hyaline cartilage fragments pulled from the vertebral endplates. Modic changes are closely associated with LDH that contains hyaline cartilage, and cartilaginous endplates seem to affect resorption of the herniated disc.

A total of 78 patients who underwent microscopic discectomy between 9 and 16 weeks after an occurrence of LDH were reviewed. Modic changes, disc degeneration, high-intensity zone, and vertebral corner defect were evaluated using magnetic resonance imaging (MRI). Histopathological observations of cartilaginous endplates and inflamed granulation tissue in the herniated disc were made. In cases with inflamed granulation tissue, neovascularization and macrophage infiltration were also evaluated using immunohistochemical analysis.

Modic changes were observed in approximately one-third of the patients (26 cases: type 1, 7; type 2, 17; and type 3, 2). Cartilaginous endplates were observed in 32 cases (41%) and in the majority of cases with Modic changes compared with cases without Modic changes (65%, p = 0.001). Although inflamed granulation tissue was observed in 60 cases (77%), no significant differences were detected in patient age and the composition of the herniated material. Immunohistochemical analysis showed that fewer CD34-positive capillaries and CD68-positive cells were found in cases with cartilaginous fragments compared with those without cartilaginous fragments (p < 0.001). In addition, a higher immunoreactivity to CD34 and CD68 was found in herniated discs <25% of whose area was occupied by cartilaginous endplates compared with discs whose area was occupied at 25% or more (p < 0.001).

There is an association between LDH with endplate degeneration and cartilaginous herniation, with Modic type 2 predominating. Furthermore, neovascularization and macrophage infiltration, especially if the amount of cartilage is high, are likely to be less frequent in cartilaginous herniation, leading to failure in the spontaneous remission of clinical symptoms.

• Adult
• Aged
• Biomarkers
• Bone Resorption/pathology
• Female
• Granulation Tissue/pathology
• Humans
• Hyaline Cartilage
• Immunohistochemistry
• Intervertebral Disc/pathology
• Intervertebral Disc Degeneration/pathology
• Intervertebral Disc Displacement/diagnostic imaging
• Intervertebral Disc Displacement/pathology
• Lumbar Vertebrae/pathology
• Macrophages/metabolism
• Macrophages/pathology
• Magnetic Resonance Imaging/methods
• Male
• Middle Aged
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology

• AGEs
• DRG
• lumbar disk herniation
• methylglyoxal
• pain

• Animals
• Ganglia, Spinal/metabolism
• Glycation End Products, Advanced/metabolism
• Humans
• Intervertebral Disc Displacement/complications
• Intervertebral Disc Displacement/metabolism
• Low Back Pain/etiology
• Low Back Pain/metabolism
• Lumbosacral Region/pathology
• Male
• Pyruvaldehyde/metabolism
• Rats
• Rats, Sprague-Dawley

• Cluster of differentiation
• Disc herniation
• Genetics
• Inflammation
• Interferon-γ
• Lumbar radicular pain
• Nucleus pulposus

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.

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.

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).

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.

Trial registration/ethics REK 2014/1725

The online version of this article (doi:10.1186/s12967-017-1194-8) contains supplementary material, which is available to authorized users.

• Disc herniation
• Immune response
• Inflammation
• Lumbar radicular pain
• miR-223
• microRNA-223

• Src-family kinases
• central sensitization
• long-term potentiation
• lumbar disc herniation
• microglia
• pro-inflammatory cytokines
• radicular pain

• Action Potentials/drug effects
• Animals
• Behavior, Animal
• Chronic Pain/complications
• Chronic Pain/enzymology
• Chronic Pain/physiopathology
• Enzyme Activation/drug effects
• Hyperalgesia/complications
• Hyperalgesia/pathology
• Interleukin-1beta/metabolism
• Intervertebral Disc Displacement/complications
• Intervertebral Disc Displacement/enzymology
• Intervertebral Disc Displacement/physiopathology
• Lumbar Vertebrae/drug effects
• Lumbar Vertebrae/pathology
• Lumbar Vertebrae/physiopathology
• Male
• Microglia/drug effects
• Microglia/enzymology
• Nucleus Pulposus/transplantation
• Phosphorylation/drug effects
• Pyrimidines/pharmacology
• Rats, Sprague-Dawley
• Spinal Cord Dorsal Horn/drug effects
• Spinal Cord Dorsal Horn/pathology
• Spinal Cord Dorsal Horn/physiopathology
• Tumor Necrosis Factor-alpha/metabolism
• Up-Regulation/drug effects
• src-Family Kinases/metabolism

• National Natural Science Foundation of China

• Humans
• Low Back Pain/immunology
• Low Back Pain/physiopathology
• Low Back Pain/therapy
• Neuroimmunomodulation/physiology
• Sciatica/immunology
• Sciatica/physiopathology
• Sciatica/therapy

• Brain
• imagery
• lumbar
• mapping
• pain
• surgery

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.

• inflammation
• intervertebral disc herniation
• lipoxin A(4)
• radicular pain
• rat
• spinal cord

• Cytokines
• Disc herniation
• ELISA
• IL-6
• IL-8
• Interleukin-6
• Interleukin-8
• Lumbar radicular pain
• Nucleus pulposus
• Radiculopathy
• Sciatica
• Serum

• Inflammation
• chemical
• distal block
• mechano sensitization
• palpation of nerve
• pseudo unipolar axon
• sciatica
• selective nerve root block
• stretch sensitivity

It has been assumed that nucleus pulposus-induced activation of the dorsal root ganglion (DRG) may be related to an activation of sodium channels in the DRG neurons. In this study we assessed the expression of Nav 1.8 and Nav 1.9 following disc puncture.

Thirty female Sprague-Dawley rats were used. The L4/L5 disc was punctured by a needle (n=12) and compared to a sham group without disc puncture (n=12) and a naive group (n=6). At day 1 and 7, sections of the left L4 DRG were immunostained with anti-Nav 1.8 and Nav 1.9 antibodies.

At day 1 after surgery, both Nav 1.8-IR neurons and Nav 1.9-IR neurons were significantly increased in the disc puncture group compared to the sham and naive groups (p<0.05), but not at day 7.

The findings in the present study demonstrate a neuronal mechanism that may be of importance in the pathophysiology of sciatic pain in disc herniation.

• DISC herniation
• dorsal root ganglion
• rat
• sciatica
• spine
• voltage-gated sodium channel.

• Chemokines
• astrocytes
• chemokine C-C motif ligand 2 (CCL2)
• chemokine C-C motif receptor 2 (CCR2)
• lumber disc herniation
• neuronal-glial interaction

• Diffusion tensor imaging
• Discoradicular conflict
• Lumbar
• Spine
• Tractography

A combination of mechanical compression caused by a protruding disc and leakage of nucleus pulposus (NP) from the disc core is presumed to contribute to intervertebral disc hernia-related pain. Experimental models of disc hernia including both components have resulted in changes in neuronal activity at the level of the dorsal root ganglion (DRG) and spinal cord, but changes within the brain have been less well studied. However, acute application of NP to a DRG without mechanical compression rapidly increases neuronal activity in the thalamus, a major brain relay nucleus processing information from sensory pathways including ascending nociceptive tracts. The combination of mechanical compression and NP might therefore result in further increases in central neuronal activity. Using an experimental disc herniation rat model including both mechanical compression and NP the present study aimed to investigate changes in neuronal activity in the contralateral thalamic ventral posterior lateral nucleus in vivo. Measurements were obtained while electrically stimulating the ipsilateral sciatic nerve at Aδ fiber intensities. The L4 DRG was subjected to light mechanical compression and NP exposure, and acute changes in evoked thalamic responses were recorded for up to 40 min. In order to compare effects in naïve animals with effects following a longer period of NP exposure, animals that were either disc-punctured or sham-operated 24 h previously were also included. In all animals, light mechanical compression of the DRG depressed the number of evoked neuronal responses. Prior NP exposure resulted in less potent changes following mechanical compression (80% of baseline) than that observed in naïve animals (50%). During the subsequent NP application, the number of evoked responses compared to baseline increased in pre-exposed animals (to 87%) as well as in naïve animals (72%) in which the removal of the mechanical compression resulted in a further increase (106%). The contribution of acute DRG compression and disc material leakage to changes in transmission in central neuronal networks is likely to be complex and to involve both short-term and long-term effects. Since a light mechanical compression may reduce transmission in nociceptive pathways, it is possible that the presence or absence of NP is crucial for pain development in the acute phase of disc herniation.

• neuroscience
• physiology

• C-fibre response
• Csf1
• FasL
• Glial cells
• L1β
• M-CSF
• Nucleus pulposus
• Proinflammatory cytokines
• Sensitization
• TNF

• cytokine
• disc herniation
• inflammation
• epidural
• rat
• il-6
• tnf-alpha
• interferon-gamma

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Anesthetics, Local/administration & dosage
• Dose-Response Relationship, Drug
• Female
• Humans
• Incidence
• Injections, Epidural/methods
• Injections, Epidural/statistics & numerical data
• Low Back Pain/drug therapy
• Low Back Pain/epidemiology
• Lumbar Vertebrae
• Male
• Middle Aged
• Pain Measurement/drug effects
• Pennsylvania/epidemiology
• Radiculopathy/drug therapy
• Radiculopathy/epidemiology
• Steroids/administration & dosage
• Treatment Outcome
• Young Adult

The principle etiology of leg pain (sciatica) from lumbar disc herniation is mechanical compression of the nerve root. Sciatica is reduced by decompression of the herniated disc, i.e., removing mechanical compression of the nerve root. Decompression surgery typically reduces sciatica more than lumbar back pain (LBP). Decompression surgery reduces mechanical compression of the nerve root. However, decompression surgery does not directly reduce sensitization of the sensory nerves in the epidural space and disc. In addition, sensory nerves in the annulus fibrosus and epidural space are not protected from topical interaction with pain mediators induced by decompression surgery. The secondary etiology of sciatica from lumbar disc herniation is sensitization of the nerve root. Sensitization of the nerve root results from a) mechanical compression, b) exposure to cellular pain mediators, and/or c) exposure to biochemical pain mediators. Although decompression surgery reduces nerve root compression, sensory nerve sensitization often persists. These observations are consistent with continued exposure of tissue in the epidural space, including the nerve root, to increased cellular and biochemical pain mediators following surgery. A potential contributor to lumbar back pain (LBP) is stimulation of sensory nerves in the annulus fibrosus by a) cellular pain mediators and/or b) biochemical pain mediators that accompany annular tears or disruption. Sensory fibers located in the outer one-third of the annulus fibrosus increase in number and depth as a result of disc herniation. The nucleus pulposus is comprised of material that can produce an autoimmune stimulation of the sensory nerves located in the annulus and epidural space leading to LBP. The sensory nerves of the annulus fibrosus and epidural space may be sensitized by topical exposure to cellular and biochemical pain mediators induced by lumbar surgery. Annulotomy or annular rupture allows the nucleus pulposus topical access to sensory nerve fibers, thereby leading to LBP. Coverage of the annulus and adjacent structures in the epidural space by absorbable viscoelastic gels appears to reduce LBP following surgery by protecting sensory fibers from cellular and biochemical pain mediators.