Spinal nociceptive hyperexcitability induced by experimental disc herniation is associated with enhanced local expression of Csf1 and FasL (original) (raw)
Related papers
Neuroscience Letters, 2003
The pain mechanisms underlying radiculopathy due to disc herniation are still incompletely understood. This study assessed changes in brain-derived neurotrophic factor (BDNF) expression, a modulator of nociceptive information, in the dorsal root ganglion (DRG) and spinal cord dorsal horn following experimental disc herniation. Immunohistochemical analysis revealed an increase in percentage of BDNFimmunoreactive (IR) neurons profiles in the affected DRG and marked elevation in the BDNF-IR regions within both the superficial and deep layers at the corresponding spinal level with a peak at 3 days after nucleus pulposus (NP) application. These results thus show that herniated NP increases the BDNF production in the pain-processing neurons. Such changes can contribute to the development of inflammatory hyperalgesia. q
Asian spine journal, 2014
Experimental animal study. To evaluate pain-related behavior and changes in nuclear factor-kappa B (NF-kB), receptor activator of NF-kB (RANK), and ligand (RANKL) in dorsal root ganglia (DRG) after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. The pathological mechanisms underlying pain from lumbar-disc herniation have not been fully elucidated. RANKL are transcriptional regulators of inflammatory cytokines. Our aim was to evaluate pain-related behavior and RANKL expression in DRG after sciatic-nerve compression and application of NP in rats. MECHANICAL HYPERALGESIA AND RANKL EXPRESSION WERE ASSESSED IN THREE GROUPS OF RATS: NP+sciatic nerve compression (2 seconds), sham-operated, and controls (n=20 each). Mechanical hyperalgesia was measured every other day for 3 weeks using von Frey filaments. RANKL expression in L5 DRGs was examined at five and ten days after surgery using immunohistochemistry. Mechanical hyperalgesia was observed over the 12-d...
European Spine Journal, 2012
Introduction The symptoms of lumbar disc herniation, such as low back pain and sciatica, have been associated with local release of cytokines following the inflammatory process induced by the contact of the nucleus pulposus (NP) with the spinal nerve. Material and methods Using an animal experimental model of intervertebral disc herniation and behavioral tests to evaluate mechanical (electronic von Frey test) and thermal (Hargreaves Plantar test) hyperalgesia in the hind paw of rats submitted to the surgical model, this study aimed to detect in normal intervertebral disc the cytokines known to be involved in the mechanisms of inflammatory hyperalgesia, to observe if previous exposure of the intervertebral disc tissue to specific antibodies could affect the pain behavior (mechanical and thermal hyperalgesia) induced by the NP, and to observe the influence of the time of contact of the NP with the fifth lumbar dorsal root ganglion (L5-DRG) in the mechanical and thermal hyperalgesia. Results The cytokines present at highest concentrations in the rat NP were TNF-a, IL-1b and CINC-1. Rats submitted to the disc herniation experimental model, in which a NP from the sacrococcygeal region is deposited over the right L5-DRG, showed increased mechanical and thermal hyperalgesia that lasted at least 7 weeks. When the autologous NP was treated with antibodies against the three cytokines found at highest concentrations in the NP (TNF-a, IL-1b and CINC-1), there was decrease in both mechanical and thermal hyperalgesia in different time points, suggesting that each cytokine may be important for the hyperalgesia in different steps of the inflammatory process. The surgical remotion of the NP from herniated rats 1 week after the implantation reduced the hyperalgesia to the level similar to the control group. This reduction in the hyperalgesia was also observed in the group that had the NP removed 3 weeks after the implantation, although the intensity of the hyperalgesia did not decreased totally. The removal of the NP after 5 weeks did not changed the hyperalgesia observed in the hind paw, which suggests that the longer the contact of the NP with the DRG, the greater is the possibility of development of chronic pain. Conclusion Together our results indicate that specific cytokines released during the inflammatory process induced by the herniated intervertebral disc play fundamental role in the development of the two modalities of hyperalgesia (mechanical and thermal) and that the maintenance of this inflammation may be the most important point for the chronification of the pain.
European Spine Journal, 2009
Nuclear factor-kappa B (NF-jB) is a gene transcriptional regulator of inflammatory cytokines. We investigated the transduction efficiency of NF-jB decoy to dorsal root ganglion (DRG), as well as the decrease in nerve injury, mechanical allodynia, and thermal hyperalgesia in a rat lumbar disc herniation model. Forty rats were used in this study. NF-jB decoy-fluorescein isothiocyanate (FITC) was injected intrathecally at the L5 level in five rats, and its transduction efficiency into DRG measured. In another 30 rats, mechanical pressure was placed on the DRG at the L5 level and nucleus pulposus harvested from the rat coccygeal disc was transplanted on the DRG. Rats were classified into three groups of ten animals each: a herniation ? decoy group, a herniation ? oligo group, and a herniation only group. For behavioral testing, mechanical allodynia and thermal hyperalgesia were evaluated. In 15 of the herniation rats, their left L5 DRGs were resected, and the expression of activating transcription factor 3 (ATF-3) and calcitonin gene-related peptide (CGRP) was evaluated immunohistochemically compared to five controls. The total transduction efficiency of NF-jB decoy-FITC in DRG neurons was 10.8% in vivo. The expression of CGRP and ATF-3 was significantly lower in the herniation ? decoy group than in the other herniation groups.
Upregulation of Inflammatory Mediators in a Model of Chronic Pain after Spinal Cord Injury
Neurochemical Research, 2011
Chronic neuropathic pain is a disabling condition observed in large number of individuals following spinal cord injury (SCI). Recent progress points to an important role of neuroinflammation in the pathogenesis of central neuropathic pain. The focus of the present study is to investigate the role of proinflammatory molecules IL-1β, TNF-α, MCP-1, MMP-9 and TIMP-1 in chronic neuropathic pain in a rodent model of SCI. Rats were subjected to spinal cord contusion using a controlled linear motor device with an injury epicenter at T10. The SCI rats had severe impairment in locomotor function at 7 days post-injury as assessed by the BBB score. The locomotor scores showed significant improvement starting at day 14 and thereafter showed no further improvement. The Hargreaves' test was used to assess thermal hyperalgesia for hindpaw, forepaw and tail. A significant reduction in withdrawal latency was observed for forepaw and tail of SCI rats at days 21 and 28, indicating the appearance of thermal hyperalgesia. Changes in expression of mRNAs for IL-1β, TNF-α, MCP-1, MMP-9 and TIMP-1 were assessed using realtime polymerase chain reaction in spinal cord including the injury epicenter along with regions above and below the level of lesion at day 28 post-injury. A significant increase was observed in
Spine, 2007
S~udy' Design. In vitro studi!,! §:'of the effects af proin-flamm<itory cytokines on the prr~uction of nerve growth factor'(,NGF) by human intervertebral disc (IVO) cells. Oh;ective. To determine th~'~bnstitutive expression arid production of NGF and the effect ofcytokines on the expression of NGF by humanJYD'cells. Sum~ary of the Background 01tta. NGF may playa role i~t6e collateral sprouting of sen'soiy''8xons, neural sUlVival, and regul(ition of nociceptive, 'se~,sory neurons. NGF is kf)owh~,to ,be up-regulated by phjinflammatory cytokines, Methods. The presence of NG~prPtejn~was analyzed by immullohistochemistry using hU,man IVD cells obtained fr°rilca9averic human spines~,it,h'IlO known disc disease {MRI.'}rbpmpson grades 2-41." The, effects, of interJeukin.1(3 (IL-J73T\~nd, tumor necrosis faCtor-g~JTNF-at on NGF production,'3~(t mHNA expression of,f':J:G~:b'i<IVD cells were examined;~T0he, expression of NGFr~qeptors, trkA and p75NGFf\ was"a,I~9,assessed immunohistol;:hemically. R~~ults.,Cadaveric amilus,fiht6s'us(AF) and nucleus 2 pdjP9~us IN?) cells culturedin:Vit~oin
Spine, 2014
Study Design. Animal study. Objective. To evaluate pain behavior and neuropeptide changes in the spinal dorsal horn after sciatic nerve compression and application of nucleus pulposus (NP) in rats. Summary of Background Data. The pathomechanisms of lumbar disc herniation pain have not been fully elucidated. Painassociated neuropeptides, including substance P and calcitonin gene-related peptide (CCRP), are produced in dorsal root ganglion neurons and transported to spinal dorsal horn nerve terminals where they function in pain transmission. However, changes in CGRPimmunoreactive (IR) sensory nerve terminals have not been reported in models of disc herniation. This study evaluated pain-related behavior and changes in CGRP-IR terminals in the spinal dorsal horn after combined sciatic nerve compression and NP application. Methods. Five groups of rats underwent either sciatic nerve compression with NP (n = 20), application of NP only (n = 20), nerve compression only (n = 20), and sham operation with neither compression nor NP (n = 20) or no operation (controls, n = 20). Mechanical hyperalgesia was measured every second day for 3 weeks. CCRP-IR terminals in each spinal dorsal horn lamina
Experimental Neurology, 2001
Cytokines may be pathophysiologically involved in hyperalgesia. Uncertainty exists about the types of cytokines and their site of action. To study the role of key pro-and anti-inflammatory cytokines in a chronic constriction model of neuropathic pain, mRNA expression of TNF, IL-1, IL-6, and IL-10 was quantified using competitive RT-PCR. Each cytokine mRNA in rat sciatic nerve was examined at days 3, 7, 14, and 45 after chronic constriction injury (CCI). We also undertook behavioral testing of these rats. Thermal warming and touch thresholds were significantly reduced at days 3, 7, and 14 in the CCI group, compared with the shamoperated group. Cytokine gene expression in sciatic nerve was significantly increased at day 7 for IL-1 and IL-6 and at day 14 for TNF. Expression of IL-10 underwent a gradual and progressive increase, reaching statistical significance at day 45.
eLife
Sciatic nerve crush injury triggers sterile inflammation within the distal nerve and axotomized dorsal root ganglia (DRGs). Granulocytes and pro-inflammatory Ly6Chigh monocytes infiltrate the nerve first and rapidly give way to Ly6Cnegative inflammation-resolving macrophages. In axotomized DRGs, few hematogenous leukocytes are detected and resident macrophages acquire a ramified morphology. Single-cell RNA-sequencing of injured sciatic nerve identifies five macrophage subpopulations, repair Schwann cells, and mesenchymal precursor cells. Macrophages at the nerve crush site are molecularly distinct from macrophages associated with Wallerian degeneration. In the injured nerve, macrophages ‘eat’ apoptotic leukocytes, a process called efferocytosis, and thereby promote an anti-inflammatory milieu. Myeloid cells in the injured nerve, but not axotomized DRGs, strongly express receptors for the cytokine GM-CSF. In GM-CSF-deficient (Csf2-/-) mice, inflammation resolution is delayed and cond...