Search

Study Design: Controlled, interventional animal study., Objective: To examine the effect of an inhibitor of acid-sensing ion channel 3 (ASIC3) on pain-related behavior induced by application of the nucleus pulposus (NP) onto the dorsal root ganglion (DRG) in rats., Summary of Background Data: ASIC3 is associated with acidosis pain in inflamed or ischemic tissues and is expressed in sensory neurons and NP cells. The ASIC3 inhibitor, APETx2, increases the mechanical threshold of pain in models of knee osteoarthritis or postoperative pain. However, the efficacy of APETx2 for pain relief in the NP application model remains unknown., Methods: Autologous NP was applied to the left L5 nerve root of 183 adult female Sprague-Dawley rats. The DRGs were treated with NP plus one of the following four treatments: saline solution (SM), low (0.01 μg: LD), medium (0.1 μg: MD), or high dose (1.0 μg: HD) of APETx2. Behavioral testing was performed to investigate the mechanical withdrawal threshold using von Frey hairs. Expression of nerve growth factor, hypoxia-inducible factor-1α (HIF1α), activating transcription factor-3, and ionized calcium-binding adaptor molecule-1 was evaluated using immunohistochemistry. Statistical differences among multiple groups were assessed using the Steel test, the Tukey-Kramer test, and the Dunnett test. P < 0.05 were considered significant., Results: The thresholds in the HD group were higher than those in the SM group at Days 14 and 21 (P < 0.05). In the MD group, the threshold was higher than in the SM group at Day 14 (P < 0.05). High doses of APETx2 reduced the expression of HIF1α after Day 14 compared with the SM group (P < 0.05)., Conclusion: APETx2 significantly improved pain-related behavior in a dose-dependent manner. APETx2 may inhibit ASIC3 and partly inhibit Nav1.8 channels. This ASIC3 channel inhibitor may be a potential therapeutic agent in early-stage lumbar disc herniation., Level of Evidence: N/A.

Background: The aim of this study was to clarify pain, quality of life and activity in the aged evacuees living in temporary housing after the Great East Japan Earthquake on 11 March 2011., Methods: The study was a cross-sectional study performed in Minamisoma City, Fukushima Prefecture 1 year and 6 months after the disaster. Inclusion criteria were the ability to walk independently and consent to answer questionnaires. Seventy-one evacuees who met the inclusion criteria were included in this study. There were 16 men and 55 women with a mean age of 75.9 years. Sixty evacuees were surveyed when they gathered at the assembly hall in the temporary housing (Assembled group) and 11 evacuees were surveyed through individual visits to their residences (Individual group). Evacuees in the Individual group agreed to participate in this study, but refused to visit the assembly hall to engage in exercise and recreation. Pain, quality of life (QOL) and level of activity were assessed with the Numeric Rating Scale (NRS), the MOS Short-Form 36 item Health Survey (SF-36) and a pedometer, respectively. Student's t-test, Mann-Whitney U test, and Fisher's exact test were used for statistical analysis., Results: Forty-four (62.0 %) residents had chronic pain with a mean NRS of 2.74. Twenty-one (29.6 %) of these residents had relatively severe pain rated 5 or above on the NRS. QOL was significantly lower for the subscales of "physical functioning," "role physical", "general health", "social functioning", "role emotional" and "mental health", when compared with the national standard values. Values were also visibly lower for "physical component summary" in the summary score. On comparing the Assembled group and the Individual group, "physical function", "role physical", "social functioning" and "physical component summary" were found to be significantly lower in the Individual group. The mean daily number of steps was 1,892 in the Individual group and 4,579 in the Assembled group. The Individual group thus significantly took less mean daily number of steps compared with the Assembled group., Conclusions: This study quantified the state of pain, QOL and activity of aged evacuees living in temporary housing after the Great East Japan Earthquake. The evacuees frequently had chronic pain and lower physical and mental QOL scores compared to the national standard values.

Study Design: Descriptive and mechanistic investigation of the anti-inflammatory and anticatabolic effect of resveratrol in intervertebral discs (IVDs) in vitro and of the analgetic effect in vivo., Objective: To determine whether resveratrol may be useful in treating nucleus pulposus (NP)-mediated pain., Summary of Background Data: Proinflammatory cytokines seem to be key mediators in the development of NP-mediated pain. Patients with discogenic or radiculopathic pain may substantially benefit from anti-inflammatory substances that could be used in a minimal-invasive treatment approach. Resveratrol, a polyphenolic phytoalexin found in red wine exhibits anti-inflammatory effects in various cell types and tissues, but no data exists so far with regards to the IVD in the context of low back and leg pain., Methods: In part 1, the anti-inflammatory and anticatabolic effect of resveratrol was investigated in a cell culture model on interleukin 1β (IL-1β) prestimulated human IVD cells on the gene and protein expression level. In part 2, the molecular mechanisms underlying the effects observed upon resveratrol treatment were investigated (toll-like receptors, nuclear factor κB, sirtuin 1 (SIRT1), mitogen-activated protein (MAP) kinases p38/ERK/JNK). In part 3, the analgetic effects of resveratrol were investigated in vivo using a rodent model of radiculopathy and von Frey filament testing. All quantitative data were statistically evaluated either by Mann-Whitney U test or by one-way analysis of variance and Bonferroni post hoc testing (P < 0.05)., Results: In vitro, resveratrol exhibited an anti-inflammatory and anticatabolic effect on the messenger RNA and protein level for IL-6, IL-8, MMP1, MMP3 and MMP13. This effect does not seem to be mediated via the MAP kinase pathways (p38, ERK, JNK) or via the NF-κB/SIRT1 pathway, although toll-like receptor 2 was regulated to a minor extent. In vivo, resveratrol significantly reduced pain behavior triggered by application of NP tissue on the dorsal root ganglion for up to 14 days., Conclusion: Resveratrol was able to reduce levels of proinflammatory cytokines in vitro and showed analgetic potential in vivo. A decrease in proinflammatory cytokines may possibly be the underlying mechanism of pain reduction observed in vivo. Resveratrol seems to have considerable potential for the treatment of NP-mediated pain and may thus be an alternative to other currently discussed (biological) treatment options.

Study Design: The effects of exogenous 5-hydroxytryptamine (5-HT), tumor necrosis factor(TNF)-α, 5-HT + TNF in combination, and autologous nucleus pulposus (NP) at dorsal root ganglion (DRG) were examined using rat models., Objective: To examine the interaction of 5-HT with TNF for pain-related behavior in a rat lumbar disc herniation (LDH) model., Summary of Background Data: 5-HT and TNF have been shown to play roles in sciatica in lumbar disc herniation as chemical factors., Methods: Adult female Sprague-Dawley rats were divided into six groups: 5-HT group, TNF group, 5-HT + TNF (combination) group, NP group, control group, and naive group. Von Frey tests were used for pain-related behavior testing. Expressions of activating transcription factor 3 and calcitonin gene-related peptide (CGRP) were evaluated immunohistochemically. Expressions of TNF, TNF receptor 1 (TNFR1), and 5-HT2A receptors in the left L5 DRG were examined using western blotting. Plasma levels of 5-hydroxyindole acetic acid, a metabolite of 5-HT, were measured., Results: Mechanical withdrawal thresholds were significantly decreased in the 5-HT, TNF, combination, and NP groups compared with controls. Thresholds recovered after 14 days in the 5-HT and TNF groups, and after 28 days in the combination group. Exogenous 5-HT and TNF to the nerve root induced pain-related behavior and lasted for a shorter period compared with combination and NP groups. Activating transcription factor 3- and calcitonin gene-related peptide-immunoreactive DRG neurons were significantly increased only in the early phase in 5-HT, TNF, combination, and NP groups. TNF induced 5-HT2A receptor expressions in the DRG, while 5-HT induced TNF and TNF receptor 1 expressions., Conclusion: The present findings suggest that both 5-HT and TNF induce pain-related behavior and interact with each other to prolong pain-related behavior in a rat LDH model.

Study Design: this study was designed to examine the neuroprotective effects of asialo-erythropoietin (A-EPO) in a rat model of lumbar disc herniation., Objective: to investigate the effects of A-EPO on pain-related behavior, the expression of phosphorylated-p38 (p-p38) mitogen activated kinase, and the expression of tumor necrosis factor alpha (TNF-α) induced by nucleus pulposus (NP) application on the nerve root., Summary of Background Data: erythropoietin (EPO) has neuroprotective effects in a variety of models of central and peripheral nerve injuries. However, EPO is a hematopoietic growth factor and can therefore cause significant side effects such as thicker blood and promotion of blood clotting. A-EPO is a neuroprotective derivative of EPO that is not hematopoietic., Methods: female Sprague-Dawley rats (n = 149) were used in this study. NP harvested from the tail was applied to the left L5 nerve root and the rats were then divided into four groups: NP + nontreatment group, no further treatment; NP + A-EPO group, 13.4 microg/kg A-EPO; NP + EPO group, 13.4 microg/kg EPO; and NP + vehicle group, received vehicle. The substances were administered subcutaneously 1 day before surgery and daily for 2 weeks. In the sham group of animals, the L5 nerve root was exposed and NP was not applied. Withdrawal thresholds were determined by the von-Frey test 28 days after surgery. The expressions of p-p38 and TNF-α were assessed by immunohistochemical and immunoblotting analysis. Data were analyzed by unpaired Student t test and Dunnett t test (significance level, P < 0.05)., Results: in the NP + nontreatment and NP + vehicle groups, withdrawal thresholds were decreased significantly for 28 days compared with the sham group (P < 0.05). In the NP + A-EPO group, the thresholds were significantly increased on day 28, and in the NP + EPO group, the thresholds were significantly increased on days 21 and 28 (P < 0.05) compared with the NP + nontreatment and NP + vehicle groups. The expression of p-p38 in the NP + A-EPO group was significantly lower than that in the NP + vehicle group on day 1 (P < 0.05). The expression of TNF in the NP + A-EPO and NP + EPO groups was significantly lower than that in the NP + vehicle group on days 1 and 7 (P < 0.05)., Conclusions: A-EPO improved pain-related behavior and reduced the expression of p-p38 and TNF-α. The effect of A-EPO may be related to the inhibitory action of p-p38 and TNF-α in the dorsal root ganglion.

Symptomatic induction of disc herniation involves both mechanical compression and chemical factors. Inhibitors of tumor necrosis factor-alpha (TNF-α) are known to reduce pain-related behavior in experimental models. Animals were divided into mechanical compression (MC) group; a stainless steel rod was inserted on the dorsal root ganglion, nucleus pulposus (NP) group: NP was harvested from the coccygeal vertebral disc, MC and NP group; rats were received stainless rod and NP, and sham group; rats were received neither rod nor NP. Rats in the MC group received a TNF-α antibody (10 mg/kg) (antibody group) or were not treatment (untreated group). The withdrawal thresholds of the MC, NP and MC+NP groups decreased significantly compared with the sham group. In the antibody group, the threshold was significantly higher than that of the untreated group. An anti-TNF-α antibody reduced allodynia caused by DRG compression.

Study Design: Controlled, interventional, animal study., Objective: To observe the reaction of glial cells and endoneurial macrophages in the dorsal root ganglion (DRG) after application of nucleus pulposus (NP) and investigate whether activated DRG glial cells play a role in the pathogenesis of neuropathic pain., Summary of Background Data: Peripheral nerve injury activated DRG and spinal cord glial cells and several cytokines and neurotrophins released from these activated glial cells might induce pain hypersensitivity., Methods: Adult male Sprague-Dawley rats were used. NP harvested from the tail was applied to the left L5 DRG. Behavioral testing was performed to investigate the mechanical withdrawal threshold. The numbers of activated satellite glial cells and endoneurial macrophages were counted, and the expressions of tumor necrosis factor-alpha (TNF-alpha) and glial cell-line derived neurotrophic factor (GDNF) were examined by double-labeled immunohistochemistry and immunoblotting., Results: The mechanical withdrawal threshold was significantly decreased for 28 days and then gradually recovered (P < 0.05). Long-term activation of endoneurial macrophages and satellite glial cells in the DRG was observed, and the reactions of these cells correlated well with pain-related behavior. TNF-alpha was expressed in both endoneurial macrophages and activated satellite glial cells, and TNF-alpha expression was significantly increased in the early stage (P < 0.05). Activated satellite glial cells also expressed GDNF, and its expression was significantly increased and persisted for 28 days (P < 0.05)., Conclusion: Activation of DRG glial cells and endoneurial macrophages plays an important role in the pathogenesis of the neuropathic pain state. TNF-alpha actively released from activated glial cells and endoneurial macrophages in the DRG might initiate and maintain the neuropathic pain together with TNF-alpha derived from the applied NP. In the recovery phase, persistent expression of GDNF from activated satellite glial cells might play an important role to restore the function of damaged neurons and recover from neuropathic pain.

Study Design: An experimental animal study., Objective: To study if antitumor necrosis factor-alpha (TNF-alpha) antibody, which is administered at different times, reduces the pain behavior induced by application of nucleus pulposus (NP) to the nerve root., Summary of Background Data: Treatment with TNF-alpha inhibitor reduces the pain-related behavior induced by epidural application of NP in rats., Methods: Left L5 partial laminectomy was performed and NP was applied to the L5 nerve root in 24 rats. The rats were divided into 4 groups. In 3 groups, anti-rat TNF-alpha antibody was intravenously administered immediately after, or 6 or 20 days after NP application. The fourth group was not treated with anti-rat TNF-alpha antibody (untreated rats). The withdrawal threshold of the plantar surface was determined 1 day before up through 28 days after NP application., Results: The withdrawal threshold of rats that had been treated with anti-rat TNF-alpha antibody immediately after or 6 days after, but not 20 days after, NP application, was significantly higher than that of the untreated rats., Conclusions: Anti-TNF-alpha antibody reduced allodynia only when it was administered soon after the onset of allodynia. Late administration of anti-TNF-alpha antibody did not have an antiallodynic effect.

Background: The aim of this study was to clarify pain, quality of life and activity in the aged evacuees living in temporary housing after the Great East Japan Earthquake on 11 March 2011.Methods: The study was a cross-sectional study performed in Minamisoma City, Fukushima Prefecture 1 year and 6 months after the disaster. Inclusion criteria were the ability to walk independently and consent to answer questionnaires. Seventy-one evacuees who met the inclusion criteria were included in this study. There were 16 men and 55 women with a mean age of 75.9 years. Sixty evacuees were surveyed when they gathered at the assembly hall in the temporary housing (Assembled group) and 11 evacuees were surveyed through individual visits to their residences (Individual group). Evacuees in the Individual group agreed to participate in this study, but refused to visit the assembly hall to engage in exercise and recreation. Pain, quality of life (QOL) and level of activity were assessed with the Numeric Rating Scale (NRS), the MOS Short-Form 36 item Health Survey (SF-36) and a pedometer, respectively. Student's t-test, Mann-Whitney U test, and Fisher's exact test were used for statistical analysis.Results: Forty-four (62.0 %) residents had chronic pain with a mean NRS of 2.74. Twenty-one (29.6 %) of these residents had relatively severe pain rated 5 or above on the NRS. QOL was significantly lower for the subscales of "physical functioning," "role physical", "general health", "social functioning", "role emotional" and "mental health", when compared with the national standard values. Values were also visibly lower for "physical component summary" in the summary score. On comparing the Assembled group and the Individual group, "physical function", "role physical", "social functioning" and "physical component summary" were found to be significantly lower in the Individual group. The mean daily number of steps was 1,892 in the Individual group and 4,579 in the Assembled group. The Individual group thus significantly took less mean daily number of steps compared with the Assembled group.Conclusions: This study quantified the state of pain, QOL and activity of aged evacuees living in temporary housing after the Great East Japan Earthquake. The evacuees frequently had chronic pain and lower physical and mental QOL scores compared to the national standard values. [ABSTRACT FROM AUTHOR]

The article reports on the evaluation of the effects of exogenous five-hydroxytryptamine (5-HT) applied on the nerve root on pain-related behavior, the release of endogenous 5-HT in plasma and the expression of receptors in dorsal root ganglion in a rat lumbar disc hermiation model. Exogenous 5-HT to the nerve root induced pain-related behavior compared with the nucleus pulposus application.

Study Design: Controlled, interventional, animal study.Objective: To investigate the spatial and temporal changes of μ-opioid receptor (MOR) expression in a rat lumbar disc herniation (LDH) model.Summary Of Background Data: MORs widely express in the peripheral and central nervous systems, and opioid drugs produce an analgesic effect through their activation. However, the efficacy of opioid drugs is sometimes inadequate in several pathological conditions of pain. MORs in the brain as well as the spinal cord (SC) and dorsal root ganglion (DRG) are thought to be associated with pain-related behavior, but the underlying mechanisms are not completely understood.Methods: In all, 91 adult female Sprague-Dawley rats were used. Autologous nucleus pulposus (NP) was applied onto the left L5 DRG in the NP group rats. Rats were divided into two surgical groups, the NP and the sham group. The von Frey test of left hind paw was performed before surgery, and 2, 7, 14, 21 and 28 days after surgery. Immunohistochemistry and immunoblotting in the DRG, SC, Caudate putamen, nucleus accumbens (NAc) and periaqueductal grey matter were performed before surgery, and 2, 7, 14, 21 and 28 days after surgery.Results: The thresholds in the NP group were significantly lower than those in the sham group from day 2 onwards. At days 7 and 14, MOR expression in the injured-side SC and DRG were significantly lower than those in the sham group. At day 21, MOR in the NAc was significantly decreased compared to that in the sham group.Conclusion: Changes of MOR expression in the NAc, SC and DRG were associated with pain-related behavior. This result might show the underling pathogenesis of the resistance to MOR agonists in the patient with LDH.Level Of Evidence: N/A. [ABSTRACT FROM AUTHOR]

Background The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) was developed in 2007, including the five domains of Pain-related disorder, Lumbar spine dysfunction, Gait disturbance, Social life disturbance, and Psychological disorder. It is used by physicians to evaluate treatment efficacy by comparing scores before and after treatment. However, the JOABPEQ does not allow evaluation of the severity of a patient's condition compared to the general population at a single time point. Given the unavailability of a standard measurement of back pain, we sought to establish reference scores and interquartile ranges using data obtained from a multicenter, cross-sectional survey taken in Japanese primary care settings. Methods The Lumbar Spinal Stenosis Diagnosis Support Tool project was conducted from 2011 to 2012 in 1657 hospitals in Japan to investigate the establishment of reference scores using JOABPEQ. Patients aged ≥ 20 years undergoing medical examinations by either non-orthopaedic primary care physicians or general orthopedists were considered for enrollment. Results A total of 10,651 consecutive low back pain patients (5331 men, 5320 women, 18 subjects with missing sex data) who had undergone a medical examination were included. Reference scores and interquartile ranges for each of the five domains of the JOABPEQ according to age and sex were recorded. The median score and interquartile range are the same in the domain of Pain-related disorder in all ages and sexes. The reference scores for Gait disturbance, Social life disturbance and Psychological disorder declined with increasing age in both age- and sex-stratified groups, while there was some different trend in Lumbar spine dysfunction between men and women. Conclusion Reference scores and interquartile ranges for JOABPEQ were generated based on the data from the examination data. These provide a measurement standard to assess patient perceptions of low back pain at any time point during evaluation or therapy. [ABSTRACT FROM AUTHOR]

Study Design: An experimental animal study.Objective: To investigate the relationship between pain-related behavior and the expression of neurotrophic factors in the dorsal root ganglion (DRG) and spinal cord (SC) using a nucleus pulposus (NP) rat model.Summary Of Background Data: Neurotrophic factors are released from activated glial cells and are associated with pain-related behavior. Nerve growth factor (NGF) is a neurotrophic factor that is induced by inflammation.Methods: Rats were divided into an NP group (n = 94) and a sham-operated group (n = 46). NP harvested from the tail was applied to the left L5 DRG. Rats in the NP group were then divided into five subgroups: one non-treatment and four treatment groups. In the treatment groups, a dose of anti-NGF antibody or phosphate-buffered saline was administered into the DRG. Behavioral testing was performed to investigate the mechanical withdrawal threshold of the left hind paw for all groups. Immunohistochemical localization of NGF, phosphorylated p38 (p38), and brain-derived neurotrophic factor (BDNF) in the DRGs and SCs was performed, and the numbers of immunoreactive (IR) cells were counted.Results: The withdrawal threshold in the nontreatment NP group was significantly decreased for 35 days, and that of the middle- and high-dose treatment rats was significantly higher than the phosphate-buffered saline group values. In the DRG, NGF-IR, p38-IR, and BDNF-IR cells were increased for days 21. In the SC, BDNF-IR, and p38-IR cells were increased from days 7 to 21.Conclusion: In the DRG, NGF expression increased, mechanical thresholds were reduced, and p38 and BDNF expression was increased in the NP group. p38 and BDNF expression was increased in SC neurons during the same period. Inhibition of NGF may be a potential treatment for neuropathic pain due to lumbar disc herniation.Level Of Evidence: 5. [ABSTRACT FROM AUTHOR]

Study Design: Controlled, interventional animal study.Objective: To examine the effect of an inhibitor of acid-sensing ion channel 3 (ASIC3) on pain-related behavior induced by application of the nucleus pulposus (NP) onto the dorsal root ganglion (DRG) in rats.Summary Of Background Data: ASIC3 is associated with acidosis pain in inflamed or ischemic tissues and is expressed in sensory neurons and NP cells. The ASIC3 inhibitor, APETx2, increases the mechanical threshold of pain in models of knee osteoarthritis or postoperative pain. However, the efficacy of APETx2 for pain relief in the NP application model remains unknown.Methods: Autologous NP was applied to the left L5 nerve root of 183 adult female Sprague-Dawley rats. The DRGs were treated with NP plus one of the following four treatments: saline solution (SM), low (0.01 μg: LD), medium (0.1 μg: MD), or high dose (1.0 μg: HD) of APETx2. Behavioral testing was performed to investigate the mechanical withdrawal threshold using von Frey hairs. Expression of nerve growth factor, hypoxia-inducible factor-1α (HIF1α), activating transcription factor-3, and ionized calcium-binding adaptor molecule-1 was evaluated using immunohistochemistry. Statistical differences among multiple groups were assessed using the Steel test, the Tukey-Kramer test, and the Dunnett test. P < 0.05 were considered significant.Results: The thresholds in the HD group were higher than those in the SM group at Days 14 and 21 (P < 0.05). In the MD group, the threshold was higher than in the SM group at Day 14 (P < 0.05). High doses of APETx2 reduced the expression of HIF1α after Day 14 compared with the SM group (P < 0.05).Conclusion: APETx2 significantly improved pain-related behavior in a dose-dependent manner. APETx2 may inhibit ASIC3 and partly inhibit Nav1.8 channels. This ASIC3 channel inhibitor may be a potential therapeutic agent in early-stage lumbar disc herniation.Level Of Evidence: N/A. [ABSTRACT FROM AUTHOR]

The article provides information on an experimental animal study that evaluated the efficacy of lactoferrin (LF) compared with diclofenac to reduce pain, using a rat lumbar disc herniation model. LF is a multifunctional protein found in milk that has been reported to reduce nociception in various experimental models. It was concluded that LF might become useful as pain-killer because its analgesic effect continued during the whole experiment, while diclofenac's effect reduced with time.

The article reports on the investigation of the contralateral pain-related behavioral and immunohistochemical changes after hernilateral spinal nerve injury in rats. Contralateral mechanical allodynia induced by hernilateral spinal nerve injury is associated with the upregulation of satellite cells and tumor necrosis factor in the contralateral dorsal root ganglion. Spinal astrocytes play an important role in the contralateral changes.