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Introduction: Various drugs are used to treat patients with neuropathic pain; however, optimal treatment using acetaminophen (A) and/or tramadol (T) remains unclear. The evidence supporting the drug choice and the timing of administration is insufficient. Therefore, the objective of the present study was to investigate the effect of T and/or A on pain-related behavior in a nucleus pulposus (NP) rat model.Materials and Methods: Sprague-Dawley rats (n = 180) were divided into NP-A (52 mg/kg), NP-T (6 mg/kg), NP-AT (combined A and T), NP-S (saline), and sham groups (n = 36 per group). The rats received 0.2 mL of treatment solution orally once daily for 7 days after application of NP on the left L5 dorsal root ganglion (DRG). Behavioral testing and immunohistochemistry analysis for some markers' expressions in DRGs and the spinal cord were performed.Results: Pain thresholds in the NP-AT group did not significantly differ from the sham at all time points, while those were significantly lower in the NP-A and in the NP-T groups at D7 and/or D14 (p < 0.05). Tumor necrosis factor-α in the NP-S group was significantly higher at D2 and D7 (p < 0.05). Among the three treatment groups, activating transcriptional factor 3 and growth-associated protein 43 showed a tendency toward an increase at D7-D21.Conclusion: Combined administration of acetaminophen and tramadol maintained in the pain threshold in the rat NP model. These findings suggest that the combination of acetaminophen and tramadol might be a potential therapeutic modality for patients with lumbar disc herniation. These slides can be retrieved under Electronic Supplementary Material. [ABSTRACT FROM AUTHOR]

Introduction: Neuropathic pain, commonly related to intervertebral disk (IVD) degeneration, responds poorly to standard pain treatments. Serotonin-noradrenaline reuptake inhibitors (SNRIs) have been reported to reduce neuropathic pain; however their effect on radiculopathy induced by lumbar disk herniation remains unclear. The aim of this study was to investigate the effect of SNRI duloxetine in rat model of IVD-related neuropathic pain.Materials and Methods: Effects of SNRI duloxetine were tested in Sprague-Dawley rats (n = 135). Neuropathic pain was induced by applying autologous nucleus pulposus (NP) on the left L5 dorsal root ganglion (DRG). Duloxetine in concentrations 0.4 mg/kg (low dose) and 1.2 mg/kg (high dose) or saline were administered orally for 10 days. Von Frey test was carried out on post-operative days 2, 7, 14, 21, and 28 to test pain sensitivity. Immunohistochemistry of L5 DRG and L5 segment of spinal cord (SC) was performed on days 7 and 21 to examine expressions of tumor necrosis factor alpha (TNF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ionized calcium-binding adapter molecule 1 (Iba1). On days 14, 21, and 28, expressions of TNF in DRG as well as NGF and BDNF in SC were tested by immunoblotting. Sham-operated rats and naive rats were used as controls.Results: Duloxetine in both concentrations significantly improved pain threshold from postoperative day 21 onward, compared to the NP + saline group (p < 0.05). High-dose duloxetine significantly inhibited the expression of TNF in DRG (day 28, p < 0.05). Both duloxetine concentrations reduced the expression of NGF in SC (day 21, p < 0.05), but the expression of BDNF remained unchanged.Conclusion: SNRI duloxetine inhibited neuropathic pain in rats possibly via down-regulating TNF, NGF, and microglia activation. We conclude that duloxetine, and most likely other SNRIs, may be used for the management of lumbar neuropathic pain. [ABSTRACT FROM AUTHOR]

Reduction of blood flow in compressed nerve roots is considered as one important mechanism of induction of neurogenic intermittent claudication in lumbar spinal canal stenosis. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, and is increased in expression in hypoxic conditions. The objective of this study was to examine if cauda equina compression affects motor function and induces expression of VEGF and angiogenesis. The cauda equina was compressed by placing a piece of silicone rubber into the L5 epidural space. Walking duration was examined by rota-rod testing. The compressed parts of the cauda equina and L5 dorsal root ganglion (DRG) were removed at 3, 7, 14, or 28 days after surgery, and processed for immunohistochemistry for VEGF and Factor VIII (marker for vascular endothelial cells). Numbers of VEGF-immunoreactive (IR) cells and vascular density were examined. Walking duration was decreased after induction of cauda equina compression. The number of VEGF-IR cells in the cauda equina and DRG was significantly increased at 3, 14, and 28 days after cauda equina compression, compared with sham-operated rats (P < 0.05). Vascular density in the cauda equina was not increased at any of the time points examined. Cauda equina compression decreased walking duration, and induced VEGF expression in nerve roots and DRG. [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.

The article presents a medical research on compensatory neovascularization after cauda equina compression in rats. The study observed the ischemic changes in the cauda equina after surgery and the increased expression of vascular endothelial growth factor (VEGF) and neovascularization. It revealed that cauda equina compression seems to induce compensatory neovascularization accompanied by an increase in VEGF expression.

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]

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: A controlled, interventional animal study.Objective: The aim of this study was to evaluate the effect of diabetes mellitus (DM) on radiculopathy due to lumbar disc herniation (LDH), by investigating pain-related behavior and the expression of tumor necrosis factor-alpha (TNF-α) and growth-associated protein 43 (GAP43) in type 2 diabetic rats following application of nucleus pulposus (NP) to the dorsal root ganglion (DRG).Summary Of Background Data: Previous clinical studies suggested negative effects of DM on radiculopathy due to LDH, and that inflammation and nerve regeneration could interact with DM and radiculopathy.Methods: We applied autologous NP to the left L5 DRG of adult male Wistar rats and Goto-Kakizaki rats. Behavioral testing measured the mechanical withdrawal threshold of rats. We immunohistochemically evaluated the localization of ionized calcium-binding adapter molecule-1 (Iba-1), receptor of advanced glycation end products (RAGE), and TNF-α in DRGs. TNF-α and GAP43 expression levels in DRG were determined by quantitative real-time PCR and western blotting.Results: The mechanical withdrawal threshold significantly declined in the non-DM NP group compared with the non-DM sham group for 28 days, whereas the decline in threshold extended to 35 days in the DM NP group compared with the DM sham group. RAGE and TNF-α expression in DRGs was colocalized in Iba-1 positive cells. The non-DM NP rats had higher TNF-α protein expression levels versus the non-DM sham rats on day 7, and the DM NP group had higher levels versus the DM sham group on days 7 and 14. The non-DM NP group had higher GAP43 mRNA expression than the non-DM sham group for 28 days, while the DM NP group had a higher level than the DM sham group for 35 days.Conclusion: DM prolongs the pain-related behavior caused by NP. The prolonged inflammation and nerve regeneration could elucidate the pathogenesis of continuous pain of radiculopathy initiated by LDH.Level Of Evidence: N /A. [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 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.

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. [ABSTRACT FROM AUTHOR]