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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: Chronic pain has an impact on psychological and social factors. It is known that stress influences physiological and behavioral changes and affects several neurotransmitter and hormonal systems. It is also known that corticosterone is increased by stress. The role of chronic stress in sciatica in lumbar disc herniation (LDH) in rats has not been investigated. The aim of this study was to investigate the effect of the restraint stress (RS) on pain-related behavior induced by application of nucleus pulposus (NP) in rats. Materials and methods: Adult female Sprague-Dawley rats were divided into six experimental groups (naive group; naive + RS; sham group; sham + RS; autologous nucleus pulposus [NP] applied on the left L5 nerve root [NP group]; and NP + RS group). Von Frey tests were used to test pain-related behavior. Concentrations of plasma corticosterone were measured to assess changes in levels of endogenous corticosterone caused by RS. Expression of ATF-3 in the left L5 DRG was examined by immunohistochemical analyses in each group. Results: Mechanical withdrawal thresholds of the NP and NP + RS groups were significantly decreased after surgery compared with the naive group. Although the thresholds in the NP group recovered after 28 days, the thresholds in the NP + RS group were significantly decreased during the 42 days after surgery. RS increased the concentration of plasma corticosterone at 21 and 42 days after surgery. In the NP and the NP + RS groups, the expression of ATF-3 was significantly increased at 7 days after surgery. The expression of ATF-3 was sustained for 21 days by RS. Conclusion: Concentrations of plasma corticosterone were increased in three groups that underwent RS. The pain-related behavior persisted for the long term in the LDH model. The expression of ATF-3 in DRG neurons increased for 21 days by RS. These results suggest that RS plays a role in the chronicity of pain-related behavior in the LDH rats. [ABSTRACT FROM AUTHOR]

Introduction: Some antidepressants are effective for treating neuropathic pain independent of any effect on depression. Selective serotonin reuptake inhibitors (SSRIs) are one of the potential agents to treat neuropathic pain. The aims of this study were to compare the effects of SSRI and non-steroidal anti-inflammatory drugs (NSAIDs) on pain-related behavior and expression of cytokines in a rat model of neuropathic pain. Materials and methods: Spinal surgery was performed to apply nucleus pulposus (NP) to the dorsal root ganglion (DRG). NP animals were treated with saline (NP + S), meloxicam (NP + M), or low-dose or high-dose paroxetine (NP + PL and NP + PH), respectively. Behavioral testing was performed to investigate the mechanical withdrawal thresholds. The numbers of TNF-immunoreactive (IR) neurons in the DRG and of Iba1-IR microglia in the spinal cord (SC) were evaluated using immunohistochemistry. Expression of TNF in the DRG was examined using Western blots. Results: The thresholds on days 14, 21, and 28 were higher in the drug-treated animals than in the NP + S group ( p < 0.05). The number of TNF-IR neurons in DRGs from the NP + M group increased on day 2 and decreased on day 7, and TNF expression in DRGs was significantly higher in the NP + S group than in the NP + M group on days 7, 14. The number of Iba1-IR microglia in the SC was significantly higher in the NP + S group than in the NP + M, NP + PL, and NP + PH groups on days 7 and 14. Conclusion: An antidepressant might be a potential agent to treat lumbar disc herniation as well as NSAIDs. [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 presents a study on the interaction of 5-hydroxytryptamine (5-HT) with tumor necrosis factor (TNF) for pain related behavior in a model of rat lumbar disc herniation (LDH). There were six groups of adult female Sprague-Dawley rats. It was found that 5-HT and TNF both induce pain-related behavior and interact with one another to prolong pain-related behavior in the model.

The article presents a study on pain mechanisms through introduction of nucleus pulposus (NP) in the dorsal root ganglion (DRG) of rats. It says that immunohistochemistry and immunoblotting were performed on rats to determine the action of NP and tumor necrosis factor-alpha (TNF-α). Pain-related behavior was noted to originate from activation of macrophages and glial cells in DRG. It concludes that neuropathic pain states are associated with activities of macrophages and glial cells.

The article presents a study which observes the reaction of glial cells and endoneural macrophages positioned in the dorsal root ganglion in rats. It states that activated satellite glial cells expressed glial cell-line derived neurotrophic factor (GDNF) which expression thereof was significantly increased and persisted for 28 days. Results show that mechanical withdrawal threshold was significantly decreased for 28 days.