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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]

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]