• The Journal of Korean Physical Therapy
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• 제22권1호
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• pp.67-73
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• 2010

Purpose: We tested whether repetitive transcranial magnetic stimulation (rTMS) improved recovery following spinal cord injury (SCI) in rats with transplantation of adipose tissue-derived stromal cells (ATSCs). Methods: Twenty Sprague-Dawley rats (200-250 g, female) were used. Moderate spinal cord injury was induced at the T9 level by a New York University (NYU) impactor. The rat ATSCs (approximately $5{\times}10^5$ cells) were injected into the perilesional area at 9 days after SCI. Starting four days after transplantation, rTMS (25 Hz, 0.1 Tesla, pulse width=$370{\mu}s$, on/off time=3 sec/3 sec) was applied daily for 7 weeks. Functional recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale as well as pain responses for thermal and cold stimuli. Results: Both groups showed similar, gradual improvement of locomotor function. rTMS stimulation decreased thermal and cold hyperalgesia after 7 weeks, but sham stimulation did not. Conclusion: rTMS after transplantation of ATSCs in an SCI model may reduce thermal hyperalgesia and cold allodynia, and may be an adjuvant therapeutic tool for pain control after stem cell therapy in SCI.

• The Korean Journal of Pain
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• 제33권1호
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• pp.13-22
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• 2020

Background: The continuous search for a novel neuropathic pain drug with few or no side effects has been a main focus of researchers for decades. This study investigated the antinociceptive and neuroprotective effects of bromelain in sciatic nerve ligation-induced neuropathic pain in Wistar rats. Methods: Forty-eight Wistar rats randomly divided into eight groups comprised of six animals each were used for this study. Peripheral neuropathy was induced via chronic constriction of the common sciatic nerve. Thermal hyperalgesic and mechanical allodynia were assessed using a hotplate and von Frey filaments, respectively. The functional recovery and structural architecture of the ligated sciatic nerve were evaluated using the sciatic functional index test and a histological examination of the transverse section of the sciatic nerve. The neuroprotective effects of bromelain were investigated in the proximal sciatic nerve tissue after 21 days of treatment. Results: Bromelain significantly (P < 0.05) attenuated both the thermal hyperalgesia and mechanical allodynic indices of neuropathic pain. There were improvements in sciatic function and structural integrity in rats treated with bromelain. These rats showed significant (P < 0.05) increases in sciatic nerve nuclear transcription factors (nuclear factor erythroid-derived-2-related factors-1 [NrF-1] and NrF-2), antioxidant enzymes (superoxide dismutase and glutathione), and reduced membranelipid peroxidation compared with the ligated control group. Conclusions: This study suggest that bromelain mitigated neuropathic pain by enhancing the activities of nuclear transcription factors (NrF-1 and NrF-2) which increases the antioxidant defense system that abolish neuronal stress and structural disorganization.

• The Korean Journal of Pain
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• 제24권4호
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• pp.191-198
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• 2011

Background: Postlaminectomy peridural fibrosis is inevitable. Some studies have compared and identified the effects of high molecular weight hyaluronic acids (HMWHA) and low molecular weight hyaluronic acids (LMWHA) on peridural fibrosis in postlaminectomy animal models. However, no studies have been found that compare pain behaviors between hyaluronic acids or among hyaluronic acids and other solid materials. The purpose of this study was to examine the correlation between pain-related behaviors and histopathologic changes in laminectomized rats using various peridurally administered materials. Methods: Forty male Sprague-Dawley rats, laminectomized at the L5 and L6 levels, were divided into four groups: group C, laminectomy only; group L, laminectomy and LMWHA application; group H, laminectomy and HMWHA application; group F, laminectomy and fat interposition. Pain behaviors were checked before, 3 days, 1 week, and 3 weeks after surgery. Histopathological changes were checked at the L5 level 3 weeks after the surgery. Results: The 50% withdrawal thresholds in groups L and H were higher than that in groups C and F three days after laminectomy (P < 0.05). The paw withdrawal time did not change among the groups and in each group during the study period. Peridural fibrosis in group F was significantly lower than in the other groups (P < 0.05). Conclusions: Hyaluronic acids significantly reduced mechanical allodynia but not thermal hyperalgesia. Peridural fibrosis did not show any correlation with pain behaviors. There have been limited studies on the correlation between peridural fibrosis and pain behavioral change, which should be verified by further studies.

• The Korean Journal of Pain
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• 제35권2호
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• pp.173-182
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• 2022

Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins' antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the anti-nociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.

• The Korean Journal of Pain
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• 제35권3호
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• pp.271-279
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• 2022

Background: Inflammation is known to underlie the pathogenesis in neuropathic pain. This study investigated the anti-inflammatory and neuroprotective mechanisms involved in antinociceptive effects of co-administration of acetaminophen and L-carnosine in chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. Methods: Fifty-six male Wistar rats were randomly divided into seven experimental groups (n = 8) treated with normal saline/acetaminophen/acetaminophen + L-carnosine. CCI was used to induce neuropathic pain in rats. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests, respectively. Investigation of spinal proinflammatory cytokines and antioxidant system were carried out after twenty-one days of treatment. Results: The results showed that the co-administration of acetaminophen and L-carnosine significantly (P < 0.001) increased the paw withdrawal threshold to thermal and mechanical stimuli in ligated rats compared to the ligated naïve group. There was a significant (P < 0.001) decrease in the levels of nuclear factor kappa light chain enhancer B cell inhibitor, calcium ion, interleukin-1-beta, and tumour necrotic factor-alpha in the spinal cord of the group coadministered with acetaminophen and L-carnosine compared to the ligated control group. Co-administration with acetaminophen and L-carnosine increased the antioxidant enzymatic activities and reduced the lipid peroxidation in the spinal cord. Conclusions: Co-administration of acetaminophen and L-carnosine has anti-inflammatory effects as a mechanism that mediate its antinociceptive effects in CCI-induced peripheral neuropathy in Wistar rat.

• Biomolecules & Therapeutics
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• 제27권4호
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• pp.414-422
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• 2019

There is accumulating evidence that microRNAs are emerging as pivotal regulators in the development and progression of neuropathic pain. MicroRNA-15a/16 (miR-15a/16) have been reported to play an important role in various diseases and inflammation response processes. However, whether miR-15a/16 participates in the regulation of neuroinflammation and neuropathic pain development remains unknown. In this study, we established a mouse model of neuropathic pain by chronic constriction injury (CCI) of the sciatic nerves. Our results showed that both miR-15a and miR-16 expression was significantly upregulated in the spinal cord of CCI rats. Downregulation of the expression of miR-15a and miR-16 by intrathecal injection of a specific inhibitor significantly attenuated the mechanical allodynia and thermal hyperalgesia of CCI rats. Furthermore, inhibition of miR-15a and miR-16 downregulated the expression of interleukin-$1{\beta}$ and tumor-necrosis factor-${\alpha}$ in the spinal cord of CCI rats. Bioinformatic analysis predicted that G protein-coupled receptor kinase 2 (GRK2), an important regulator in neuropathic pain and inflammation, was a potential target gene of miR-15a and miR-16. Inhibition of miR-15a and miR-16 markedly increased the expression of GRK2 while downregulating the activation of p38 mitogen-activated protein kinase and $NF-{\kappa}B$ in CCI rats. Notably, the silencing of GRK2 significantly reversed the inhibitory effects of miR-15a/16 inhibition in neuropathic pain. In conclusion, our results suggest that inhibition of miR-15a/16 expression alleviates neuropathic pain development by targeting GRK2. These findings provide novel insights into the molecular pathogenesis of neuropathic pain and suggest potential therapeutic targets for preventing neuropathic pain development.