• The Korean Journal of Pain
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• v.33 no.1
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• pp.23-29
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• 2020

Background: Neuropathic pain (NP) is considered a clinically incurable condition despite various treatment options due to its diverse causes and complicated disease mechanisms. Since the early 2000s, multipotent human mesenchymal stem cells (hMSCs) have been used in the treatment of NP in animal models. However, the effects of hMSC injections have not been studied in chronic post-ischemia pain (CPIP) mice models. Here, we investigated whether intrathecal (IT) and intrapaw (IP) injections of hMSCs can reduce mechanical allodynia in CPIP model mice. Methods: Seventeen CPIP C57/BL6 mice were selected and randomized into four groups: IT sham (n = 4), IT stem (n = 5), IP sham (n = 4), and IP stem (n = 4). Mice in the IT sham and IT stem groups received an injection of 5 μL saline and 2 × 10⁴ hMSCs, respectively, while mice in the IP sham and IP stem groups received an injection of 5 μL saline and 2 × 10⁵ hMSCs, respectively. Mechanical allodynia was assessed using von Frey filaments from pre-injection to 30 days post-injection. Glial fibrillary acidic protein (GFAP) expression in the spinal cord and dorsal root ganglia were also evaluated. Results: IT and IP injections of hMSCs improved mechanical allodynia. GFAP expression was decreased on day 25 post-injection compared with the sham group. Injections of hMSCs improved allodynia and GFAP expression was decreased compared with the sham group. Conclusions: These results suggested that hMSCs may be also another treatment modality in NP model by ischemia-reperfusion.

• Journal of Acupuncture Research
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• v.21 no.3
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• pp.145-167
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• 2004

Objective : Neuropathic pain can be caused by a partial peripheral nerve injury. This kind of pain is usually accompanied by spontaneous burning pain, allodynia and hyperalgesia. It is not clear that scolopendrid aqua-acupuncture can control neuropathic pain effectively. The purpose of this study is to examine if scolopendrid aqua-acupuncture may be effective to the neuropathic pain (mechanical allodynia, cold allodynia) in a rat model of neuropathic pain. Methods : To produce the model of neuropathic pain, under isoflurane 2.5% anesthesia, tibial nerve and sural nerve was resected. After the neuropathic surgery, the author examined if the animals exhibited the behavioral signs of allodynia. The allodynia was assessed by stimulating the medial malleolus with von Frey filament and acetone. Three weeks after the neuropathic surgery, scolopendrid aqua-acupuncture was injected at Hwando(GB30) one time a day for one week. After that the author examined the withdrawl response of neuropathic rats' legs by von Frey filament and acetone stimulation. And also the author examined c-fos in the midbrain central gray of neuropathic rats and the change of WBC count in the blood of neuropathic rats. Results & Conclusion : 1. The scolopendrid aqua-acupuncture injected at Hwando(GB30) decreased the withdrawl response of mechanical allodynia in SHA-1, SHA-2 and SAH-3 group as compared with control group. 2. The scolopendrid aqua-acupuncture injected at Hwando(GB30) decreased the withdrawl response of chemical allodynia(cold allodynia) in SHA-1, SHA-2 and SAH-3 group as compared with control group. 3. The scolopendrid aqua-acupuncture injected at Hwando(GB30) showed the significant difference between sham group and control group(p=0.01), sham and SHA-3 group(p=0.026), control group and SHA-1 group(p=0.01), control group and SHA-2 group(p=0.024) in the c-fos expression. 4. The scolopendrid aqua-acupuncture injected at Hwando(GB30) showed the significant difference between sham group and SHA-3 group(p=0.010), control group and SHA-3 group(p=0.006) in the WBC count.

• The Korean Journal of Pain
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• v.22 no.1
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• pp.21-27
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• 2009

Background: The neuropathic pain arising from nerve injury is difficult to treat and the therapeutic effects of opioid drugs remain debatable. Agonists acting at the ${\alpha}_2$ adrenergic and opioid receptors have analgesic properties and they act synergistically when co-administered in the spinal cord. The lack of subtype-selective pharmacological agents has previously impeded the synergistic effects that are mediated by the adrenergic receptor subtypes. Methods: We created neuropathic pain model by ligating the L5 spinal nerve in Sprague-Dawley rats (n = 18). We divided the rats into three groups (n = 6 for each group), and we administered intraperitoneal morphine (1 mg/kg, 3 mg/kg, 5 mg/kg) and then we measured the mechanical allodynia with using von-Frey filaments for 8 hours. We then injected morphine (5 mg/kg) intraperitoneally, twice a day for 2 weeks. We measured the tactile and cold allodynia in the morphine group (n = 9) and the saline group (n = 9). After 2 weeks, we decapitated the rats and harvested the spinal cords at the level of lumbar enlargement. We compared the ${\alpha}_2$ subtype mRNA expression with that of control group (n = 6) by performing real time polymerase chain reaction (RTPCR). Results: Intraperitoneal morphine reduced the neuropathic pain behavior in the dose-dependent manner. Chronic morphine administration showed an antiallodynic effect on the neuropathic pain rat model. The rats did not display tolerance or hyperalgesia. The expression of the mRNAs of the ${\alpha}_{2A}$, ${\alpha}_{2B}$, ${\alpha}_{2C}$ subtypes decreased, and morphine attenuated this effect. But we could not get statistically proven results. Conclusions: Systemic administration of morphine can attenuate allodynia during both the short-term and long-term time course. Morphine has an influence on the expression of ${\alpha}_2$ receptor subtype mRNA. Yet we need more research to determine the precise effect of morphine on the ${\alpha}_2$ subtype gene expression.

• The Korean Journal of Pain
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• v.24 no.4
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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.

• Biomolecules & Therapeutics
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• v.27 no.4
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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.

• The Korean Journal of Pain
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• v.34 no.1
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• pp.27-34
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• 2021

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major reason for stopping or changing anticancer therapy. Among the proposed pathomechanisms underlying CIPN, proinflammatory processes have attracted increasing attention. Here we assessed the role of prostaglandin D2 (PGD2) signaling in cisplatin-induced neuropathic pain. Methods: CIPN was induced by intraperitoneal administration of cisplatin 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. PGD2 receptor DP1 and/or DP2 antagonists were administered intrathecally and the paw withdrawal thresholds were measured using von Frey filaments. Spinal expression of DP1, DP2, hematopoietic PGD synthase (H-PGDS), and lipocalin PGD synthase (L-PGDS) proteins were analyzed by western blotting. Results: The DP1 and DP2 antagonist AMG 853 and the selective DP2 antagonist CAY10471, but not the DP1 antagonist MK0524, significantly increased the paw withdrawal threshold compared to vehicle controls (P = 0.004 and P < 0.001, respectively). Western blotting analyses revealed comparable protein expression levels in DP1 and DP2 in the spinal cord. In the CIPN group the protein expression level of L-PGDS, but not of H-PGDS, was significantly increased compared to the control group (P < 0.001). Conclusions: The findings presented here indicate that enhanced PGD2 signaling, via upregulation of L-PGDS in the spinal cord, contributes to mechanical allodynia via DP2 receptors in a cisplatin-induced neuropathic pain model in rats, and that a blockade of DP2 receptor activation may present a novel therapeutic target for managing CIPN.

• Journal of Acupuncture Research
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• v.22 no.1
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• pp.77-90
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• 2005

Objective : Neuropathic pain sometimes arises from a partial peripheral nerve injury. This kind of pain is usually accompanied by spontaneous burning pain, allodynia and hyperalgesia. It has been well known that acupuncture is effective to the pain control from ancient time in Asia. However, it is not clear whether Electroacupuncture(EA) & Acupuncture(AC) can control neuropathic pain effectively. The aim of this study is to examine if Electroacupuncture&Acupuncture at Hu-gye(SI03), Wijung(BL4O), Hu-gye(SI03) Wijung(BL40) may be effective to the neuropathic pain (mechanical allodynia cold allodynia) in a rat model of neuropathic pain. Methods : A rat model of neuropathic pain was made by injurying tibial nerve and sural nerve while common peroneal nerve was maintained. After the neuropathic surgery, we examined if the rats exhibited the behavioral signs allodynia. The allodynia was assessed by stimulating the medial malleolus with von frey filament and acetone. Three weeks after the neuropathic surgery, electroacupuncture &, acupuncture stimulation was delivered to Hu-gye(SI03), Wijung(BL40), Hu-gye(SI03) Wijung(BL40) one time a day for one week. After that we examined the withdrawal response of neuropathic rats' legs by von frey filament and acetone stimulation, c-fos and AchE(Acetylcholine esterase) in the periaqe- ductal gray(PAG) of neuropathic rats' brain. Results : 1. Electroacupuncture&Acupuncture at Hu-gye(SI03), Wijung(BL40), Hu-gye(SI03) Wijung(BL4O) significantly decreased the withdrawal response of mechanically allodynia in EA-BL40+SI03 group and AC-SI03 group as compared with control group on 6th day. 2. Electroacupuncture &Acupuncture at Hu-gye(SI03), Wijung(BL40), Hu-gye (SI03) Wijung (BL40) significantly decreased the withdrawal response of chemical allodynia(cold allodynia) in EA-SI03 group, EA-BL40+SI03 group and AC-SI03 group as compared with control group on 6th day. 3. Electroacupuncture & Acupuncture at Hu-gye ( SI03), Wijung (BL40), Hu-gye (SI03) Wijung(BL40) significantly decreased the expression of c-fos in the periaqe- ductal gray(PAC) of neuropathic rats' brain in EA-BL40+SI03 group and AC-SI03 group as compared with control group. 4. Electroacupuncture&Acupuncture at Hu-gye(SI03), Wijung(BL40), Hu-gye (SI03) Wijung(BL40) significantly decreased the expression of AchE in the periaqe- ductal gray(PAG) of neuropathic rats' brain in EA-BL40+SI03 group and AC-SI03 group as compared with control group. Conclusions : Based on the above results it is assumed that Electroacupuncture at Hu-gye(SI03) Wijung(BL40) and Acupuncture at Hu-gye(SI03) can help the treatment of neuropathic pain.