• 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.

• Korean Journal of Acupuncture
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• 제22권2호
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• pp.9-24
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• 2005

Objective: We have studied the effects of acupuncture and low level He-Ne laser therapy(LLLT) at $SI_3$, $BL_{40}$ on the tibial, sural nerve injury due to sports-damage or traffic accident and L5 spinal nerve ligature model like general herniation of nucleus pulposus(HNP) in a rat of neuopathic pain. Methods: A model of neuropathic pain was made by injuring tibial nerve and sural nerve while common peroneal nerve was maintained. Also, it was made by isolating left 5th lumbar spinal nerve. Three weeks after the neuropathic surgery, acupuncture and LLLT was injected at $SI_3$,$BL_{40}$ one time a day for one week. LLLT was divided three groups, that is LLLT-1(5mW), LLLT-2(10mW) and LLLT-3(30mW). After that, we examined the withdrawal response of neuropathic rats' legs by Von frey filament and acetone stimulation. And also we examined c-Fos, Nocieptin and KOR-3 in the midbrain central gray of neuropathic rats. Results: As we have observed the effect of mechanical allodynia, LLLT-3 group were diminished on 4 day, 5 day, 6 day and 7 day in the resection model compared with control model, LLLT-1 group were diminished on 5 day, LLLT-2 group were diminished on 3 day and 6 day, LLLT-3 group were diminished on 3 day, 4 day, 5 day, 6 day and 7 day in connected model compared with control group. As we have observed the effect of cold allodynia, LLLT-3 group were diminished on 7 day in the resection model compared with control model, LLLT-1 group were diminished on 6 day, 7 day, LLLT-3 group were diminished on 7 day in connected model compared with control group. As we have observed the effect of activity of c-Fos in the central gray part, LLLT-3 were diminished in resection model compared with control group, LLLT-1 group were diminished in connected model compared with control group. As we have observed the effect of activity of Nociceptin in the central gray part, resection model were not increased compared with control group, LLLT-1 group and LLLT-3 group were increased in connected model compared with control model. As we have observed the effect of activity of KOR-3 in the central gray part, resection model were not increased compared with control group, LLLT-3 group were increased in connected model compared with control model. Conclusions: We have noticed that LLLT-1 and LLLT-3 group have more controllable effect than acupuncture group. This study can be used in clinical therapy for neuropathic pain. But it is not reliability that Nociceptin and KOR-3 have effectively to control pain. Therefore We have to follow up about that.

• Annals of Clinical Neurophysiology
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• 제11권2호
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• pp.41-47
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• 2009

Background: Discogenic pain can develop into chronic low back pain that is very difficult to treat effectively, because the pathogenesis of the disease still remains controversial. To clarify the pathogenesis, numerous animal models of intervertebral disc degeneration have been proposed in the literature, each with attendant advantages and disadvantages. The aim of this study was to determine the most efficacious method and dose of complete Freund's adjuvant (CFA) injection into intervertebral disc to develop a discogenic pain in a rat. Methods: CFA was injected into the L5-L6 or L4-L5 disc of male Sprague-Dawley rats in various conditions including a dose of CFA (10, 20, or 50 uL), drilling, injection site sealing using cyanoacrylate, and injection velocity. Sham animals were subjected to the same procedure, except for the CFA injection. Mechanical and heat allodynia were serially measured at both hindpaws until 8 weeks post-operatively. Serial MRI analyses were performed to observe degenerative changes of the discs. In addition, CGRP & Substance P-immunoreactivities (ir) in the superficial dorsal horn were evaluated at 4 weeks using immunohistochemistry. Results: Each condition provoked various problems such as development of hindpaw paralysis, CFA leakage, and no pain development. Mid-sagittal T2 MRI revealed no significant degenerative changes in the CFA injected disc. The CGRP-ir of the bilateral superficial dorsal horns at the level of L5-L6 was significantly increased in the CFA group. Conclusions: A total of 10 uL CFA injection into L5-L6 disc for a period of 10 minutes using a 26-gauge needle without drilling was the most efficacious way to develop discogenic pain animal model.

• The Journal of Korean Physical Therapy
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• 제21권2호
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• pp.117-124
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• 2009

Purpose: This study examined the effects of swimming exercise and Achyranthes Radix extracts on the inflammatory and behavioral responses in type II collagen-induced arthritic rats for 28 days. Methods: Sprague-Dawley rats were allocated randomly to one of the following four groups: only type II collageninduced (group Ⅰ), application of swimming exercise after type II collagen-induced (group II), application of Achyranthes Radix ointment after type II collagen-induced (group III), application of swimming exercise and Achyranthes Radix ointment after type II collagen-induced (group IV). Arthritis was established in SD rats by an intradermal injection of Chick type II collagen plus incomplete Freund's adjuvant at the base of the tail of the animals. The swimming exercise program consisted of a 25 min swimming session/day with a load corresponding to 5.5% of the weight bearing, three days/week for four weeks. The Achyranthes Radix ointment (0.1g) was applied twice a day for five days. The changes in behavior, H & E stain, and cyclooxygenase-2 (COX-2) level in the knee joint were assessed. Results: The gross and histological examination, after RA induction showed reddening, edema and erythema. The H & E stain revealed the destruction of articular cartilage, bony erosion and the infiltration of inflammatory cells after RA induction. The mechanical allodynia test results were significantly higher in group I than in groups II, III and IV (p<0.01). The immunohistochemistrical response of COX-2 in the knee joint showed that groups II, III, IV had a lower response effect than group I. Conclusion: Swimming exercise training and Achyranthes Radix ointment decreased the inflammatory responses and enhanced the behavioral responses in the arthritic rats.

• Journal of Acupuncture Research
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• 제30권3호
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• pp.125-134
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• 2013

Objectives : We studied the effects of electro and laser acupuncture treatment with $GB_{39}$ and $GB_{34}$ on neuropathic pain in rats induced by tibial and sural nerve ligation. Methods : To produce the model of neuropathic pain, the tibial and sural nerves of rats were ligated by a 6-0 silk thread. Three days after the neuropathic surgery, only electro acupuncture(EA), electro acupuncture and 830 nm laser acupuncture(EA-LA-1), and electro acupuncture and 904 nm laser acupuncture(EA-LA-2) were treated with $GB_{39}$ and $GB_{34}$ twice a week for 8 weeks. We observed the withdrawal response of neuropathic rats' legs by von Frey filament and acetone stimulation. We also observed c-fos and nocieptin on the central gray area in the midbrain of neuropathic rats. Results : As we observed the effect of mechanical allodynia, the EA and EA-LA-1 groups in 5 and 6 weeks and the EA-LA-2 group in 6 weeks increased significantly compared with the control group. As for the effect of c-fos activity in the central gray region, the EA, EA-LA-1, and EA-LA-2 groups decreased significantly compared with the control group. The EA-LA-2 group increased significantly compared with the control group as regards the effect of nociceptin activity in the central gray region. Conclusions : We noticed the synergic effect of electro and laser acupuncture treatment because the EA-LA-1 and EA-LA-2 groups had more controllable effect compared with the control group. This study can be used in clinical therapy for neuropathic pain.

• 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.

• The Korean Journal of Pain
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• 제34권1호
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• pp.58-65
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• 2021

Background: Supraspinal delivery of neurotensin (NTS), which may contribute to the effect of a systemically administered agonist, has been reported to be either pronociceptive or antinociceptive. Here, we evaluated the effects of systemically administered NTSR1 agonist in a rat model of neuropathic pain and elucidated the underlying supraspinal mechanism. Methods: Neuropathic pain was induced by L5 and L6 spinal nerve ligation in male Sprague-Dawley rats. The effects of intraperitoneally administered NTSR1 agonist PD 149163 was assessed using von Frey filaments. To examine the role of 5-HT neurotransmission, a serotonin (5-HT) receptor antagonist dihydroergocristine was pretreated intrathecally, and spinal microdialysis studies were performed to measure the change in extracellular level of 5-HT in response to PD 149163 administration. To investigate the supraspinal mechanism, NTSR1 antagonist 48692 was microinjected into the rostral ventromedial medulla (RVM) prior to systemic PD 149163. Additionally, the effect of intrathecal DHE on intra-RVM PD 149163 was assessed. Results: Intraperitoneally administered PD 149163 exhibited a dose-dependent attenuation of mechanical allodynia. This effect was partially reversed by intrathecal pretreatment with dihydroergocristine and was accompanied by an increased extracellular level of 5-HT in the spinal cord. The PD 149163-produced antinociception was also blocked by intra-RVM SB 48692. Direct injection of PD 149163 into the RVM mimicked the maximum effect of the same drug delivered intraperitoneally, which was reversed by intrathecal dihydroergocristine. Conclusions: These observations indicate that systemically administered NTSR1 agonist produces antinociception through the NTSR1 in the RVM, activating descending serotonergic projection to release 5-HT into the spinal dorsal horn.

• The Korean Journal of Pain
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• 제34권1호
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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.