• The Korean Journal of Pain
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• v.25 no.1
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• pp.7-15
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• 2012

Background: Neuropathic pain is a chronic pain due to disorder in the peripheral or central nervous system with different pathophysiological mechanisms. Current treatments are not effective. Analgesic drugs combined can reduce pain intensity and side effects. Here, we studied the analgesic effect of nimesulide, nefopam, and morphine with different mechanisms of action alone and in combination with other drugs in chronic constriction injury (CCI) model of neuropathic pain. Methods: Male Wistar rats (n = 8) weighing 150-200 g were divided into 3 different groups: 1- Saline-treated CCI group, 2- Saline-treated sham group, and 3- Drug-treated CCI groups. Nimesulide (1.25, 2.5, and 5 mg/kg), nefopam (10, 20, and 30 mg/kg), and morphine (1, 3, and 5 mg/kg) were injected 30 minutes before surgery and continued daily to day 14 post-ligation. In the combination strategy, a nonanalgesic dose of drugs was used in combination such as nefopam + morphine, nefopam + nimesulide, and nimesulide + morphine. Von Frey filaments for mechanical allodynia and acetone test for cold allodynia were, respectively, used as pain behavioral tests. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7,10, and 14 post injury. Results: Nefopam (30 mg/kg) and nimesulide (5 mg/kg) blocked mechanical and thermal allodynia; the analgesic effects of morphine (5 mg/kg) lasted for 7 days. Allodynia was completely inhibited in combination with nonanalgesic doses of nefopam (10 mg/kg), nimesulide (1.25 mg/kg), and morphine (3 mg/kg). Conclusions: It seems that analgesic drugs used in combination, could effectively reduce pain behavior with reduced adverse effects.

• The Korean Journal of Pain
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• v.35 no.1
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• pp.43-58
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• 2022

Background: Current therapies are quite unsuccessful in the management of neuropathic pain. Therefore, considering the inhibitory characteristics of GABA mediators, the present systematic review and meta-analysis aimed to determine the efficacy of GABAergic neural precursor cells on neuropathic pain management. Methods: Search was conducted on Medline, Embase, Scopus, and Web of Science databases. A search strategy was designed based on the keywords related to GABAergic cells combined with neuropathic pain. The outcomes were allodynia and hyperalgesia. The results were reported as a pooled standardized mean difference (SMD) with a 95% confidence interval (95% CI). Results: Data of 13 studies were analyzed in the present meta-analysis. The results showed that administration of GABAergic cells improved allodynia (SMD = 1.79; 95% CI: 0.87, 271; P < 0.001) and hyperalgesia (SMD = 1.29; 95% CI: 0.26, 2.32; P = 0.019). Moreover, the analyses demonstrated that the efficacy of GABAergic cells in the management of allodynia and hyperalgesia is only observed in rats. Also, only genetically modified cells are effective in improving both of allodynia, and hyperalgesia. Conclusions: A moderate level of pre-clinical evidence showed that transplantation of genetically-modified GABAergic cells is effective in the management of neuropathic pain. However, it seems that the transplantation efficacy of these cells is only statistically significant in improving pain symptoms in rats. Hence, caution should be exercised regarding the generalizability and the translation of the findings from rats and mice studies to large animal studies and clinical trials.

• 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.

• The Korean Journal of Pain
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• v.28 no.4
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• pp.236-243
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• 2015

Background: Chemotherapy-induced peripheral neuropathy is a major side effect of anti-cancer drugs, and our knowledge of its mechanisms is lacking. Several models for chemotherapy-induced neuropathy have been introduced. However, the outcomes of these models differ significantly among laboratories. Our object was to create a model of chemotherapy-induced neuropathy in rats with cancer. Methods: Female Sprague-Dawley rats were used. Mammary rat metastasis tumor (MRMT-1) cells were implanted subcutaneously in rats. Chemotherapy-induced peripheral neuropathy was induced by injection of cisplatin once a day for four days. The responses to mechanical and thermal stimuli were examined using von Frey filaments, acetone, and radiant heat. Results: Cisplatin (2 mg/kg/day) produced mechanical allodynia, while it did not induce cold allodynia or thermal hyperalgesia. This dose of cisplatin could work successfully against cancer. Body weight loss was not observed in cisplatin-treated rats, nor were other abnormal behaviors noted in the same rats. Conclusions: Repeated injection of intraperitoneal cisplatin induced peripheral neuropathic pain in rats. Thus, this type of rat model has broad applicability in studies related to searching for the mechanism of cisplatin-induced mechanical allodynia and agents for the treatment of neuropathic pain.

• Journal of Korean Neurosurgical Society
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• v.43 no.2
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• pp.85-89
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• 2008

Objective: The purpose of this study is to identify the factors affecting the failure of trials (<50% pain reduction in pain for trial period) to improve success rate of spinal cord stimulation (SCS) trial. Methods: A retrospective review of the failed trials (44 patients, 36.1 %) among the patients (n=122) who underwent SCS trial between January 1990 and December 1998 was conducted. We reviewed the causes of failed trial stimulation, age, sex, etiology of pain, type of electrode, and third party support. Results: Of the 44 patients, 65.9% showed unacceptable pain relief in spite of sufficient paresthesia on the pain area with trial stimulation. Four of six patients felt insufficient paresthesia with stimulation had the lesions of the spinal cord. Seventy five percent of the patients experienced unpleasant or painful sensation during stimulation had allodynia dominant pain. Third-party involvement, sex, age and electrode type had no influence on the outcome. Conclusion: We conclude that SCS trial is less effective for patients with neuropathic pain of cord lesions, postherpetic neuropathy or post-amputation state. Further, patients with allodynia dominant pain can feel unpleasant or painful during trial stimulation.

• The Korean Journal of Pain
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• v.35 no.1
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• pp.59-65
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• 2022

Background: There is still unmet need in treating neuropathic pain and increasing awareness regarding the use of drug combinations to increase the effectiveness of treatment and reduce adverse effects in patients with neuropathic pain. Methods: This study was performed to determine the individual and combined effects of pregabalin, tianeptine, and clopidogrel in a rat model of neuropathic pain. The model was created by ligation of the L5-L6 spinal nerve in male Sprague-Dawley rats; mechanical allodynia was confirmed using von Frey filaments. Drugs were administered to the intrathecal space and mechanical allodynia was assessed; drug interactions were estimated by isobolographic or fixed-dose analyses. Results: Intrathecal pregabalin and tianeptine increased the mechanical withdrawal threshold in a dose-dependent manner, but intrathecal clopidogrel had little effect on the mechanical withdrawal threshold. An additive effect was noted between pregabalin and tianeptine, but not between pregabalin and clopidogrel. Conclusions: These findings suggest that intrathecal coadministration of pregabalin and tianeptine effectively attenuated mechanical allodynia in the rat model of neuropathic pain. Thus, pregabalin plus tianeptine may be a valid option to enhance the efficacy of neuropathic pain treatment.

• Journal of Korean Neurosurgical Society
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• v.61 no.2
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• pp.186-193
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• 2018

Objective : The purpose of this study was to evaluate pain-related behaviors after bilateral C2 root resection and change in pain patterns in the suboccipital region in rats. Methods : Male Sprague-Dawley rats were randomly assigned to three groups (n=25/group); $n{\ddot{a}}ive$, sham, and C2 resection. Three, 7, 10, and 14 days after surgery, cold allodynia was assessed using $20{\mu}L$ of 99.7% acetone. c-Fos and c-Jun were immunohistochemically stained to evaluate activation of dorsal horn gray matter in C2 segments of the spinal cord 2 hours, 1 day, 7 days, and 14 days after surgery. Results : Three days after surgery, the response to acetone in the sham group was significantly greater than in the $n{\ddot{a}}ive$ group, and this significant difference between the $n{\ddot{a}}ive$ and sham groups was maintained throughout the experimental period (p<0.05 at 3, 7, 10, and 14 days). Seven, 10, and 14 days after surgery, the C2 root resection group exhibited a significantly greater response to acetone than the $n{\ddot{a}}ive$ group (p<0.05), and both the sham and C2 resection groups exhibited significantly greater responses to acetone compared with 3 days after surgery. No significant difference in cold allodynia was observed between the sham and C2 root resection groups throughout the experimental period. Two hours after surgery, both the sham and C2 root resection groups exhibited significant increases in c-Fos- and c-Jun-positive neurons compared with the naive group (p=0.0021 and p=0.0358 for the sham group, and p=0.0135 and p=0.014 for the C2 root resection group, respectively). One day after surgery, both the sham and C2 root resection groups exhibited significant decreases in c-Fos -positive neurons compared with two hours after surgery (p=0.0169 and p=0.0123, respectively), and these significant decreases in c-Fos immunoreactivity were maintained in both the sham and C2 root resection groups 7 and 14 days after surgery. The sham and C2 root resection groups presented a tendency toward a decrease in c-Jun-positive neurons 1, 7, and 14 days after surgery, but the decrease did not reach statistical significance. Conclusion : We found no significant difference in cold allodynia and the early expression of c-Fos and c-Jun between the sham and C2 resection groups. Our results may support the routine resection of the C2 nerve root for posterior C1-2 fusion, but, further studies are needed.

• The Korean Journal of Pain
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• v.21 no.1
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• pp.11-17
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• 2008

Background: Peripheral nerve injury induces up-regulation of the calcium channel alpha2delta (${\alpha}2{\delta}$) subunit and TRPM8 in the dorsal root ganglion (DRG) which might contribute to allodynia development. We investigated the expression of the ${\alpha}2{\delta}$ subunit and TRPM8 in the DRG of sympathetically maintained pain (SMP) and sympathetic independent pain (SIP) rat model. Methods: For the SMP model, the L5 and L6 spinal nerves were ligated tightly distal to the DRG. For the SIP model, the tibial and sural nerves were transected, while the common peroneal nerve was spared. After a 7 day postoperative period, tactile and cold allodynia were assessed using von Frey filaments and acetone drops, respectively. Expression of the ${\alpha}2{\delta}$ subunit and TRPM8 in the L5 and L6 DRG were subsequently examined by a Western blot. Results: There were no significant differences between the two models for the thresholds of tactile and cold allodynia. Expression of the ${\alpha}2{\delta}$ subunit in the ipsilateral DRG to the injury was increased as determined on a Western blot as compared to that in the contralateral or sham-operated DRG of the SMP model, but there was no difference in expression seen with the use of the SIP model. There was no difference in the expression of TRPM8 in the ipsilateral DRG to the injury and the contralateral or sham-operated DRG of either model. Conclusions: Up-regulation of the ${\alpha}2{\delta}$ subunit in injured DRG may play a role that contributes to tactile allodynia development in SMP, but not TRPM8 to cold allodynia after peripheral nerve injury.

• Journal of Acupuncture Research
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• v.24 no.5
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• pp.137-150
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• 2007

Objectives : To find effects of acupuncture, electro-acupuncture, low level He-Ne laser therapy(LLLT) at $TE_5$, $GB_{41}$ in the neuropathic pain. We made experiment on rats ligated L5 spinal nerve like general herniation of nucleus pulposus(HNP). Methods : A model of neuropathic pain was made by isolating Left 5th lumbar spinal nerve of rats. Three days after the neuropathic surgery, acupuncture and LLLT, electro-acupuncture was injected at $TE_5$, $GB_{41}$ one time a day for a week. Each group was divided two. one is opposite side performed the surgery which is right, another is left side performed the surgery. After that, the author examined the withdrawal response of neuropathic rats' legs by van Frey filament and acetone stimulation. And also the author examined c-Fos, Nociceptin and KOR-3 in the midbrain central gray of neuropathic rats. Results : As we have observed the effect of mechanical allodynia, LT-R group were diminished on 6th day compared with control group, EA-L group, EA-R group and LT-L group were diminished on 7th day compared with control group. As we have observed the effect of cold allodynia, EA-R group were diminished on 6th day, 7th day compared with control group. As we have observed the effect of activity of c-Fos in the central gray part, EA-R group and LT-R group were diminished compared with control group. As we have observed the effect of activity of Nociceptin in the central gray part, EA-R group were a little increased compared with control group but it is not reliability. As we have observed the effect of activity of KOR-3 in the central gray part, EA-R group were significantly increased compared with control group. Conclusions : We have noticed that effect of acupuncture at opposite side of sickness and powerful stimulation could be more effective, because of EA-R group have more controllable effect all test we have done on the other hand EA-L group have only effect on mechanical allodynia. This study can be used in clinical therapy for neuropathic pain. But it is not reliability that Nociceptin have effectively to control pain. Therefore We have to follow up about that.

• International Journal of Oral Biology
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• v.34 no.1
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• pp.1-6
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• 2009

The purpose of the present study was to examine the role of peripheral nitric oxide (NO) pathways in the onset of interleukin (IL)-1$\beta$-induced mechanical allodynia in the orofacial area. Experiments were carried out on male Sprague-Dawley rats weighing 230-280 gm and surgical procedures were performed under pentobarbital sodium (40 mg/kg, i.p.). Under anesthesia, a polyethylene tube (PE10) was implanted into the subcutaneous area of one vibrissa pad, which enabled the injection of IL-1$\beta$ or other chemicals. We subcutaneously injected 50 ${\mu}L$ of IL-1$\beta$ into a vibrissa pad through the implanted polyethylene tube with a 100 ${\mu}L$ Hamilton syringe. After the administration of 0.01, 0.1, 1, or 10 pg of IL-1$\beta$, withdrawal behavioral responses were examined. The subcutaneous injection of saline had no effects on the air-puff thresholds. Following the subcutaneous injection of 0.01, 0.1, 1, or 10 pg of IL-1$\beta$, the threshold of air puffs decreased significantly to 12 $\pm$ 3, 7 $\pm$ 2, 5 $\pm$ 1, or 5 $\pm$ 1 psi, respectively, in a dose dependent manner. Pretreatment with L-NAME, a nitric oxide synthase (NOS) inhibitor, blocked IL-1$\beta$-induced mechanical allodynia. However, neither D-NAME, an inactive isomer of L-NAME, nor vehicle affected the IL-1$\beta$-induced mechanical allodynia. Subcutaneous injection of IL-1$\beta$ increased the number of c-fos-like immunoreactive neurons, whereas pretreatment with L-NAME decreased this number, in the trigeminal caudal nucleus. These results suggest that pro-inflammatory cytokines and NO are important contributors to the pathogenesis of persistent and exaggerated IL-1$\beta$-induced pain states. Based on these observations, peripheral application of NOS inhibitors may be of therapeutic value in treating pain disorders in the clinic.