• The Korean Journal of Pain
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• v.8 no.1
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• pp.18-24
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• 1995

We produced the causalgiform pain by the tight ligation of L5 and L6 spinal nerves in the adult rats. To evalute the effect of Ketamine -noncompetitive NMDA (N-methyl-D aspartate) antagoinst- on the causalgiform pain, we tested the changes of; withdrawal sensitivity to the innocuous mechanical stimulation of Von Frey hair 2.35 g(mechanical allodynia); withdrawal frequency to the cold stimulation of acetone (cold allodynia); and total withdrawal time (second) to the cold ($4^{\circ}C$) plate stimulation (cold hyperalgesia) after the administration of 1 mg, 3 mg, 10 mg/kg ketamine. The results were as follows: 1) Cold hyperalgesia was significantly reduced (p<0.05) by 1 mg, 3mg, 01 mg/kg ketamine. 2) Cold allodynia and mechanical allodynia was significantly reduced (p<0.05) by 10 mg/kg ketamine. Above results suggest a therapeutic utility of ketamine in treatment of causalgia - especially, cold hyperalgesia.

• Journal of Korean Physical Therapy Science
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• v.10 no.1
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• pp.180-189
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• 2003

The experiments were designated to evaluate the anti-nociceptive effect of low power laser stimulation on acupoint or non-acupoint using arthrogenic solution induced poly arthritis animal model. Evaluation of potential antinociceptive effect of low power laser on arthritis has employed measurements of the foot bending test, the development of either thermal or mechanical hyperalgesia following the arthritis induction. The analysis of thermal hyperalgesia includes Hargreaves's method. Randall-Sellitto test was utilized for evaluating mechanical hyperalgesia. In addition, the antinociceptive effect of low power laser stimulation on arthritis induced spinal Fos expression was analyzed using a computerized image analysis system. The results were summerized as follows: 1. In laser stimulation on acupoint treated animal, laser stimulation dramatically inhibited the development of pain in foot bending test as compared to those of non acupoint treated animal group and non treated animal group. 2. The threshold of thermal stimulation was significantly increased by low power laser stimulation on acupoint as compared to that of non treated control group. 3. Laser stimulation on acupoint dramatically attenuated the development of mechanical hyperalgesia as compared to that of non treated group. 4. Low power laser stimulation on acupoint significantly suppressed arthritis induced Fos expression in the lumbar spinal cord at 3 week post arthritis induction. In conclusion, the results of the present study demonstrated that low power laser stimulation on acupoint has potent anti-nociceptive effect on arthritis. Additional supporting data for an antinociceptive effect of laser stimulation was obtained using Fos immunohistochemical analysis on spinal cord section. Those data indicated that laser stimulation induced antinociception was mediated by suppression of spinal neuron activity in pain sensation.

• The Korean Journal of Pain
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• v.35 no.4
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• pp.433-439
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• 2022

Background: Repeated administration of opioid analgesics for pain treatment can produce paradoxical hyperalgesia via peripheral and/or central mechanisms. Thus, this study investigated whether spinally (centrally) administered orexin A attenuates opioid-induced hyperalgesia (OIH). Methods: [D-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin (DAMGO), a selective µ-opioid receptor agonist, was used to induce mechanical hypersensitivity and was administered intradermally (4 times, 1-hour intervals) on the rat hind paw dorsum. To determine whether post- or pretreatments with spinal orexin A, dynorphin A, and anti-dynorphin A were effective in OIH, the drugs were injected through an intrathecal catheter whose tip was positioned dorsally at the L3 segment of the spinal cord (5 ㎍ for all). Mechanical hypersensitivity was assessed using von Frey monofilaments. Results: Repeated intradermal injections of DAMGO resulted in mechanical hypersensitivity in rats, lasting more than 8 days. Although the first intrathecal treatment of orexin A on the 6th day after DAMGO exposure did not show any significant effect on the mechanical threshold, the second (on the 8th day) significantly attenuated the DAMGO-induced mechanical hypersensitivity, which disappeared when the type 1 orexin receptor (OX1R) was blocked. However, intrathecal administration of dynorphin or an anti-dynorphin antibody (dynorphin antagonists) had no effect on DAMGO-induced hypersensitivity. Lastly, pretreatment with orexin A, dynorphin, or anti-dynorphin did not prevent DAMGO-induced mechanical hypersensitivity. Conclusions: Spinal orexin A attenuates mechanical hyperalgesia induced by repetitive intradermal injections of DAMGO through OX1R. These data suggest that OIH can be potentially treated by activating the orexin A-OX1R pathway in the spinal dorsal horn.

• International Journal of Oral Biology
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• v.40 no.3
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• pp.117-125
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• 2015

The present study investigated the role of central $GABA_A$ and $GABA_B$ receptors in orofacial pain in rats. Experiments were conducted on Sprague-Dawley rats weighing between 230 and 280 g. Intracisternal catheterization was performed for intracisternal injection, under ketamine anesthesia. Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia and inferior alveolar nerve injury-induced mechanical allodynia were employed as orofacial pain models. Intracisternal administration of bicuculline, a $GABA_A$ receptor antagonist, produced mechanical allodynia in naive rats, but not thermal hyperalgesia. However, CGP35348, a $GABA_B$ receptor antagonist, did not show any pain behavior in naive rats. Intracisternal administration of muscimol, a $GABA_A$ receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. On the contrary, intracisternal administration of bicuculline also attenuated the mechanical allodynia in rats with inferior alveolar nerve injury. Intracisternal administration of baclofen, a $GABA_B$ receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. In contrast to $GABA_A$ receptor antagonist, intracisternal administration of CGP35348 did not affect either the thermal hyperalgesia or mechanical allodynia. Our current findings suggest that the $GABA_A$ receptor, but not the $GABA_B$ receptor, participates in pain processing under normal conditions. Intracisternal administration of $GABA_A$ receptor antagonist, but not $GABA_B$ receptor antagonist, produces paradoxical antinociception under pain conditions. These results suggest that central GABA has differential roles in the processing of orofacial pain, and the blockade of $GABA_A$ receptor provides new therapeutic targets for the treatment of chronic pain.

• The Korean Journal of Pain
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• v.27 no.3
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• pp.219-228
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• 2014

Background: A lipo-prostaglandin E1 agonist is effective for the treatment of neurological symptoms of spinal stenosis when administered by an oral or intravenous route. we would like to reveal the therapeutic effect of an epidural injection of lipo-prostaglandin E1 on hyperalgesia in foraminal stenosis. Methods: A total of 40 male Sprague-Dawley rats were included. A small stainless steel rod was inserted into the L5/L6 intervertebral foramen to produce intervertebral foraminal stenosis and chronic compression of the dorsal root ganglia (DRG). The rats were divided into three groups: epidural PGE1 (EP) (n = 15), saline (n = 15), and control (n = 10). In the EP group, $0.15{\mu}g{\cdot}kg-1$ of a lipo-PGE1 agonist was injected daily via an epidural catheter for 10 days from postoperative day 3. In the saline group, saline was injected. Behavioral tests for mechanical hyperalgesia were performed for 3 weeks. Then, the target DRG was analyzed for the degree of chromatolysis, chronic inflammation, and fibrosis in light microscopic images. Results: From the fifth day after lipo-PGE1 agonist injection, the EP group showed significant recovery from mechanical hyperalgesia, which was maintained for 3 weeks (P < 0.05). Microscopic analysis showed much less chromatolysis in the EP group than in the saline or control groups. Conclusions: An epidurally administered lipo-PGE1 agonist relieved neuropathic pain, such as mechanical hyperalgesia, in a rat foraminal stenosis model, with decreasing chromatolysis in target DRG. We suggest that epidurally administered lipo-PGE1 may be a useful therapeutic candidate for patients with spinal stenosis.

• The Korean Journal of Physiology and Pharmacology
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• v.8 no.5
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• pp.237-243
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• 2004

Glial cells are activated in neuropathy and play a key role in hyperalgesia and allodynia. This study was performed to determine whether minocycline could attenuate heat hyperalgesia and mechanical allodynia, and how glial cell activation and nuclear factor kappa B (NF-kappaB) were regulated by minocycline in a model of chronic constriction of sciatic nerve (CCl). When minocycline (50 mg/kg, oral) was daily administered from 1 day before to 9 days after ligation, heat hyperalgesia and mechanical allodynia were attenuated. Furthermore, when minocycline treatment was initiated 1 or 3 days after ligation, attenuation of the hypersensitive behavior was still robust. However, the effect of attenuation was less when minocycline was started from day 5. In order to elucidate the mechanism of pain attenuation by minocycline, we examined the changes of glia and NF-kappaB, and found that attenuated hyperalgesia and allodynia by minocycline was accompanied by reduced microglial activation. Furthermore, the number of NF-kappaB immunoreactive cells increased after CCI treatment and this increase was attenuated by minocycline. We also observed translocation of NF-kappaB into the nuclei of activated glial cells. These results suggest that minocycline inhibits activation of glial cells and NF-kappaB, thereby attenuating the development of behavioral hypersensitivity to stimuli.

• Journal of Korean Neurosurgical Society
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• v.49 no.2
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• pp.83-91
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• 2011

Objective : Minocycline, a second-generation tetracycline-class antibiotic, has been well established to exert a neuroprotective effect in animal models and neurodegenerative disease through the inhibition of microglia. Here, we investigated the effects of minocycline on motor recovery and neuropathic pain in a rat model of spinal cord injury. Methods : To simulate spinal cord injury, the rats' spinal cords were hemisected at the 10th thoracic level (T10). Minocycline was injected intraperitoneally, and was administered 30 minutes prior surgery and every second postoperative day until sacrifice 28 days after surgery. Motor recovery was assessed via the Basso-Beattie-Bresnahan test Mechanical hyperalgesia was measured throughout the 28-day post -operative course via the von Frey test Microglial and astrocyte activation was assessed by immunohistochemical staining for ionized calcium binding adaptor molecule 1 (lba1) and glial fibrillary acidic protein (GFAP) at two sites: at the level of hemisection and at the 5th lumbar level (L5). Results : In rats, spinal cord hemisection reduced locomotor function and induced a mechanical hyperalgesia of the ipsilateral hind limb. The expression of lba1 and GFAP was also increased in the dorsal and ventral horns of the spinal cord at the site of hemisection and at the L5 level. Intraperitoneal injection of minocycline facilitated overall motor recovery and attenuated mechanical hyperalgesia. The expression of lba1 and GFAP in the spinal cord was also reduced in rats treated with minocycline. Conclusion : By inhibiting microglia and astrocyte activation, minocycline may facilitate motor recovery and attenuate mechanical hyperalgesia in individuals with spinal cord injuries.

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.4
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• pp.895-897
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• 2009

Lonicera japonica has been widely used for chronic inflammatory diseases in many Asian countries. Its analgesic effect has not been explored yet. This study aimed to test the analgesic potential of methanol extracts from Lonicera japonica (MELJ) in rat neuropathic mctel. Neuropathic pain was pacts ed by partial sciatic nerve injury. Two weeks after surgery, neuropathic rats received oral administration of MELJ at doses of either 0.0 g/kg, 0.2 g/kg or 0.4 g/kg. At dose of 0.0 g, rats were administered with saline only and used as conracl. The behavioral tests for f 0.0 g, raand ccld hs were adma were weformed up to 2 hours after treatment. The MELJ at the dose 0.4 g/kg dmg gfg, ntly alleviated f 0.0 g, rahyperalgesia, but not cold hyperalgesia. These results showed that the MELJ had, although transient, analgesic effect on mechanical hyperalgesia in the rat neuropathic model.

• The Korean Journal of Pain
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• v.34 no.2
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• pp.176-184
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• 2021

Background: Diabetes-related neuropathic pain frequently occurs, and the underpinning mechanism remains elusive. The periaqueductal gray (PAG) exhibits descending inhibitory effects on central pain transmission. The current work aimed to examine whether inflammatory cytokines regulate mechanical allodynia and thermal hyperalgesia induced by diabetes through the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway in the PAG. Methods: Streptozotocin (STZ) was administered intraperitoneally to mimic allodynia and hyperalgesia evoked by diabetes in rats. Behavioral assays were carried out for determining mechanical pain and thermal hypersensitivity. Immunoblot and ELISA were performed to examine PAG protein amounts of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as their corresponding receptors in STZ rats, and the expression of PI3K/protein kinase B (Akt)/mTOR signaling effectors. Results: Increased PAG p-PI3K/p-Akt/p-mTOR protein amounts were observed in STZ-induced animals, a PI3K-mTOR pathway inhibition in the PAG attenuated neuropathic pain responses. Moreover, the PAG concentrations of IL-1β, IL-6, and TNF-α and their receptors (namely, IL-1R, IL-6R, and tumor necrosis factor receptor [TNFR] subtype TNFR1, respectively) were increased in the STZ rats. Additionally, inhibiting IL-1R, IL-6R, and TNFR1 ameliorated mechanical allodynia and thermal hyperalgesia in STZ rats, alongside the downregulation of PI3K-mTOR signaling. Conclusions: Overall, the current study suggests that upregulated proinflammatory cytokines and their receptors in the PAG activate PI3K-mTOR signaling, thereby producing a de-inhibition effect on descending pathways in modulating pain transmission, and eventually contributing to neuropathic pain.

• Journal of Society of Preventive Korean Medicine
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• v.20 no.3
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• pp.55-65
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• 2016

Objectives : Mibyeong is a korea medicine have original concept of the disease. However, no previous report has effect of mibyeong herbal medicine in fatigue types of mibyeong. This study investigated the question of whether Dang Gui Bo Hyul-tang(DGBHT) of effect on fatigue types of Mibyeong. Methods : C57BL/6 mice were randomaly divided into three group (n=10). The mice were then group (1) Nocontrol, (2) Restraunt stress(veh), (3) Dang Gui Bo Hyul-tang 200mg/kg. The administered Dang Gui Bo Hyul-tang 200mg/kg or distilled water (orally) 1 hr prior to daily exposure to repeated restraint stress (2 h) for 15 days. The performed behavior test (Mechanical hyperalgesia test,, Open-field test, Forced swimming test, Sucrose preference test and immunostaining and biochemical measured in serum. Results : Stress fatigue induced mices significantly increased lethargic, hyperalgesia through behavior test (Mechanical hyperalgesia test (decrease 43%), Open-field test ($4,809{\pm} 226.13cm$ vs. $3121{\pm}226.64cm$), Forced swimming test ($11.45{\pm}3.96$ vs. $79.10{\pm}8.12sec$), Sucrose preference test (decrease 58%)). In addition, chronic fatigue model evidently increased corticosterone level ($122.54{\pm}18.88$ vs. $186.94{\pm}18.26ng/ml$), AST level ($46.22{\pm}3.23$ vs. $31.40{\pm}3.86U/L$), ALT level ($38.78{\pm}5.72$ vs. $17.60{\pm}1.30$), liver necrosis, lateral ventricle size. These alterations were significantly ameliorated by DGBHT. DGBHT significantly attend the elevated serum concentrations of corticosterone ($155.90{\pm}6.29ng/ml$), AST ($31.40{\pm}3.86U/L$), ALT ($17.60{\pm}1.30U/L$). Moreover, DGBHT improved lethargic, hyperalgesia when compared the stress fatigue (Mechanical hyperalgesia test (improve 28%), Open-field test ($4,038{\pm}615.81cm$), Forced swimming test ($7.56{\pm}1.88sec$), Sucrose preference test (increase 21%) Conclusions : Theses result suggest that DGBHT have improved lethargic, hyperalgesia and fatigue-associated hormone and liver protective on stress fatigue model. It will be necessary to research to present evidences on benefits and effects of Korean medical treatment for Mibyeong through clinical researches based on benefits and effects of those animal models.