• Journal of Acupuncture Research
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• v.17 no.2
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• pp.231-246
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• 2000

Acupuncture has been used for treatment of numerous diseases, especially for pain control in the oriental culture. However, the mechanism of pain control by acupuncture was not clear so far. The present study was examined that the effects of electro-acupuncture (EA) applied to the acu-point of extra-segmental area on modulation of formalin induced pain in Sprague - Dawley rats. In order to apply EA to acu-points in the plantar area of right fore paws, a pair of teflon - coated stainless steel wires were implanted in HT 7 (shin-mun) and PC 7 (dae-neong) 5 days before behavioral test. A behavioral test was performed by means of video camera after injection of 5% formalin ($50{\mu}l$) into the lateral plantar region of left hind paw. EA was delivered by a constant current stimulator at 4~5 mA, 2 ms, and 10 Hz for 30 min. The electromyographic activities were recorded in the biceps femoris muscle under chloral hydrate anesthesia. Test stimuli with 1~9mA were applied to the sural nerve territory including the medial portion of the 4th toe and the lateral portion of the 5th toe. Behavioral responses including favoring, flinching and bitting were occured in the biphasic pattern, such as the lst phase (0~5 min) and the 2nd phase (20~45 min) after formalin injection. However, EA (4~5 mA, 2 ms, 10 Hz) significantly inhibited Che behavioral responses. EMG activities of flexor reflex had a latency of 100~300 ms and thresholds of test stimuli for EMG were 4~5 mA in normal rats. Injection of formalin decreased threshold of test stimuli and increased EMG activities for 2hrs after injection. However, EA significantly inhibited EMG activities of flexor reflex increased by formalin and recovered EMG evoked thresholds. These results suggest that contralateral extra-segmental EA inhibits the first and second phases of formalin induced pain but their mechanism be needed to examine additionally.

• The Korean Journal of Pain
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• v.18 no.1
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• pp.1-9
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• 2005

Background: Spinal metabotropic glutamate receptors (mGluRs) and opioid receptors are involved in the modulation of nociception. Although opioid receptors agonists are active for pain, the effects of the compounds for the mGluRs have not been definitely investigated at the spinal level. We examined the effects of the intrathecal mGluR compounds and morphine in the nociceptive test, and then we further clarified the role of the spinal mGluRs. In addition, the nature of the pharmacological interaction after the coadministration of mGluRs compounds with morphine was determined. Methods: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, $50{\mu}l$ of 5% formalin solution or a thermal stimulus was applied to the hindpaw. An isobolographic analysis was used for the evaluation of the drug interaction. Results: Neither group I mGluR compounds nor group III mGluR compounds produced any antinociceptive effect in the formalin test. The group II mGluR agonist (APDC) had little effect on the formalin-induced nociception. The group II mGluR antagonist (LY 341495) caused a dose-dependent suppression of the phase 2 flinching response on the formalin test, but it did not reduce the phase 1 response of the formalin test nor did it increase the withdrawal latency of the thermal stimulus. Isobolographic analysis revealed a synergistic interaction after the intrathecal delivery of a LY 341495-morphine mixture. Conclusions: These results suggest that group II mGluRs are involved in the facilitated processing at the spinal level, and the combination of LY 341495 with morphine may be useful to manage the facilitated pain state.

• The Korean Journal of Pain
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• v.20 no.2
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• pp.106-110
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• 2007

Background: A phosphodiesterase 5 inhibitor, sildenafil, has been effective against nociception. Several lines of evidence have demonstrated the role of the GABAergic pathway in the modulation of nociception. The impact of the GABA receptors on sildenafil was studied using the formalin test at the spinal level. Methods: Male SD rats were prepared for intrathecal catheterization. The formalin test was induced by subcutaneous injection of formalin solution. The change in the activity of sildenafil was examined after pre-treatment with GABA receptor antagonists ($GABA_A$ receptor antagonist, bicuculline; $GABA_B$ receptor antagonist, saclofen). Results: Intrathecal sildenafil dose-dependently attenuated the flinching observed during phase 1 and 2 in the formalin test. The antinociceptive effect of sildenafil was reversed by the $GABA_B$ receptor antagonist (saclofen) but not by the $GABA_A$ receptor antagonist (bicuculline) in both phases. Conclusions: Intrathecal sildenafil suppressed acute pain and the facilitated pain state. The antinociception of sildenafil is mediated via the $GABA_B$ receptor, but not the $GABA_A$ receptor, at the spinal level.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.1
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• pp.23-27
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• 2005

The present study was performed to investigate the effects of intra-articular injection of interleukin-1${\beta}$ (IL-1${\beta}$) on the formalin-induced temporomandibular joint (TMJ) pain. Under anesthesia, a 30-gauge needle was introduced into the right TMJ region for injection of formalin. Microinjection of 50 ${\mu}l$ of 5% formalin significantly produced noxious scratching behavioral response, and the scratching behavior lasted for 40 min. Although the responses produced by formalin injection were divided into two phases, the response of 1st phase did not significantly differ from the scratching behavior response in the saline-treated group. We examined the effects of intra-articular injection of IL-1${\beta}$ on the number of noxious behavioral responses produced by 50${\mu}l$ of 5% formalin injection. Intra-articular injection of 100 pg and 1 ng of IL-1${\beta}$ significantly increased the number of behavioral responses of the 2nd phase, while 10 pg of IL-1${\beta}$ did not change the formalin-induced behavioral responses. To investigate whether IL-1 receptor was involved in the intra-articular administration of IL-1${\beta}$-induced hyperalgesic response, IL-1 receptor antagonist (IL- ra, 50 ng) was administrated together with IL-1${\beta}$ injection. IL-1${\beta}$ receptor antagonist blocked IL-1${\beta}$- induced hyperalgesic response in the TMJ formalin test. These results suggest that intra-articular injection of IL-1${\beta}$ facilitated the transmission of nociceptive information in the TMJ area.

• The Korean Journal of Pain
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• v.19 no.2
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• pp.142-145
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• 2006

Background: Nitric oxide (NO) is involved in the transmission and modulation of nociceptive information at the peripheral, spinal cord and supraspinal levels. We conducted this experiment to assess the antinociceptive effects of a nonselective nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME), on the modulation of pain in rats subjected to the formalin test. Methods: Formalin 5% was injected in the right hind paw after intraperitoneal (IP) injection of various doses of L-NAME (0.5 mg/kg, 1.5 mg/kg with and without L-arginine 100 mg/kg, 5.0 mg/kg). The number of flinches was measured. Results: Formalin injected into the rat hind paw induced a biphasic nociceptive behavior. IP injected L-NAME diminished the nociceptive behaviors in a dose-dependent manner during phases 1 and 2. The concomitant injection of L-arginine reversed the antinocipetive effect of L-NAME. Conclusions: The data demonstrates that a nonselective NOS inhibitor, L-NAME, possesses antinociceptive properties in rats subjected to the formalin test, and the antinociceptive effect of L-NAME is reversed by the concomitant administration of L-arginine.

• Journal of the Korean Society of Physical Medicine
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• v.6 no.2
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• pp.207-213
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• 2011

Purpose: The purpose of this study was to determine the preventive effect of joint mobilization on biphasic pain response induced formalin test. Methods: Sprague-dawley rats(n=30) were ramdomly divided into the control group without intervention, sham control group with application of hand contact without mobilization, joint mobilization group with application of hand contact with mobilization. Joint mobilization of knee procedure involved an grade III extension mobilization basically with anterior-posterior gliding of the tibia on the femur. Formalin injection caused biphasic pain response which is lated for 60 minute. The first phase result from primary afferent sensory fiber, wheareas the second phase has been proposed to central sensitization in the central nervous system. Behavioral analysis was performed by digital camera after 5% formalin subcutaneous injection into the dorsal foot. Results: Pain response of joint mobilization group show significant lower than control gorup and sham control group. Conclusion: This result suggest that pre-application of joint mobilization may be effective intervention to prevent the formalin induced pain.

• The Korean Journal of Pain
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• v.27 no.2
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• pp.118-124
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• 2014

Background: The chronic pain can disturb physical, psychological, and social performances. Analgesic agents are widely used but some antidepressants (ADs) showed analgesia also. Bupropion is using for smoke cessation but it can change morphine withdrawal signs such as pain. This study tested the acute systemic effect of bupropion on formalin induced pain behavior in rats. Methods: Wistar male healthy rats were divided into 7 groups (control, sham, and 5 treated groups with 10, 30, 90, 120, and 200 mg/kg of bupropion, i.p.). The bupropion injected 3 hours prior to formalin induced pain behavior. Formalin (50 ${\mu}l$, 2.5%) was injected subcutaneously in dorsal region of right hindpaw in all animals. Nociceptive signs were observed continuously on-line and off-line each minute. Common pain scoring was used for pain assessment. Results: The analysis of data by one-way ANOVA showed that bupropion can reduce pain scores in the second phase but not in first phase. Bupropion decreased the licking/biting duration significantly in first and second phase of formalin test. Conclusions: The results showed that bupropion has analgesic effects at systemic application. The change of second phase of the pain behavior was significant and it revealed that central mechanisms involve in bupropion analgesia.

• Journal of Acupuncture Research
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• v.34 no.2
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• pp.61-74
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• 2017

Objectives : This study was carried out to evaluate analgesic effects of Zanthoxylum bungeanum Maxim (ZM) pharmacopuncture on formalin-induced pains in Sprague-Dawley (SD) rats and ICR-mice. Methods : The subjects were divided 8 weeks aged rats with constant pain sensitivity into five groups; normal (treated with normal saline at Taegye (KI3) and before injected with normal saline at hindpaw), Con-1 (treated with normal saline at KI3 before injected with formalin at hindpaw), Lido-1 (treated with lidocaine at KI3), ZMWG-1 (treated with Hot water extraction pharmacopuncture of Zanthoxylum bungeanum Maxim at KI3), ZMEG-1 (treated with ethanol extraction pharmacopuncture of Zanthoxylum bungeanum Maxim at KI3). After 35 minutes, we measured ultrasonic vocalization (USV) and enzyme activities of both Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) in rat serum. In addition, Tail flick test is performed by injecting ICR mice at 5 weeks of age. And it classified into 4 groups (Con-2, Lido-2, ZMWG-2, ZMEG-2) according to the kind of drug (normal saline, lidocaine, ZMW, ZME). After each drug injection, we examined the reaction by placing the tail in water at $50^{\circ}C$. Results : ZME had analgesic effects in the early and late phase of USV during the formalin test. There were no significant differences between ZMEG-1 and Lido-1 in early and late phase of USV. Also, No significant differences observed in serum AST and ALT activity in ZMWG-1 and ZMEG-1 compared with Con-1. For tail-flick test, analgesic effect on warmth significantly increased in Lido-2 and ZMEG-2 compare to that of Con-2. Conclusion : ZME pharmacopuncture had analgesic effects on formalin-induced pain without liver toxicity. Also, tail-flick test suggest that ZME pharmacopuncture could be useful technique on analgesic effect on warmth and treatment of pains.

• The Korean Journal of Pain
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• v.14 no.1
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• pp.1-6
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• 2001

Background: Subcutaneous injection of 5% formalin into the hind paw of the rat produces a biphasic nociceptive response. The second phase depends on changes in the dorsal horn cell function that occur shortly after an initial C-fiber discharge, spinal sensitization, or windup phenomenon. This study was performed to investigate the role of glutamate during spinal sensitization. Methods: Sprague-Dawley rats weighing 200 to 250 g were used for this study. Under light anesthesia (0.5% isoflurane) the rats were segregated in a specially designed cage and $50{\mu}l$ 0.5% formalin was injected subcutaneously in the foot dorsum of right hindlimb. Forty minutes after the formalin injection, the rat was quickly decapitated and spinal cord was removed. The spinal segments at the level of L3 (largest area) was collected and stored in a deep freezer ($-70^{\circ}C$). The mRNA gene expression of N-methyl-D-aspartate receptor (NMDAR) and the metabotropic glutamate receptor subtype 5 (mGluR5) were determined by the polymerase chain reaction. Results: The number of flinches was $19.8{\pm}2.3/min$. at one minute after formalin injection and decreased to zero after then. The second peak appeared at 35 and 40 minutes after formalin injection. The values were $17.8{\pm}2.2$ and $17.2{\pm}3.0/min$. The mRNA gene expressions of NMDAR and mGluR5 were increased by $459.0{\pm}46.8%$ (P < 0.01) and $111.1{\pm}4.8%$ (P > 0.05) respectively at 40 minutes after formalin injection. The increased rate of NMDAR was significantly higher than that of mGluR5 (P < 0.01). Conclusions: From these results it suggested that NMDAR partly contributed to the mechanism of central sensitization after the formalin test but mGluR5 did not.

• Natural Product Sciences
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• v.20 no.4
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• pp.301-305
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• 2014

The aim of our study is to investigate the anti-nociceptive and anti-inflammatory properties of an ethanol extract of the leaf and stem of Aralia cordata. Writhing responses induced by acetic acid, tail immersion test, and formalin-induced paw pain response for nociception and formalin-induced paw edema for inflammation were evaluated in mice. A. cordata (50 - 200 mg/kg, p.o.) and ibuprofen (100 mg/kg, p.o.), a positive non-steroidal anti-inflammatory drugs (NSAIDs), inhibited the acetic acid-induced writhing response, but they did not protect the thermal nociception in tail immersion test. However, morphine (5 mg/kg, s.c.) used as positive opioid control alleviated both the acetic acid-induced writhing response and thermal nociception in tail immersion test. In the formalin test, A. cordata (50 - 200mg/kg) and ibuprofen (200mg/kg) inhibited the second phase response (peripheral inflammatory response), but not the first phase response (central response), whereas morphine inhibited both phase pain responses. Both A. cordata (100 mg/kg) and ibuprofen (200 mg/kg) significantly alleviated the formalin-induced increase of paw thickness, the index of inflammation. These results show for the first time that the leaf and stem of A. cordata has a significant anti-nociceptive effect that seems to be peripheral, but not central. A. cordata also displays an anti-inflammatory activity in an acute inflammation model. The present study supports a possible use of the leaf and stem of A. cordata to treat pain and inflammation.