• The Korean Journal of Pain
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• v.20 no.1
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• pp.21-25
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• 2007

Background: Intrathecal sildenafil has produced antinociception by increasing the cGMP through inhibition of phosphodiesterase 5. Spinal opioid receptor has been reported to be involved in the modulation of nociceptive transmission. The aim of this study was to examine the role of opioid receptor in the effect of sildenafil on the nociception evoked by formalin injection. Methods: Rats were implanted with lumbar intrathecal catheters. Formalin testing was used as a nociceptive model. Formalin-induced nociceptive behavior (flinching response) was observed. To clarify the role of the opioid receptor for the analgesic action of sildenafil, naloxone was administered intrathecally 10 min before sildenafil delivery, and formalin was then injected 10 min later. Results: Intrathecal sildenafil produced dose-dependent suppression of flinches in both phases during the formalin test. Intrathecal naloxone reversed the analgesic effect of sildenafil in both phases. Conclusions: Sildenafil is active against the nociceptive state that's evoked by a formalin stimulus, and the opioid receptor is involved in the analgesic action of sildenafil at thespinal level.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.2
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• pp.143-149
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• 1997

We studied the effects of ginseng protopanaxadiol (PD) and protopanaxatriol (PT) saponins on the analgesia using several pain tests such as writhing, formalin, and tail-flick test. Using mouse, pretreatment of PD or PT saponins (i.p.) induced inhibition of abdominal constrictions caused by 0.9% acetic acid administration(i.p.). The $AD_{50}$ was around 27 (17-43) mg/kg for PD and 13.5 (3-61) mg/kg for PT saponins in writhing test. Both PD and PT saponins also showed the inhibition of bitings and lickings of hindpaw after administration of 1% formalin. In particular, both PD and PT saponins showed analgesic effects on second phase of pain. The $AD_{50}$ was 44.5 (26-76) mg/kg for PD and 105 (55-200) mg/kg for PT saponins in second phase of formalin test. For first phase pain inhibition by PD or PT saponins, they were required higher concentrations. However, PD saponins showed weak analgesic effects in tail-flick test with high concentration. In conclusion, we found that both PD and PT saponins have the analgesic effects in writhing test and second phase of pain in formalin test. These results suggest that both PD and PT saponins inhibit neurogenic or tonic pain rather than acute pain.

• The Korean Journal of Pain
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• v.30 no.2
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• pp.98-103
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• 2017

Background: The root of Peucedanum japonicum Thunb., a perennial herb found in Japan, the Philippines, China, and Korea, is used as an analgesic. In a previous study, sec-O-glucosylhamaudol (SOG) showed an analgesic effect. This study was performed to examine the antinociceptive effect of intrathecal SOG in the formalin test. Methods: Male Sprague-Dawley rats were implanted with an intrathecal catheter. Rats were randomly treated with a vehicle and SOG ($10{\mu}g$, $30{\mu}g$, $60{\mu}g$, and $100{\mu}g$) before formalin injection. Five percent formalin was injected into the hind-paw, and a biphasic reaction followed, consisting of flinching and licking behaviors (phase 1, 0-10 min; phase 2, 10-60 min). Naloxone was injected 10 min before administration of SOG $100{\mu}g$ to evaluate the involvement of SOG with an opioid receptor. Dose-responsiveness and ED50 values were calculated. Results: Intrathecal SOG showed a significant reduction of the flinching responses at both phases in a dose-dependent manner. Significant effects were showed from the dose of $30{\mu}g$ and maximum effects were achieved at a dose of $100{\mu}g$ in both phases. The ED50 value (95% confidence intervals) of intrathecal SOG was 30.3 $(25.8-35.5){\mu}g$ during phase 1, and 48.0 (41.4-55.7) during phase 2. The antinociceptive effects of SOG ($100{\mu}g$) were significantly reverted at both phases of the formalin test by naloxone. Conclusions: These results demonstrate that intrathecal SOG has a very strong antinociceptive effect in the formalin test and it seems the effect is related to an opioid receptor.

• The Korean Journal of Pain
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• v.27 no.1
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• pp.23-29
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• 2014

Background: Nefopam has shown an analgesic effect on acute pain including postoperative pain. The reuptake of monoamines including serotonin and noradrenaline has been proposed as the mechanism of the analgesic action of nefopam, but it remains unclear. Although alpha-adrenergic agents are being widely used in the perioperative period, the role of noradrenergic modulation in the analgesic effect of nefopam has not been fully addressed. Methods: Changes in the antinociceptive effect of intrathecal (i.t.) nefopam against formalin-elicited flinching responses were explored in Sprague-Dawley rats pretreated with i.t. 6-hydroxydopamine (6-OHDA), which depletes spinal noradrenaline. In addition, antagonism to the effect of nefopam by prazosin and yohimbine was evaluated to further elucidate the antinociceptive mechanism of i.t. nefopam. Results: Pretreatment with i.t. 6-OHDA alone did not alter the flinching responses in either phase of the formalin test, while it attenuated the antinociceptive effect of i.t. nefopam significantly during phase 1, but not phase 2. The antagonist of the alpha-2 receptor, but not the alpha-1 receptor, reduced partially, but significantly, the antinociceptive effect of i.t. nefopam during phase 1, but not during phase 2. Conclusions: This study demonstrates that spinal noradrenergic modulation plays an important role in the antinociceptive effect of i.t. nefopam against formalin-elicited acute initial pain, but not facilitated pain, and this action involves the spinal alpha-2 but not the alpha-1 receptor.

• Journal of Acupuncture Research
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• v.26 no.6
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• pp.91-100
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• 2009

Objectives : The objective of this study is to investigate Anti-nociceptive and anti-inflammatory effects of Clematidis Radix (CR) herbal-acupuncture on the test rats with induced acute pain. Methods : The effects of Clematidis Radix (CR)-distillates were investigated in three types of models with three different pain. Highly purified distillate of CR called CR herbal-acupuncture was injected to Zusanli ($ST_{36}$) acupoint. In the tail flick test, the CR herbal-acupuncture treatment did not show a significant effect of relieving acute pain. To investigate the anti-inflammatory effect of CR herbal-acupuncture, the second testing model'pain was induced by injecting formalin to its planter. For the last model, carrageenan was injected into tarsal joint. the medicinal effect of CR herbal-acupuncture was evaluated through the behavioral analyses such as licking time, weight distribution ratio and ankle circumference. Results : In the formalin test, the analgesic effect of CR herbal-acupuncture was more pronounced in the late phase (for 20 min after the early phase) than in the early phase (for the first 10 min post formalin injection). It was proven by weight distribution ratio testing and ankle edema testing that herbal-acupuncture of CR inhibited arthritis caused by the carrageenan. Conclusions : These results revealed that CR herbal-acupuncture was effective to alleviate the inflammatory pain and could be used as an analgesic treatment with an anti-inflammatory effect.

• The Korean Journal of Pain
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• v.32 no.2
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• pp.79-86
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• 2019

Background: The use of aroma oils dates back to at least 3000 B.C., where it was applied to mummify corpses and treat the wounds of soldiers. Since the 1920s, the term "aromatherapy" has been used for fragrance therapy with essential oils. The purpose of this study was to determine whether the essential oil of Eucalyptus (EOE) affects pain pathways in various pain conditions and motor coordination. Methods: Mice were subjected to inhalation or intraperitoneal injection of EOE, and its analgesic effects were assessed by conducting formalin, thermal plantar, and acetic acid tests; the effects of EOE on motor coordination were evaluated using a rotarod test. To determine the analgesic mechanism, 5'-guanidinonaltrindole (${\kappa}$-opioid antagonist, 0.3 mg/kg), naltrindole (${\delta}$-opioid antagonist, 5 mg/kg), glibenclamide (${\delta}$-opioid antagonist, 2 mg/kg), and naloxone (${\mu}$-opioid antagonist, 4, 8, 12 mg/kg) were injected intraperitoneally. Results: EOE showed an analgesic effect against visceral pain caused by acetic acid (EOE, 45 mg/kg); however, no analgesic effect was observed against thermal nociceptive pain. Moreover, it was demonstrated that EOE did not have an effect on motor coordination. In addition, an anti-inflammatory effect was observed during the formalin test. Conclusions: EOE, which is associated with the ${\mu}$-opioid pain pathway, showed potential effects against somatic, inflammatory, and visceral pain and could be a potential therapeutic agent for pain.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.2
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• pp.365-371
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• 2006

Bee Venom aqua-acupuncture (BVA) simultaneously exerts pharmacological effects of biologically active compounds, existed in the whole bee venom, and medicinal effect of the stimulation of acupuncture points. BVA has been considered as a promising therapeutic method for treating various chronic diseases, mainly accompanying severe pain and inflammation. As a painless injection device, jet injectors have been commercially marketed for various clinical applications including insulin injection and vaccination. Among them, a pressure-driven jet injector system could be used for intradermal delivery of a variety of drugs. The aim of this study was to investigate the analgesic effects of the BVA using a needle-free injector (Biojector $2000^{\circledR}$, Bioject Inc., OR, USA), compared to the conventional BV aqua-acupuncture using a typical syringe. Adult Sprague-Dawley rats were injected with bee venom $(0.08mg/kg,\;50{\mu}l)$ using Biojector $2000^{\circledR}$ (BVA-B) or a syringe (BVA-5) into the Zusanli (ST36) acupoint, 30 minutes before plantar injection of 2% formalin. It was found that BVA-B-, or BVA-5-treated rats, compared to controls, exhibited significantly less licking behavior during the late phase in the rat formalin test, when compared to controls. During early phase, however, those effects were not significant but substantial. The analgesic effect of BVA-B was also compatible with that of the conventional BVA-5. In the immunohistochemical studies, BVA-B significantly suppressed the expression of formalin-evoked c-fos, a biomarker of neuronal activity, in the lumbar dorsal horn of the spinal cord. These results indicated that BVA-B waseffective in the modulation of pain in the rat formalin test, compared to BVA-5. Taken together, the needle-free jet injector system could be substituted for the conventional aqua- acupuncture with the advantage of little pain.

• The Korean Journal of Pain
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• v.29 no.3
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• pp.164-171
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• 2016

Background: Nefopam has been known as an inhibitor of the reuptake of monoamines, and the noradrenergic and/or serotonergic system has been focused on as a mechanism of its analgesic action. Here we investigated the role of the spinal dopaminergic neurotransmission in the antinociceptive effect of nefopam administered intravenously or intrathecally. Methods: The effects of intravenously and intrathecally administered nefopam were examined using the rat formalin test. Then we performed a microdialysis study to confirm the change of extracellular dopamine concentration in the spinal dorsal horn by nefopam. To determine whether the changes of dopamine level are associated with the nefopam analgesia, its mechanism was investigated pharmacologically via pretreatment with sulpiride, a dopaminergic D2 receptor antagonist. Results: When nefopam was administered intravenously the flinching responses in phase I of the formalin test were decreased, but not those in phase II of the formalin test were decreased. Intrathecally injected nefopam reduced the flinching responses in both phases of the formalin test in a dose dependent manner. Microdialysis study revealed a significant increase of the level of dopamine in the spinal cord by intrathecally administered nefopam (about 3.8 fold the baseline value) but not by that administered intravenously. The analgesic effects of intrathecally injected nefopam were not affected by pretreatment with sulpiride, and neither were those of the intravenous nefopam. Conclusions: Both the intravenously and intrathecally administered nefopam effectively relieved inflammatory pain in rats. Nefopam may act as an inhibitor of dopamine reuptake when delivered into the spinal cord. However, the analgesic mechanism of nefopam may not involve the dopaminergic transmission at the spinal level.

• The Journal of Korean Medicine
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• v.28 no.3 s.71
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• pp.261-272
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• 2007

Objectives : This study was conducted to determine the analgesic effect of Acanthopanax sessiliflorus using the model of neuropathic pain and formalin-induced pain. Methods : A model of neuropathic pain was made by injuring the tibial nerve and sural nerve while the common peroneal nerve was maintained. After 2 weeks, the Acanthopanax sessiliflorus was orally administered to rats. The author performed behavioral teststo try out mechanical allodynia using von frey filament and cold allodynia using acetone, which are calculated by counting withdrawal response on foot. Thirty minutes after the Acanthopanax sessiliflorus injection in the abdominal cavity, the formalin test was performed. 2% formalin in a volume of $20{\mu}l$was injected subcutaneously into the plantar surface of the hindpaw with 26-G needle. To access formalin-induced pain behavior, paw licking time was measured every 5 min. Results : The Acanthopanax sessiliflorus 400mg/10ml/kg group showed significant decrease the withdrawal response of mechanical allodynia using von frey filament in the 10min, 30min, 60min and 120min increments compared with the control group. There were no significant differences in each group in the withdrawal response of cold allodynia using acetone. The Acanthopanax sessiliflorus group showed significant decrease in the formalin-induced pain behavior in the 15min, 20min and 25min increments compared with the control group. Conclusions : The Acanthopanax sessiliflorus may have a significant analgesic effect on the general pain as well as nerve injury pain.

• The Korean Journal of Pain
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• v.18 no.2
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• pp.113-117
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• 2005

Background: Serotonin 3 receptor is involved in the modulation of nociceptive transmission in the spinal cord. The serotonin 3 receptor antagonist has been used for the management of opioid-induced nausea and vomiting. The aim of this study was to examine whether the analgesic effect of morphine is antagonized by serotonin 3 receptor antagonists at the spinal level. Methods: Rats were implanted with lumbar intrathecal catheters. For nociception, a formalin solution (5%, $50{\mu}l$) was injected into the hind paw of male Sprague-Dawley rats. To determine whether the effect of intrathecal morphine was mediated via serotonin 3 receptors, serotonin 3 receptor antagonists were intrathecally administered 10 min prior to the morphine delivery. Following the formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. Results: Intrathecal morphine produced a dose-dependent suppression of the flinches in both phases during the formalin test. The analgesic action of morphine was not reversed by serotonin 3 receptor antagonists (LY-278,584, ondansetron), which had little per se effect on the formalin-induced nociception. Conclusions: Spinal serotonin 3 receptors may not be involved in the analgesia of morphine on a nociceptive state evoked by a formalin stimulus.