• The Korean Journal of Physiology and Pharmacology
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• v.9 no.2
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• pp.77-86
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• 2005

In this study, we examined the morphine-induced modulation of the nociceptive spinal dorsal horn neuronal activities before and after formalin-induced inflammatory pain. Intradermal injection of formalin induced time-dependent changes in the spontaneous activity of nociceptive dorsal horn neurons. In naive cats before the injection of formalin, iontophoretically applied morphine attenuated the naturally and electrically evoked neuronal responses of dorsal horn neurons. However, neuronal responses after the formalin-induced inflammation were significantly increased by morphine. Bicuculline, $GABA_A$ antagonist, increased the naturally and electrically evoked neuronal responses of dorsal horn neurons. This increase in neuronal responses due to bicuculline after the formalin-induced inflammation was larger than that in the naive state, suggesting that basal $GABA_A$ tone increased after the formalin injection. Muscimol, $GABA_A$ agonist, reduced the neuronal responses before the treatment with formalin, but not after formalin treatment, again indicating an increase in the GABAergic basal tone after the formalin injection which saturated the neuronal responses to GABA agonist. Morphine-induced increase in the spinal nociceptive responses after formalin treatment was inhibited by co-application of muscimol. These data suggest that formalin-induced inflammation increases $GABA_A$ basal tone and the inhibition of this augmented $GABA_A$ basal tone by morphine results in a paradoxical morphineinduced increase in the spinal nociceptive neuronal responses after the formalin-induced inflammation.

• International Journal of Oral Biology
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• v.41 no.4
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• pp.191-197
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• 2016

The present study was to evaluate effects of vitamin E on intravenous administration of lidocaine-induced antinociception. Experiments were carried out using male Sprague-Dawley rats. Orofacial formalin-induced nociceptive behavioral responses were used as the orofacial animal pain model. Subcutaneous injection of formalin produced significant nociceptive scratching behavior. Intraperitoneal injection of 5 and 10 mg/kg of lidocaine attenuated formalin-induced nociceptive behavior in the 2nd phase, compared to the vehicle-treated group. Intraperitoneal injection of 1 g/kg of vitamin E also attenuated the formalin-induced nociceptive behavior in the 2nd phase, compared to the vehicle-treated group. However, low dose of vitamin E (0.5 g/kg) did not affect the nociceptive behavioral responses produced by subcutaneous injection of formalin. The present study also investigated effects of intraperitoneal injection of both vitamin E and lidocaine on orofacial formalin-induced behavioral responses. Vehicle treatment affected neither formalin-induced behavioral responses nor lidocaine-induced antinociceptive effects. However, intraperitoneal injection of 0.5 g/kg of vitamin E enhanced the lidocaine-induced antinociceptive effects in the 2nd phase compared to the vehicle-treated group. Intraperitoneal injection of naloxone, an opioid receptor antagonist, did not affect antinociception produced by intraperitoneal injections of both vitamin E and lidocaine. These results suggest that treatment with vitamin E enhances the systemic treatment with lidocaine-induced antinociception and reduces side effects when systemically treated with lidocaine. Therefore, the combined treatment with vitamin E and lidocaine is a potential therapeutic for chronic orofacial pain.

• IMMUNE NETWORK
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• v.13 no.6
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• pp.289-294
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• 2013

Lipocalin-2 (LCN2) is an acute-phase protein induced by injury, infection, or other inflammatory stimuli. LCN2 binds small hydrophobic ligands and interacts with cell surface receptor to regulate diverse cellular processes. The role of LCN2 as a chemokine inducer in the central nervous system (CNS) has been previously reported. Based on the previous participation of LCN2 in neuroinflammation, we investigated the role of LCN2 in formalin-induced nociception and pathological pain. Formalin-induced nociceptive behaviors (licking/biting) and spinal microglial activation were significantly reduced in the second or late phase of the formalin test in Lcn2 knockout mice. Likewise, antibody-mediated neutralization of spinal LCN2 attenuated the mechanical hypersensitivity induced by peripheral nerve injury in mice. Taken together, our results suggest that LCN2 can be therapeutically targeted, presumably for both prevention and reversal of acute inflammatory pain as well as pathological pain.

• The Korean Journal of Pain
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• v.21 no.1
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• pp.27-32
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• 2008

Background: Experimental evidence indicates that ginseng modulate the nociceptive transmission. Authors examined the role of adrenergic and cholinergic receptors on the antinociceptive action of Korean red ginseng against the formalin-induced pain at the spinal level. Methods: Catheters were inserted into the intrathecal space of male Sprague-DawIey rats. Fifty ${\mu}l$ of 5% formalin solution was injected to the hindpaw for induction of pain and formalin-induced pain (flinching response) was observed. The role of spinal adrenergic and cholinergic receptors on the effect of Korean red ginseng was assessed by antagonists (Prazosin, yohimbine, atropine and mecamylamine). Results: Intrathecal Korean red ginseng produced a dose-dependent suppression of the flinching response in the rat formalin test. All of prazosin, yohimbine, atropine and mecamylamine antagonized the antinociception of Korean red ginseng. Conclusions: Spinal Korean red ginseng is effective against acute pain and facilitated pain state evoked by formalin injection. All of alpha 1, alpha 2, muscarinic and nicotinic receptors may play an important role in the antinociceptive action of Korean red ginseng at the spinal level.

• 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.

• The Korean Journal of Pain
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• v.19 no.1
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• pp.17-21
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• 2006

Background: Cyclic guanosine monophosphate (cGMP) plays an important role in the modulation of nociception. Although local sildenafil produces antinociception, by increasing cGMP through the inhibition of phosphodiesterase 5, the effect of spinal sildenafil has not been determined. The authors evaluated the effects of intrathecal sildenafil on the nociceptive behavior evoked by formalin injection and thermal stimulation. Methods: Lumbar intrathecal catheters were implanted into rats, with formalin and Hot-Box tests used as nociceptive models. The formalin-induced nociceptive behavior (flinching response) and withdrawal latency to radiant heat were measured, and the general behaviors also observed. Results: The intrathecal administration of sildenafil produced dose-dependent suppression of the flinches in both phases in the formalin test, and increased the withdrawal latency in the Hot-Box test. No abnormal behaviors were noted. Conclusions: Sildenafil, an inhibitor of phosphodiesterase 5, is active against the nociceptive state evoked in the spinal cord by formalin and thermal stimulations. Accordingly, spinal sildenafil may be useful in the management of 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.

• Journal of Ginseng Research
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• v.22 no.1
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• pp.43-50
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• 1998

We demonstrated in previous study that protopanaxadiol and protopanxatriol saponins show antinociceptive activity in acetic acid induced writhing test and in the second phase (11-40 min) of formalin test but not tail-flick test. To identify further which ginsenoside has antinociceptive activity among various ginseng saponins, we have investigated antinociceptive effects of several ginsenosides using writhing and formalin test. Ginsenoside Rc, Rd, Re, and Rf induced antinociception in writhing test. These four ginsenosides also induced antinociception in the second phase of formalin (11-40 min) test but these ginsenosides showed a slight antinociception in the first phase (010 min) of formalin test except ginsenoside Rf. The antinociceptive effects induced by the ginsenosides were dose dependent and were not blocked by an opioid receptor antagonist, naloxone. The order of antinociceptive potency was Rd > Rc > Re > Rf in the formalin test. However, these ginsenosides did not show any significant analgesic effects in a tail-flick test. These results suggest that ginsenosides such as Rc, Rd, Re, and Rf inhibit tonic pain rather than acute pain induced by noxious heat. These results also indicate that the antinociceptive activity. Induced by ginsenosides may be one of the actions for pharmacological effects of Panax ginseng.

• The Korean Journal of Physiology
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• v.30 no.1
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• pp.97-104
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• 1996

Different neural substrates have been reported to be implicated in analgesic mechanisms in the acute phasic and the sustained tonic pains. To explore the differential antinociceptive action of diphenylhydantoin (DPH) and carbamazepine (CBZ) on the acute phasic and the tonic pains, changes in tail flick latency, hot plate latency and the formalin-induced nociceptive score were assessed prior to and after intraperitoneal administration of DPH (20 & 40 mg/Kg) and CBZ (20 mg/Kg). In 11 rats, CBZ was administered repeatedly for 6 days at the dose of 20 mg/Kg/day. Also studied were the effects of strychnine and picrotoxin (1 mg/Kg, i.p.) on the CBZ-produced changes in the formalin-induced pain behaviors. The tail flick and hot plate ltencies were not changes after administration of DPH and CBZ. However DPH strongly suppressed the formalin-induced tonic pain. A single and the repeated administration of CBZ inhibited both the early phasic and the late tonic pain responses to formalin in n similar manner. On the other hand, the antinociceptive actions of CBZ were not altered by strychnine or picrotoxin. These experimental findings lead to the conclusion that DPH and CBZ have differential antinociceptive action on the acute and the tonic pains and that their antinociceptive actions are independent of the GABA- and glycine-receptors.

• 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.