• The Korean Journal of Pain
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• v.37 no.1
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• pp.26-33
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• 2024

Background: Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Methods: Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/K_ATP pathway in the antinociceptive effect of sitagliptin (5 mg/kg). Results: Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT₂) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect. Conclusions: NO/cGMP/K_ATP, 5HT₃ and D₂ pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.

• The Korean Journal of Pain
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• v.13 no.2
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• pp.137-142
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• 2000

Background: Systemic or intrathecal administration of gabapentin has been shown to reverse various pain states. However, until now, the effect of intracerebroventricular (ICV) gabapentin to noxious stimuli has not been reported. The authors' aim of this study was to determine the effect of ICV gabapentin on the inflammatory nociceptive model, formalin test, in rats. Methods: ICV catheters were implanted under halothane anesthesia. For the nociceptive test, $50{\mu}l$ of 5% formalin was subcutaneously injected into the hindpaw. The effect of ICV gabapentin, administered 10 min before formalin injection, were examined on flinching, mean arterial pressure and heart rate evoked by a injection of formalin. Results: Injection of formalin into the paw resulted in a biphasic flinching and cardiovascular response. ICV gabapentin produced a dose-dependent suppression of the flinching and mean arterial pressure response during phase 1. In contrast, in phase 2, ICV gabapentin did not attenuate the pain behavior. ICV gabapentin did not affect on the baseline mean arterial pressure and heart rate. Conclusions: ICV gbapentin was effective for the acute noxious stimulus but it had no effect on the facilitated states induced by tissue injury.

• The Korean Journal of Pain
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• v.26 no.1
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• pp.14-20
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• 2013

Background: Nefopam, a non-opiate analgesic, has been regarded as a substance that reduces the requirement for morphine, but conflicting results have also been reported. The inhibition of monoamine reuptake is a mechanism of action for the analgesia of nefopam. The spinal cord is an important site for the action of monoamines however, the antinociceptive effect of intrathecal nefopam was not clear. This study was performed to examine the antinociceptive effect of intrathecal (i.t.) nefopam and the pattern of pharmacologic interaction with i.t. morphine in the formalin test. Methods: Male Sprague-Dawley rats were implanted with an i.t. catheter, and were randomly treated with a vehicle, nefopam, or morphine. Formalin was injected into the hind-paw 10 min. after an i.t. injection of the above experiment drugs. After obtaining antinociceptive $ED_{50}$ of nefopam and morphine, the mixture of nefopam and morphine was tested for the antinociceptive effect in the formalin test at a dose of 1/8, 1/4, 1/2 of $ED_{50}$, or $ED_{50}$ of each drug followed by an isobolographic analysis. Results: Intrathecal nefopam significantly reduced the flinching responses in both phases of the formalin test in a dose-dependent manner. Its effect, however, peaked at a dose of $30{\mu}g$ in phase 1 (39.8% of control) and $10{\mu}g$ during phase 2 (37.6% of control). The isobolograhic analysis indicated an additive interaction of nefopam and morphine during phase 2, and a synergy effect in antinociception during phase 1. Conclusions: This study demonstrated that i.t. nefopam produces an antinociceptive effect in formalin induced pain behavior during both phases of the formalin test, while interacting differently with i.t. morphine, synergistically during phase 1, and additively during phase 2.

• The Korean Journal of Pain
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• v.22 no.3
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• pp.206-209
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• 2009

Background: The essential oil of Ocimum basilicum (EOOB) has a pleasant aroma and is known to have antimicrobial and insecticidal activities. In addition, it is used as a pain reliever in folk medicine. However, there are few reports on the antinociceptive activities of EOOB. Methods: This study examined the antinociceptive effects of EOOB using formalin and a plantar test in mice. In the formalin test, EOOB (50 mg/kg, 100 mg/kg, 150 mg/kg) was administered intraperitoneally and the licking time of the mice was measured. In the plantar test, intraperitoneal EOOB (50 mg/kg, 100 mg/kg) was administered and the withdrawal latency was measured using the Hargreaves method. Results: In the formalin test, EOOB (50 mg/kg, IP) showed significant decreases in licking time in the second phase. On the other hand, in the plantar test, there were no significant effects in any of the groups examined. Conclusions: These results support the traditional use of EOOB for the treatment of painful conditions. However, there is a need for more research to determine the active chemical constituents and the precise mechanism.

• The Journal of Korean Medicine
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• v.24 no.2
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• pp.193-203
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• 2003

Objectives : In this study, we investigated the effect and pathway of contralateral heterotropic electroacupuncture (EA) on pain induced by fonualin in rats. Methods : Acu-points in the right forepaws, HT 7 and PC 7 were stimulated with 3~4mA, 2ms, and 10Hz after 5% formalin (50ul) s.c. injection to the left hind paw. In addition, it was investigated whether the dorsolateral funiculus (DLF), known to be related the descending inhibition, mediates analgesic effects of the contralateral heterotropic EA or whether administration of naltrexone, an opioid antagonist, blocks the effect of EA. Results : The results showed that contralateral heterotropic electroacupuncture (EA) inhibited late phase (63.311.7%) of pain induced by fonualin in the behavioral test, but sham-EA had little effect on pain behavior (85.616.8%) and no analgesic effects after transection of the dorsolateral funiculus (95.718.7%). The pretreatment of naltrexone (10mg/kg, i.p.) could not inhibit the analgesic effects of EA on formalin-induced pain behavior (70.713.1%). Also,EA suppressed formalin injection induced expression of cFos like protein (cFL) in the dorsal homo but not sham-EA. Suppressed expressions of cFL in the spinal cord were eliminated after transection of the ipsilateral dorsolateral funiculus at T10-11 leve1s. However, pretreatment of naltrexone could not prevent the suppressive expressions of cFL at the spinal cord. Conclusions : These results suggest that the analgesic effect of contralateral heterotropic electroacupuncture may be modulated through the dorsolateral funiculus constituting the descending inhibition.

• YAKHAK HOEJI
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• v.43 no.3
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• pp.404-410
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• 1999

Administration of capsaicin produces acute pain and subsequent long-lasting antinociception. The antinociceptive action site of capsaicin is primarily small afferent nerve fibers. However, the effect of capsaicin on the neural activity of dorsal horn neurons are not well understood. The goal of the present experiment was to study the action of capsaicin on activity of dorsal horn neurons using c-fos immunoreactivity in the spinal cord. Intradermal injection of formalin in the hindpaw produced inflammation in the foot pad and increased the number of cells exhibiting Fos-like immunoreactivity (FLI) in the dorsal horn of the spinal cord, suggesting the hyperalgesia because of the apparent inflammation. Intradermal injection of capsaicin prior to formalin injection significantly reduced the number of cells exhibiting FLI induced by formalin and increased the paw-withdrawal latency, suggesting the hypoalgesic effect of capsaicin. Coadministeration with capsaicin of capsazepine and ruthenium red, antagonists of capsaicin receptor reversed the reduction of formalin-induced FLI by capsaicin. he antagonists also partially antagonized the antinociceptive effect of capsaicin in the paw-withdrawal test. These results further suggest that capsaicin reduces prsponses of dorsal horn neurons to the inflammatory nociceptive stimuli in the periphery. Thus, the reduction of FLI subserves the neural mechanisms underlying analgesia produced by capsaicin.

• Journal of Veterinary Clinics
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• v.24 no.4
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• pp.499-502
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• 2007

The study was performed to assess the antinociceptive efficacy of Korean bee venom(BV) in the rat formalin test. Korean BV was collected using BV collector devices in which an electrical impulse is used to stimulate the worker bee(Apis mellifera L.) to sting and release venom. After collection, whole Korean BV was evaporated until dry using BV collector. Experiments were performed on male Sprague-Dawley rats(weighing 260-270, 6 weeks old). Rats divided into 4 groups, each comprising 8 rats. BV was diluted and amounts of 6 mg/kg body weight(BW), 0.6 mg/kg BW and 0.06 mg/kg BW were tested. BV was subcutaneously injected to produce an antinociceptive effect and the antinociceptive efficacy was evaluated using a rat formalin test. BV was subcutaneously injected into an acupoint(Zusanli, ST36) at 15 min prior to 1% formalin($50{\mu}l$) injection. The antinociceptive effect observed during 60 min following formalin administration. BV produced antinociceptive efficacy from 10 to 60 min after formalin injection. The antinociceptive efficacy of Korean BV showed a dose-dependent response. These results suggest that Korean BV may be a suitable and preferred choice for antinociceptive efficacy in pain management.

• 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.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.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.