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쥐의 포르말린 시험에서 척수강 Sildenafil의 항통각효과에 대한 GABA<sub>B</sub> 수용체 조절성
김웅모,윤명하,이형곤,한용구,김여옥,황란희,최금화,Kim, Woong Mo,Yoon, Myung Ha,Lee, Hyung Gon,Han, Yong Gu,Kim, Yeo Ok,Huang, Lan Ji,Cui, Jin Hua 대한통증학회 2007 The Korean Journal of Pain Vol.20 No.2
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.
Role of PKG-L-type calcium channels in the antinociceptive effect of intrathecal sildenafil
김웅모,윤명하,Jin Hua Cui 대한수의학회 2010 JOURNAL OF VETERINARY SCIENCE Vol.11 No.2
Sildenafil increases the cyclic guanosine monophosphate (cGMP) by inhibition of a phosphodiesterase 5, thereby leading to an antinociceptive effect. The increased cGMP may exert the effect on an L-type calcium channel through the activation of protein kinase G (PKG). The purpose of this study was to examine the possible involvement of a PKG-Ltype calcium channel on the effect of sildenafil at the spinal level. Catheters were inserted into the intrathecal space of male SD rats. Pain was induced by applying 50 μL of a 5% formalin solution to the hindpaw. The sildenafil-induced effect was examined after an intrathecal pretreatment of a PKG inhibitor (KT 5823), or a L-type calcium channel activator (FPL 64176). Intrathecal sildenafil produced an antinociceptive effect during phase 1 (0∼10 min interval) and phase 2 (10∼60 min interval) in the formalin test. Intrathecal KT 5823 and FPL 64176 attenuated the antinociceptive effect of sildenafil during both phases. Sildenafil is effective against both acute pain and the facilitated pain state at the spinal level. In addition, the inhibition of an L-type calcium channel by activation of the PKG may contribute to the antinocieptive mechanism of sildenafil in the spinal cord.
이형곤,김웅모,박천희,윤명하 연세대학교의과대학 2010 Yonsei medical journal Vol.51 No.6
Purpose: The phosphodiesterase 5 inhibitor sildenafil has antinociceptive effects,mediated by an increase in cGMP. This study examined the role of spinal adenosine and serotonin receptors played in the antinociceptive effects of intrathecal sildenafil. Materials and Methods: Intrathecal catheters were inserted into the subarachnoid space of Sprague-Dawley male rats as a drug delivery device. Pain was induced by injecting formalin into the plantar surface of rats and observing nociceptive behavior (flinching response) for 60 mininutes. Then, the effects of intrathecal adenosine and serotonin receptor antagonists on the antinociceptive activity of intrathecal sildenafil were examined. Results: Intrathecal sildenafil suppressed the flinching response in a dose-dependent manner during phases 1 and 2 in the formalin test. Both CGS 15943 and dihydroergocristine decreased the antinociceptive effects of sildenafil during phases 1 and 2 in the formalin test. Conclusion: Intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Both adenosine and serotonin receptors may be involved in the antinociceptive action of sildenafil at the spinal level.
이형곤,김웅모,윤명하,A Reum Park,최정일 대한마취통증의학회 2013 Korean Journal of Anesthesiology Vol.65 No.4
Background: Thalidomide has been recognized as having an anti-allodynic effect against neuropathic pain induced by spinal nerve ligation. Its clinical beneficial effects are mainly derived from its immune-modulating property, which is known to influence the analgesic action of morphine. The possible characteristics of systemic interactions between thalidomide and morphine in the context of spinal nerve ligation-induced neuropathic pain were examined in rats. Methods: Neuropathic pain was induced by ligation of the L5/6 spinal nerves in male Sprague-Dawley rats and mechanical allodynia was assessed using von Frey filaments. The ED50 was calculated for thalidomide and for morphine, and the mixture of both drugs was intraperitoneally administered at different doses of ED50 of each drug (1/8, 1/4, 1/2, 1/1 of ED50) to obtain the experimental ED50 value for the combination of thalidomide and morphine. Isobolographic analysis was used to evaluate the characteristics of drug interactions between morphine and thalidomide. Results: The ED50 of thalidomide was three-fold higher than that of morphine. The experimental ED50 value of the mixture of thalidomide and morphine was significantly lower than the calculated theoretical ED50 value. Isobolographic analysis revealed a synergistic interaction for anti-allodynic effect after intraperitoneal delivery of the thalidomide-morphine mixture. Conclusions: These results suggest that thalidomide acts synergistically with morphine to produce an anti-allodynic effect in neuropathic pain induced by spinal nerve ligation in rats. Thus, the combination of thalidomide with morphine may be one of the useful strategies in the management of neuropathic pain.
최정일,김웅모,윤명하,이형곤 대한통증학회 2010 The Korean Journal of Pain Vol.23 No.3
Background:Tumor necrosis factor-alpha and other proinflammatory cytokines are becoming well recognized as key mediators in the pathogenesis of many types of neuropathic pain. Thalidomide has profound immunomodulatory actions in addition to their originally intended pharmacological actions. There has been debate on the analgesic efficacy of opioids in neuropathic pain. The aim of this study was to investigate the effect of thalidomide and morphine on a spinal nerve ligation model in rats. Methods:Male Sprague-Dawley rats weighing 100−120 g were used. Lumbar (L) 5 and 6 spinal nerve ligations were performed to induce neuropathic pain. For assessment of mechanical allodynia, mechanical stimulus using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of intraperitoneal thalidomide (6.25, 12.5, 25 and 50 mg/kg, respectively) and morphine (3 and 10 mg/kg, respectively) were examined on a withdrawal threshold evoked by spinal nerve ligation. Results:After L5 and 6 spinal nerve ligation, paw withdrawal thresholds on the ipsilateral side were significantly decreased compared with pre-operative baseline and with those in the sham-operated group. Intraperitoneal thalidomide and morphine significantly increased the paw withdrawal threshold compared to controls and produced dose-responsiveness. Conclusions:Systemic thalidomide and morphine have antiallodynic effect on neuropathic pain induced by spinal nerve ligation in rat. These results suggest that morphine and thalidomide may be alternative therapeutic approaches for neuropathic pain. (Korean J Pain 2010; 23: 172-178)
생쥐의 골 암성통증 모형에서 ginsenosides의 효과
윤명하,이형곤,김웅모,주진,김여옥,최금화 대한마취통증의학회 2010 Anesthesia and pain medicine Vol.5 No.4
Background:Ginsenosides have been used for a long time as an oriental folk medicine. Although ginsenosides modulate the nociceptive transmission, the effect of ginsenosides on a bone cancer pain has not been elucidated. The authors examined the effect of ginsenosides in a mouse model of bone cancer pain. Methods:Bone cancer was induced by intramedullary injection of osteolytic sarcoma cells in to the femur in male C3H/HeJ mice. Mice showing mechanical allodynia after 14 days after cancer cells inoculation were included in this study. Mechanical allodynia was evaluated by measuring the withdrawal threshold to von Frey filament applying on the femoral cancer site. Effect of ginsenosides (30, 100, 300 mg/kg) was examined at 15, 30, 60, 90, 120 min after intraperitoneal administration of ginsenosides. Results:After cancer cells injection into the femur, bone cancer was developed in simple X-ray. A paw withdrawal threshold in a cancer site was significantly decreased. Intraperitoneal ginsenosides did not effectively alter the withdrawal threshold in the cancer site. Conclusions:Taken together, ginsenosides may not be effective to attenuate the bone cancer pain.