• The Korean Journal of Pain
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• 제28권1호
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• pp.1-3
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• 2015

• Biomolecules & Therapeutics
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• 제30권4호
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• pp.328-333
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• 2022

Repeated morphine administration induces tolerance to its analgesic effects. A previous study reported that repeated morphine treatment activates transient receptor potential vanilloid type 1 (TRPV1) expression in the sciatic nerve, dorsal root ganglion, and spinal cord, contributing to morphine tolerance. In the present study, we analyzed TRPV1 expression and binding sites in supraspinal pain pathways in morphine-tolerant mice. The TRPV1 mRNA levels and binding sites were remarkably increased in the cortex and thalamus of these animals. Our data provide additional insights into the effects of morphine on TRPV1 in the brain and suggest that changes in the expression of, and binding to TRPV1 in the brain are involved in morphine tolerance.

• The Korean Journal of Pain
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• 제14권2호
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• pp.225-230
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• 2001

Background: Opioids such as morphine are widely used in the treatment for pain, but chronic treatment with morphine can be complicated by the development of tolerance. The mechnisms of tolerance were still not completely understood, but recently it has been reported that NOS inhibitors can prevent development of morphine tolerance in animals. The present study accessed the possible role of supraspinal NO on antinociceptive effect of morphine in morphine tolerance using a highly specific inhibitor of the neuronal isoform of NOS, 1-(2-trifluoromethylphenyl) imidazole (TRIM). Methods: Thirty two male SD rats (300 g) were prepared with intracerebroventricular (icv) and IV cannulae. We administrated IV morphine, 3 mg/kg, daily for 4 days, resulting in tolerance. On the fifth day, a challenge dose of morphine, 3 mg/kg, was administered following pretreatment with icv TRIM, $10{\mu}g$. We also evaluated the antinociceptive effect of icv TRIM alone and the effect on a single dose of morphine (3 mg/kg) in morphine nave rats. Antinociception from morphine was determined by response to intraplantar injection of 5% formalin $100{\mu}l$ was qualified as the number of flinches in the first 0-10 min (first phase), 10-40 min Phase IIa, and 40-60 min (Phase IIb). Results: Pretreatment with icv TRIM significantly enhanced the antinociceptive effects of systemically administered morphine in morphine tolerant rats. The antinociceptive effect of morphine in opioid nave rats was also significantly increased by pretreatment with icv TRIM. Conclusions: Our results further support the hypothesis that supraspinal NO modulates morphine-sensitive nociceptive process in morphine tolerance due to chronic intravenous administration.

• The Korean Journal of Pain
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• 제34권1호
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• pp.58-65
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• 2021

Background: Supraspinal delivery of neurotensin (NTS), which may contribute to the effect of a systemically administered agonist, has been reported to be either pronociceptive or antinociceptive. Here, we evaluated the effects of systemically administered NTSR1 agonist in a rat model of neuropathic pain and elucidated the underlying supraspinal mechanism. Methods: Neuropathic pain was induced by L5 and L6 spinal nerve ligation in male Sprague-Dawley rats. The effects of intraperitoneally administered NTSR1 agonist PD 149163 was assessed using von Frey filaments. To examine the role of 5-HT neurotransmission, a serotonin (5-HT) receptor antagonist dihydroergocristine was pretreated intrathecally, and spinal microdialysis studies were performed to measure the change in extracellular level of 5-HT in response to PD 149163 administration. To investigate the supraspinal mechanism, NTSR1 antagonist 48692 was microinjected into the rostral ventromedial medulla (RVM) prior to systemic PD 149163. Additionally, the effect of intrathecal DHE on intra-RVM PD 149163 was assessed. Results: Intraperitoneally administered PD 149163 exhibited a dose-dependent attenuation of mechanical allodynia. This effect was partially reversed by intrathecal pretreatment with dihydroergocristine and was accompanied by an increased extracellular level of 5-HT in the spinal cord. The PD 149163-produced antinociception was also blocked by intra-RVM SB 48692. Direct injection of PD 149163 into the RVM mimicked the maximum effect of the same drug delivered intraperitoneally, which was reversed by intrathecal dihydroergocristine. Conclusions: These observations indicate that systemically administered NTSR1 agonist produces antinociception through the NTSR1 in the RVM, activating descending serotonergic projection to release 5-HT into the spinal dorsal horn.

• The Korean Journal of Physiology
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• 제30권1호
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• pp.85-96
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• 1996

Adenosine and its analogues are known to possess analgesic effects and to be involved in the opiate-induced antinociception as well. This study was designed to investigate the effects of three adenosine agonists, 5'- (N-cyclopropyl) -carboxamidoadenosine(CPCA), 5'-N-ethylcarboxamidoadeno-sine (NECA) and $N^6-cyclohexyladenosine$ (CHA) on the signal transmission in the spinal cord and also to elucidate mechanisms of their actions in the anesthetized cat. All the tested adenosine agonists(i.v,) exerted inhibitory effects on the responsiveness of the wide dynamic range (WDR) cells, the inhibitory action of CHA, an adenosine $A_1$ receptor agonist, $(80{\mu}g/Kg)$ being most weak. The intravenous CPCA, an adenosine $A_2$ receptor agonist, $(20{\mu}g\;/Kg)$ and NECA, nonspecific adenosine receptor agonist, $(20{\mu}g\;/Kg)$ inhibited the responses of WDR cells to pinch and C fiber stimulation more strongly than those to brush and A fiber stimulation. CPCA (i.v.) also suppressed the responses of WDR cells to thermal stimulus. And all the CPCA-induced inhibitions were caffeine-reversible. When CPCA was directly applied onto the spinal cord or intravenously administered into the spinal cat, on average, about three quarters of the CPCA-induced inhibitory effect was abolished. On the other hand, in the animal with spinal lesions in the ipsilateral dorsolateral area, the CPCA-induced inhibition was comparable to that observed in the spinal cats. In conclusion, this study shows that adenosine agonists strongly suppress the responses of WDR cells to pinch, C fiber stimulation and thermal stimuli mainly through the supraspinal adenosine $A_2-receptors$.

• 한국전문물리치료학회지
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• 제6권4호
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• pp.8-14
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• 1999

이 연구의 목적은 우세한 손과 그렇지 않은 손에서 방사효과가 악력에 어떤 영향을 미치는가 알아보는데 있다. 연구대상은 의료기관에 있는 30명이며 연령은 $32{\pm}9.23$세, 체중분포 $73.8{\pm}23.7$ kg이며, 신장은 $170.26{\pm}10.24$ cm 이었다. 연구 대상자들의 악력은 4가지 다른 조건에서 측정되어졌다. 첫째 조건은, 방사효과가 잠재적으로 가능한 상태에서 우세한 손의 최대악력을 측정, 둘째 조건은, 방사효과가 잠재적으로 불가능한 상태에서 우세한 손의 최대악력을 측정, 셋째 조건은, 방사효과가 잠재적으로 가능한 상태에서 우세하지 않은 손의 최대악력을 측정, 넷째 조건은, 방사효과가 잠재적으로 불가능한 상태에서 우세하지 않은 손의 최대악력을 측정하였다. 연구결과로는 어떤 조건에서도 방사효과가 잠재가능과 불가능의 최대악력비교에서 이원분산분석(two-way ANOVA) 결과 통계학적으로 어떤 차이점도 없었다(F[1, 116] = .0016, p<.05). 이 연구결과는 정상인에 있어서 방사효과가 악력에 미치는 영향을 통계학적으로 발견할 수 없다는 결론을 내렸다. 그 이유로는 방사효과가 최대악력에 미치는 영향이 10~20%의 최대 근육 수축범위이며 척추상위 억제 기전(supraspinal inhibitory mechanism)이 방사효과의 활동을 억제한다는 이론에 의한다.

• Journal of Ginseng Research
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• 제24권3호
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• pp.143-147
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• 2000

앞의 연구에서 우리는 진세노사이드 Rc, Rd, Re 및 Rr를 복강내 전 처리할 경우 포르말린으로 유도된 통증을 억제하다는 것을 보고하였다 그러나 이러한 진세노사이드가 어느 위치에서 항통증작용을 발휘하는가에 대하여서는 아직 알려지지 않고 있다. 본 연구에서는 이들 진세노사이드를 뇌실내, 척수강내 혹은 피하내 전처리한 다음 포르밀린에 의하여 유도되는 통증이 어느 위치에서 억제되는가를 연구하였다. 연구 결과 이들 진세노사이드는 척수강내 전처리할 경우 포르말린에 의하여 유도되는 통증을 억제하는 것으로 나타났다. 급성 통증 phase에서 ED$_{50}$는 Rc가 1.0 (0.SS~l.75mg/kg)이었고, Rd가 1.15 (0.6~2.25 mg/kg)이었고, Re가 8.9(3.9~20.5 mg/kg)이었다. 지속성 통증 phase에서 ED$_{50}$는 Rc가0.3 (0.1~0.85 mg/kg)이었고, Rd가 0.6 (0.35~l.1 mg/kg)이었고, Re가 2.45 (1.2s~4.65 mg/kg)이었고, Rf가 1.9(1.5~4.25 mg/kg)인 것으로 나타났다. 또한 뇌실내 전처리할 경우에도 이들 진세노사이드들은 포르말린에 의하여 유도되는 통증을 억제하였다. 급성통증 phase에서 ED$_{50}$는 Rc가 0.9 (0.55~l.4 mg/kg)이었고, Rd가0.9 (0.45~l.7 mg/kg)이었고, Re가 0.93 (0.Sol.75 mg/kg), Rf가1.85 (0.95~3.5 mg/kg)인 것으로 나타났다. 지속성 통증 phase에서는 ED$_{50}$는 Rc가 0.7 (0.45~l.05 mg/kg)이었고, Rd가 1.25(0.7~2.2 mg/kg)이었고, Re가 0.85 (0.45~l.6 mg/kg)이었고, H의 경우에는 0.8 (0.4~l.45 mg/kg) 이었다. 항통증 효능 potency는 두 가지 투여 경로에 있어서 Rc$\geq$Rd>Re>Rf인 것으로 나타났다. 그러나, 피하내 주사는 포르말린에 의하여 유도되는 통증을 억제하지 않은 것으로 나타났다. 이러한 연구 결과는 진세노사이드에 의한 항통증 작용은 척수 수준 및 척수위 수준에서 이루어진다는 것을 보여주고 있다.보여주고 있다.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 1990년도 Proceedings of International Symposium on Korean Ginseng, 1990, Seoul, Korea
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• pp.36-44
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• 1990

The analgesic effect of morphine was antagonized and the development of tolerance was suppressed by the modification of the neurologic function in the animals treated with ginseng saponins. The activation of the spinal descending inhibitory systems as well as the supraspinal structures by the administration of morphine was inhibited in the animals treated with ginseng saponins intracerebrally or intrathecally The development of morphine tolerance and dependence, and the abrupt expression of naloxone induced abstinence syndrome were also inhibited by ginsenoside Kbl , Rba, Rgl and Re. These results suggest that ginsenoside Kbl, Rba, Rgl and Re are the bioactive components of panax ginseng on the inhibition of the development of morphine tolerance and dependence, and the inhibition of abrupt abstinence syndrome. In addition, further research on the minor components of Panax ginseng should be investigated. A single or daily treatment with ginseng saponins did not induce any appreciable changes in the brain level of monoamines at the various time intervals and at the various day intervals, respectively The inhibitory or facilitated effects of ginseng saponins on electrically evoked contractions in guinea pig ileum (U-receptor) and mouse was definers (5·receptor) were not mediated through opioid receptors. The antagonism of a x receptor agonist, U-, iO.488H was also not mediated through opioid receptors in the animals treated with ginseng saponins, bolt mediated through serotonergic mechanisms. Ginseng saponins inhibited morphine S-dehydrogenase that catalyzed the production of morphine from morphine, and increased hepatic glutathione contents for the detoxification of morphine. This result suggests that the dual action of the above plays an important role in the inhibition of the development of morphine tolerance and dependence.

• The Korean Journal of Pain
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• 제19권2호
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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.

• The Korean Journal of Physiology
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• 제22권1호
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• pp.89-100
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• 1988

Effect of clonidine on the dorsal horn cell responses to mechanical stimulations were studies in 3 spinalized cats and 10 cats with intact spinal cord. The type of dorsal horn cells was determined according to their response patterns to four graded mechanical stimulations (brush, pressure, pinch and squeeze) applied to the respective receptive fields. In the present study the results obtained only from the wide dynamic range (WDR) cells were included. The responses of the WDR cells to noxious mechanical stimuli were selectively suppressed following intravenous administration of clonidine into the experimental animals. The clonidine-induced changes in responses of the WDR cells to mechanical stimulation were not affected by naloxone or propranolol whereas effect of clonidine on WDR cell responses was almost completely abolished after intravenous administration of yohimbine. Also in the spinalized cats results parallel to those observed in cats with intact spinal cord were obtained. The results of present study strongly implies that analgesic action of clonidine can be mediated through excitation of ${\alpha}_{2}-adrenoceptor$ even at the spinal cord level without supraspinal mechanism.