The Analgesic Effects and Mechanisms of Orally Administered Eugenol

박수현,서홍원,심윤범,이진구,Seon-Mi Kim,Yu-Jung Kang,Jun-Sub Jung 대한약학회 2011 Archives of Pharmacal Research Vol.34 No.3

In the present study, the antinociceptive profiles of eugenol were examined in ICR mice. Eugenol administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dosedependent manner as measured in the acetic acid-induced writhing test. Duration of antinociceptive action of eugenol maintained at least for 30 min. Moreover, the cumulative response time of nociceptive behaviors induced by an intraplantar formalin injection was reduced by eugenol treatment during the 2^nd phases. Furthermore, the cumulative nociceptive response time for intrathecal injection of substance P (0.7 μg) or glutamate (20 μg) was diminished by eugenol. Intraperitoneal pretreatment with yohimbine (α2-adrenergic receptor antagonist) or naloxone (opioid receptor antagonist) attenuated antinociceptive effect induced by eugenol in the writhing test. However, methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by eugenol in the writhing test. Our results suggest that eugenol shows an antinociceptive property in various pain models. Furthermore, this antinociceptive effect of eugenol may be mediated by α2-adrenergic and opioidergic receptors, but not serotonergic receptor.

작열통모델 흰쥐의 등쪽뿌리신경절 및 척수에서 α2-아드레날린 수용체 유전자발현의 변화

이남혁(Nam-Hyuk Lee),김동선(Dong-sun Kim),김정기(Jeong-Ki Kim),김광진(Kwang-Jin Kim),조희중(Hee-Jung Cho) 대한해부학회 1998 Anatomy & Cell Biology Vol.31 No.6

말초신경이 손상을 입었을 때 교감신경계가 어떠한 기전에 의하여 작열통을 유발시키는지 확실히 알려진 바는 없지만, 아마도 α-아드레날린 수용체 (α-adrenergic receptor, α-AR)를 매개로 하는 것으로 추측되고 있다. 본 연구에서는 정상흰쥐의 DRG 및 척수에서 α2A, α2B 및 α2C-AR mRNA의 분포를 in situ hybridization (ISH)기법으로 관찰하고 L5, 6 척수신경을 결찰한 작열통모델 흰쥐의 α2A, α2B 및 α2C-AR mRNA의 양적변화를 reverse transcriptase-polymerase chain reaction (RT-PCR) 법으로 관찰하여 다음의 결과들을 얻을 수 있었다. 1. 정상군의 ISH 결과, DRG의 작은, 중간 그리고 큰신경세포들에서 α2C-AR mRNA가 발현되었고 α2A-AR mRNA는 전체 신경세포의 16%에서 발현되었으며 주로 중간 및 큰세포에 분포하였다. 한편 α2B-AR mRNA의 발현은 관찰되지 않았다. 척수에서는 α2A-AR mRNA의 경우 등쪽뿔의 제 II, III층의 신경세포와 배쪽뿔의 운동신경세포에서 주로 관찰되었다. α2B-AR mRNA함유 신경세포는 관찰할 수 없었으며 α2C-AR mRNA는 배쪽뿔의 운동신경세포에서 주로 관찰되었다. 2. 결찰군에서 RT-PCR 결과, 결찰측의 L5, 6 DRG에서는 α2A-AR mRNA가 반대측 및 Sham군의 DRG의 그것에 비하여 유의하게 증가하였으며 α2C-AR mRNA의 경우 유의하게 감소하였다. L5 및 L6 척수의 결찰측은 반대측이나 Sham군의 척수에 비하여 α2A, α2B, 및 α2C-AR mRNA의 발현에는 유의한 차이를 발견할 수 없었다. 이상의 결과들에 의하면 DRG에 분포하는 α2A 및 α2C-AR는 말초신경 손상후 교감신경 의존성의 작열통 유발에 중요한 역할을 하며 척수의 α2-AR는 연관성이 없는 것으로 사료된다. While the pathophysiological mechanism by which sympathetic nervous system generates neuropathic pain is not clear, it is thought to involve an α-adrenergic receptor (AR). In the present experiment, we have elucidated the distribution of α2-AR subtypes mRNA in the DRG and spinal cord of normal rat with in situ hybridization (ISH) and analyzed changes in their expression in an experimental model of neuropathic pain with reverse transcriptase-polymerase chain reaction (RT-PCR). The results obtained were as follows; 1. The majority of small, medium and large DRG neurons of non-operated rats expressed α2C-AR mRNA. α2A-ARexpressing neurons were primarily medium-sized and large, comprising about 16% of the total neurons present. α2BAR-expressing neurons were not identified. In the spinal cord, α2A-AR mRNA were localized in neurons of lamina II and III, and large motor neurons in the ventral horn. α2C-AR mRNA was found in large motor neurons. 2. In the ligated animals, RT-PCR results showed that α2A-AR mRNA levels in L5, 6 DRGs on the ipsilateral side significantly increased compared to those of the contralateral sides and also to those of sham-operated rats. α2C-AR mRNA levels showed a marked decrease in ipsilateral L5, 6 DRGs. In the spinal cord, there was no detectable changes in α2A- and α2C-AR mRNAs levels. The present results indicate that α2A- and α2C-ARs in the DRG may play an important role in generating sympathetically maintained neuropathic pain and that α2-AR in the spinal cord seems not to be involved.

실험연구 : 말초신경손상 쥐에서 중추신경계 α2-아드레날린성 수용체 아형의 발현

최소론 ( So Ron Choi ),이형창 ( Hyung Chang Lee ),정찬종 ( Chan Jong Chung ),김해규 ( Hae Kyu Kim ) 대한마취과학회 2006 Korean Journal of Anesthesiology Vol.51 No.4

Background: The change of expression of the α2-adrenergic receptor (α2-AR) subtypes in the thalamus and hypothalamus were investigated in a neuropathic pain rat model. Methods: The left sciatic nerve was clamped for creating a neuropathic pain model in five rats. A sham operation was done in three rats as control group. Behavioral tests for pain were conducted by using mechanical stimuli applied to the hind paws. After 7 days, the expression of α2-AR subtype mRNA in the rat thalamus and hypothalamus was measured using real time polymerase chain reaction. Results: Mechanical allodynia were developed on postoperative 1, 3, and 7 days in the neuropathic pain model. The expression of α2A-AR, α2B-AR, and α2C-AR was significantly higher in the thalamus and hypothalamus in the neuropathic pain model (P > 0.05). Conclusions: These results would suggest that the subtypes of α2-AR in thalamus and hypothalamus may contribute to produce neuropathic pain. (Korean J Anesthesiol 2006; 51: 468~75)

백서의 척수신경결찰모델에서 Morphine의 투여가 항이질통 효과와 척수 α2 아드레날린계 수용체 아형 mRNA 발현에 미치는 영향

정규연 ( Kyu Yeon Chung ),신상욱 ( Sang Wook Shin ),권수아 ( Su Ah Kwon ),김태균 ( Tae Kyun Kim ),백승훈 ( Seung Hoon Baek ),백승완 ( Seong Wan Baik ) 대한통증학회 2009 The Korean Journal of Pain Vol.22 No.1

Bioactive Materials : Antinociception Effect and Mechanism of Ruta graveolens L. in Mice

Soo Hyun Park,Yun Beom Sim,Seon Mi Kim,Jin Koo Lee,Song Sung Lim,Jin Kyu Kim,Hong Won Suh 한국응용생명화학회 2010 Applied Biological Chemistry (Appl Biol Chem) Vol.53 No.5

Antinociceptive profiles of Ruta graveolens L extract were examined in ICR mice. R. graveolens L extract administered orally (200 mg/kg) showed an antinociceptive effect as measured by the tailflick and hot-plate tests and attenuated the writhing numbers i

The activation of α₂-adrenergic receptor in the spinal cord lowers sepsis-induced mortality

Sung-Su Kim,Soo-Hyun Park,Jae-Ryung Lee,Jun-Sub Jung,Hong-Won Suh 대한생리학회-대한약리학회 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.5

The effect of clonidine administered intrathecally (i.t.) on the mortality and the blood glucose level induced by sepsis was examined in mice. To produce sepsis, the mixture of D-galactosamine (GaLN; 0.6 g/10 ml)/lipopolysaccharide (LPS; 27 µg/27 µl) was treated intraperitoneally (i.p.). The i.t. pretreatment with clonidine (5 µg/5 µl) increased the blood glucose level and attenuated mortality induced by sepsis in a dose-dependent manner. The i.t. post-treatment with clonidine up to 3 h caused an elevation of the blood glucose level and protected sepsis-induced mortality, whereas clonidine post-treated at 6, 9, or 12 h did not affect. The pre-treatment with oral D-glucose for 30 min prior to i.t. post-treatment (6 h) with clonidine did not rescue sepsis-induced mortality. In addition, i.t. pretreatment with pertussis toxin (PTX) reduced clonidine-induced protection against mortality and clonidine-induced hyperglycemia, suggesting that protective effect against sepsis-induced mortality seems to be mediated via activating PTX-sensitive G-proteins in the spinal cord. Moreover, pretreatment with clonidine attenuated the plasma tumor necrosis factorα (TNF-α) induced by sepsis. Clonidine administered i.t. or i.p. increased p-AMPKα1 and p-AMPKα2, but decreased p-Tyk2 and p-mTOR levels in both control and sepsis groups, suggesting that the up-regulations of p-AMPKα1 and p-AMPKα2, or down-regulations of p-mTOR and p-Tyk2 may play critical roles for the protective effect of clonidine against sepsis-induced mortality.

Dexmedetomidine alleviates cerebral ischemia-induced short-term memory impairment by inhibiting the expression of apoptosis-related molecules in the hippocampus of gerbils

Choi, In-Young,Hwang, Lakkyong,Jin, Jun-Jang,Ko, Il-Gyu,Kim, Sung-Eun,Shin, Mal-Soon,Shin, Key-Moon,Kim, Chang-Ju,Park, Sung-Wook,Han, Jin-Hee,Yi, Jae-Woo D.A. Spandidos 2017 Experimental and therapeutic medicine Vol.13 No.1

<P>Cerebral ischemia results from cerebrovascular occlusion, which leads to neuronal cell death and eventually causes neurological impairments. Dexmedetomidine is a potent and highly selective α<SUB>2</SUB>-adrenoreceptor agonist with actions such as sedation, anxiolysis, analgesia and anesthetic-sparing effects. We investigated the effect of dexmedetomidine on apoptosis in the hippocampus after transient global ischemia in gerbils. Transient global ischemia was induced by ligation of both common carotid arteries. Dexmedetomidine was administrated intraperitoneally at three respective doses (0.1, 1 and 10 µg/kg) once per day for 14 consecutive days beginning a day after surgery. Short-term memory was assessed by use of a step-down avoidance task. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay, immunohistochemistry for caspase-3, and western blot analysis of Bcl-2-associated X protein, B-cell lymphoma 2, Bid, cytochrome <I>c</I>, apoptotic protease activating factor-1 and caspase-9 in the hippocampus. Induction of global ischemia deteriorated short-term memory by enhancing the expression of apoptosis-related molecules in the hippocampus. Treatment with dexmedetomidine suppressed the expression of apoptosis-related molecules under ischemic conditions, resulting in short-term memory improvement. Under normal conditions, dexmedetomidine exerted no significant effect on apoptosis in the hippocampus. The present results suggest that the α<SUB>2</SUB>-adrenoceptor agonist dexmedetomidine may be a useful therapeutic agent for the treatment of ischemic brain diseases.</P>

The activation of α2-adrenergic receptor in the spinal cord lowers sepsis-induced mortality

김성수,박수현,이재령,정준섭,서홍원 대한약리학회 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.5

The effect of clonidine administered intrathecally (i.t.) on the mortality and the blood glucose level induced by sepsis was examined in mice. To produce sepsis, the mixture of D-galactosamine (GaLN; 0.6 g/10 ml)/lipopolysaccharide (LPS; 27 µg/27 µl) was treated intraperitoneally (i.p.). The i.t. pretreatment with clonidine (5 µg/5 µl) increased the blood glucose level and attenuated mortality induced by sepsis in a dose-dependent manner. The i.t. post-treatment with clonidine up to 3 h caused an elevation of the blood glucose level and protected sepsis-induced mortality, whereas clonidine post-treated at 6, 9, or 12 h did not affect. The pre-treatment with oral D-glucose for 30 min prior to i.t. post-treatment (6 h) with clonidine did not rescue sepsis-induced mortality. In addition, i.t. pretreatment with pertussis toxin (PTX) reduced clonidine-induced protection against mortality and clonidine-induced hyperglycemia, suggesting that protective effect against sepsis-induced mortality seems to be mediated via activating PTX-sensitive G-proteins in the spinal cord. Moreover, pretreatment with clonidine attenuated the plasma tumor necrosis factor α (TNF-α) induced by sepsis. Clonidine administered i.t. or i.p. increased p-AMPKα1 and p-AMPKα2, but decreased p-Tyk2 and p-mTOR levels in both control and sepsis groups, suggesting that the up-regulations of p-AMPKα1 and p-AMPKα2, or downregulations of p-mTOR and p-Tyk2 may play critical roles for the protective effect of clonidine against sepsis-induced mortality.