• The Korean Journal of Pain
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• v.13 no.2
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• pp.156-163
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• 2000

Background: Peripheral nerve injury sometimes leads to chronic neuropathic pain such as causalgia. A subset of patients with causalgia have a sympathetically maintained pain which is often evoked by cooling stimuli. However, our knowledge on adrenergic receptor types responsible for cold-evoked pain that is sympathetically dependent is lacking. The present study was conducted to investigate subtypes of adrenoceptors involved in mediating cold-evoked pain that developed following peripheral nerve injury. Methods: Neuropathic surgery was performed by a unilateral ligation of L5 and L6 spinal nerves of rats. Behavioral sign of cold-evoked pain was examined for 5 min by measuring cumulative duration of time that the rat lifted its foot off a metal plate held at cold temperature ($5^{\circ}C$). Whether cold-evoked pain behavior was affected by antagonists of various subtypes of adrenoceptors, which were administered intraperitoneally before and after the ligation, was investigated. Results: After ligation, duration of foot lifting on the ligated side at cold temperature increased as compared to the pre-operative period. This increase maintained for the entire 40-day test period. Pretreatment with alpha-antagonist phentolamine produced a suppression of cold-evoked pain behavior that was not affected by beta-antagonist propranolol pretreatment. Prazosin, alpha-1 antagonist, suppressed cold- evoked pain behavior when treated either before or after nerve ligation. On the other hand, alpha-2 antagonist yohimbine was without effect on cold-evoked pain behavior whether it was treated before or after the ligation. Conclusions: The results suggest that peripheral nerve injury develops cold-evoked pain that is sympathetically dependent, and that alpha-1 adrenoreceptor plays a critical role for the generation of this type of pain in its initiation as well as maintenance.

• Archives of Pharmacal Research
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• v.11 no.1
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• pp.65-73
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• 1988

The effects of clonidine on the negative chronotropic response induced by stimulation of vagus nerve were studied in the presence of propranolol in reserpinized and anesthetized rats. When the heart rate was decreased by stimulation of the vagus nerve, clonidine significantly inhibited vagally induced heart rate decrease (negative chronotropic response) in dose dependent manner. This inhibitory effect of clonidine was virtually abolished by phentolamine, ${\alpha}_1-\;and\;{\alpha}_2-adrenoceptor$ antagonist, and partially antagonized by prazosin, ${\alpha}_1-adrenoceptor$ antagonist. On the other hand, when the heart rate was decreased by the infusion of bethanechol, a muscarinic parasympathetic stimulant, clonidine had no effect on the bethanechol-induced heart rate decrease. These results suggest that clonidine inhibits vagally induced negative chronotropic response by activation of presynaptic ${\alpha}-adrenoceptors$ located on the parasympathetic cholinergic nerve terminal in the heart and this effect of clonidine is more related to ${\alpha}_2-adrenoceptors$ than ${\alpha}_1-adrenoceptors$.

• Archives of Pharmacal Research
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• v.12 no.4
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• pp.243-248
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• 1989

Effects of B-HT 920 on the vagally stimulated gastric acid secretion were studied in anesthetized and gastric fistula rats. When the gastric acid secretion was increased by stimulation of the vagus nerve, B-HT 920 was partially attenuated by prazosin, $\alpha_1-$adrenoceptor antagonist and virtually abolished by yohimbine, $\alpha_2-$adrenoceptor antagonist. On the other hand, when the gastric acid secretion was increased by the infusion of bethanechol, a muscarinic parasympathetic stimulant, B-HT 920 had no effect on the bethanechol-induced gastric acid secretion. These results suggest that B-HT 920 inhibits vagally induced gastric acid secretion by activation of presynaptic $\alpha-$adrenoceptors located on the vagally stimulated pathways in the gastric wall and this effect of B-HT 920 is more related to $\alpha_2-$adrenoceptors than $\alpha_1-$adrenoceptors.

• Archives of Pharmacal Research
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• v.23 no.4
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• pp.353-359
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• 2000

${\alpha}_2$-Adrenoceptor antagonists, which can enhance synaptic norepinephrine levels by blocking feedback inhibition processes, are potentially useful in the treatment of disease states such. as depression, memory impairment, impotence and sexual dysfunction. (10bS)-1,2,3,5,6,10b-Hexahydropyrrolo[2,1-a]isoquinoline oxalate (YSL-3S) was evaluated in several in vitro biological tests to establish its pharmacological profile of activities as an ${\alpha}_2$-adrenoceptor antagonist. Saturation binding assay revealed that$^{3}[H]$rauwolscine bound to the $\alpha$$_2$-adrenoceptors with a Kd value of 6.3$\pm$0.5 nM and a Bmax value of 25l$\pm$39 fmol/mg protein in rat cortical synaptic membranes. Competitive binding assay showed that YSL-3S inhibited the binding of$^3[H]$rauwolscine (1 nM) in a concentration-dependent manner with a Ki value of 98.2$\pm$12.1 nM while it did not inhibit the binding of [$^3$H]cytisine (1.25 nM) to neuronal nicotinic cholinergic receptors. The Ki values of yohimbine, clonidine and norepinephrine for $^3[H]$rauwolscine binding were 15.8$\pm$1.0, 40.1$\pm$5.9 and 40.0$\pm$11.5 nM, respectively. In addition, the binding affinity of YSL-3S for ${\alpha}_2$-adrenoceptors was higher than that of its antipode and the racemic mixture. The functional activity of YSL-3S at the presynaptic ${\alpha}_2$-adrenoceptors was assessed using the prostatic portion of the rat vas deferens. Clonidine inhibited field-stimulated contractions of the vas deference in a dose-dependent manner. The presence of YSL-3S or yohimbine caused a parallel, rightward the dose-response curve of clonidine in a dose-dependent manner, indicating an antagonistic action at the presynaptic ${\alpha}_2$-adrenoceptors. The $pA_2$values of yohimbine and YSL-3S were 7.66$\pm$0.13 and 6.64$\pm$0.18, respectively. The results indicate that YSL-3S acts as a competitive antagonist at presynaptic ${\alpha}_2$ -adrenoceptors with a potency approximately ten times lower than yohimbine, but is devoid of binding affinity for neuronal nicotinic cholinergic receptors.

• Journal of Acupuncture Research
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• v.22 no.1
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• pp.99-108
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• 2005

Objective : The aim of this study is to investigate the analgesic effect and its mechanism of bee venom acupuncture on collagen-induced arthritis(CIA) rats. Methods : Bee venom (1 mg/kg) was subcutaneously punctured into Choksamni (ST36) of CIA Analgesic effect was evaluated by using the tail flick latency (TFL). Opioid and ${\alpha}2$-adrenergic neurotransmitter system were examined by naloxone as an opioid receptor antagonist and yohimbine as ${\alpha}2$-adrenoceptor antagonist prior to bee venom cupuncture. Results : The results were as follows; 1. The TFL for the CIA rat was decreased as time went by. 2. The TFL in CIA rat was increased in bee venom acupuncture group compared with control group (no treatment). 3. Analgesic effect of bee venom acupuncture was not abolished by naloxone pre-treatment in the CIA rat. 4. Analgesic effect of bee venom aqua-acupuncture was abolished by yohimbine pre-treatment in the CIA rat. 5. Two weeks bee venom acupuncture had the continous analgesic effect for 4 weeks. Conclusions : Bee venom acupuncture has an analgesic effect on the CIA rat and has an antinociception mediated by ${\alpha}2$-adrenergic system.

• Journal of the Korean Chemical Society
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• v.43 no.5
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• pp.540-546
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• 1999

Solution conformation of cyclo-($Gln^1-Trp^2-Phe^3-{\beta}Ala^4-Leu^5-Met^6$), new NK-2 antagonist in dimethyl sulfoxide solution, has been determined by the use of two-dimensional nuclear magnetic resonance spectroscopy combined with simulated annealing calculations. The peptide exhibited converged structures with the atomic root-mean-square difference for the backbone atoms ($N,\;C^{\alpha},\;C'$) of all residues being 0.02${\AA}$ in the 25 annealed structures. The analysis of the structures indicated that the cyclic peptide has three intramolecular hydrogen bonds between $Met^6NH$ and ${\beta}Ala^4CO$, ${\beta}Ala^4NH$ and $Met^6CO$, $Phe^3NH$ and $Met^6CO$, and contain a type-I ${\beta}$-turn with Gln and Trp and ${\gamma}$-turn with Leu. The addition of an extra methylene group to Gly, i.e. P-Ala residue, may relax some unfavorable restraints in the cyclic backbone structure, hence enabling an additional hydrogen bond, which results in stabilizing one conformation.

• Biomolecules & Therapeutics
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• v.8 no.2
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• pp.132-139
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• 2000

This study was performed far investigation of influence on renal function of idazoxan, $\alpha_{2}$-adrenergic antagonist, using the dog. Idazoxan, when giver. into vein, produced the decrease of urine volume(vol) accompanied with the reduction of free water clearance($C_{H2O}$), amounts of sodium excreted in urine($E_{Na}$), with the increase of potassium excreted in urine($E_{K}$), and so ratios of potassium against sodium($K^{+}/Na^{+}$) were elevated, at this time, greatened reabsorption rate of sodium and diministered that of potassium in renal tubules were appeared. Idazoxan administered into a renal artery elicited the augmentation of vol, glomerular filtration rate(GFR), renal plasma flow(RPF) and no change of filtration fraction(FF) in only ipsilateral kidney, whereas $E_{Na},\;E_{K}\;and\;K^{+}/Na^{+}$ were increased and $C_{H2O}$ was decreased in both control and experimental kidney. Idazoxan given into carotid artery showed partial increased vol, remarkable expanded RPF and unchanged GFR, and so filtration fraction(FF) was markedly reduced. Above results suggest that anti- diuretic action of idazoxan given into vein is mediated by reduction of $C_{H2O}\;and\;E_{Na}$, diuretic action only in the ipsilateral kidney by idazoxan given into a renal artery is caused by hemodynamic improvement through expansion of vas afferens in glomeruli.

• Korean Journal of Veterinary Research
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• v.37 no.2
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• pp.331-338
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• 1997

최근 동물의 진통 및 진정을 목적으로 널리 사용되고 있는 imidazole 유도체인 clonidine, medetomidine, etomidate 등의 약물과 xylazine의 효과를 발정정지기의 척출 돼지 자궁근에서 검토하였다. Clonidine($10^{-8}{\sim}10^{-6}M$)이나 medetomidine($10^{-8}{\sim}10^{-6}M$)은 xylazine과 비슷한 정도로 용량의존적인 자궁근의 수축을 일으켰다. Clonidine, medetomidine, xylazine 등의 $EC_{50}$는 각각 24.7nM, 19.9nM, 45.1nM이었다. 그러나 etomidate는 $10^{-6}M$ 미만의 농도에서 반응이 거의 없었으며, $10^{-6}M$ 이상에서 수축반응을 일으켰다. 이들 agonists의 효과는 yohimbine($10^{-8}{\sim}10^{-6}M$), idazoxan($10^{-7}{\sim}10^{-5}M$), tolazoline($10^{-7}{\sim}10^{-5}M$) 등의 ${\alpha}_2-adrenoceptor$ antagonists에 의해서 차단되었으나, ${\alpha}_1-adrenoceptor$ antagonist인 prazosin ($10^{-6}M$)에 의해서는 차단되지 않았다. 또한 $Ca^{2+}-free$ medium이나 verapamil($10^{-5}M$)의 전처치에 의해서 이들 agonist의 효과가 완전히 차단되었다. 결론적으로 발정정지기의 돼지 자궁근에서 clonidine, medetomidine, etomidate, xylazine 등은 ${\alpha}_2-adrenoceptors$의 흥분을 통해 자궁근의 수축을 일으키며, 이 효과는 voltage-dependent $Ca^{2+}$ channels을 통한 extracellular $Ca^{2+}$ influx의 증가에 의한 것으로 추론하였다.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.2
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• pp.119-123
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• 2012

In the present study, the antinociceptive profiles of $Agrimonia$ $pilosa$ $Ledeb$ extract were examined in ICR mice. $Agrimonia$ $pilosa$ $Ledeb$ extract administered orally (200 mg/kg) showed an antinociceptive effect as measured by the tail-flick and hot-plate tests. In addition, $Agrimonia$ $pilosa$ $Ledeb$ extract attenuated the writhing numbers in the acetic acid-induced writhing test. Furthermore, the cumulative nociceptive response time for intrathecal (i.t.) injection of substance P (0.7 ${\mu}g$) was diminished by $Agrimonia$ $pilosa$ $Ledeb$ extract. Intraperitoneal (i.p.) pretreatment with yohimbine (${\alpha}_2$-adrenergic receptor antagonist) attenuated antinociceptive effect induced by $Agrimonia$ $pilosa$ $Ledeb$ extract in the writhing test. However, naloxone (opioid receptor antagonist) or methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by $Agrimonia$ $pilosa$ $Ledeb$ extract in the writhing test. Our results suggest that $Agrimonia$ $pilosa$ $Ledeb$ extract shows an antinociceptive property in various pain models. Furthermore, this antinociceptive effect of $Agrimonia$ $pilosa$ $Ledeb$ extract may be mediated by ${\alpha}_2$-adrenergic receptor, but not opioidergic and serotonergic receptors.

• The Korean Journal of Pharmacology
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• v.21 no.2
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• pp.90-98
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• 1985

1) In the study of the forced-swimming test in mice (FSM), the duration of immobility posture was dose-dependently shortened by ${\alpha}_2$-agonists, clonidine and guanabenz. BH-T 933 and oxymetazoline also decreased it . Xylazine rather increased the immobility duration at low dose. 2) ${\alpha}_1$-Agonists, cirazoline, amidephrine and methoxamine, however, showed inconsistent effect on the immobility duration (ID). 3) The decrease in ID by clonidine and guanabenz was antagonized by pretreatment with yohimbine, idazoxan and phentolamine (${\alpha}_2$antagonist), but not by prazosin and corynanthine (${\alpha}_1$-antagonist) .4) The ID in the FSM was shortened dose-dependently by d-amphetamine, and it was also antagonized by yohimbine, but not by prazosin. 5) In the mice pretreated with either ${\alpha}$-methyl-p-tyrosine or reserpine, or with combination of both, the decrease in ID was still evoked by clonidine. 6) When the mice were chronically treated with antidepressants (desipramine and imipramine), or with electroconvulsive shock, clonidine still decreased the ID as it did in the control. 7) These results provided the evidences to hypothesize that the change of the ID in the FSM is closely related with the postsynaptie ${\alpha}_2$-adrenoceptor located on the central noradrenergic neuron body. Furthermore, it is assumed that this escape-directed behavior enhanced by ${\alpha}_2$-adrenoceptor agonist may be the result in some analogy with the incentive of drives which are directed toward the self-preservation.