• The Korean Journal of Pain
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• v.21 no.3
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• pp.179-186
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• 2008

Background: The adrenergic nervous system in the spinal cord contributes to the development of neuropathic pain after nerve injury. Brain derived neurotrophic factor may facilitate the sympathetic change in the spinal cord and influence the state of neuropathic pain. We probed the effect of chronic repetitive administration of systemic 4-methylcatechol, which is known to be a neurotrophic factor inducer, in a spinal nerve ligation model. Methods: We made the rat neuropathic pain model by the ligation of the L5 spinal nerve. Intraperitoneal 4-methylcatechol ($10{\mu}g/kg$) or the same volume of saline wasadministrated twice daily just after the operation for 7 days. The tactile allodynia was measured by using von Frey filaments and its change was followed up from 3 days after SNL. The lumbosacral enlargement of the spinal cord was taken out and the mRNA contents of the ${\alpha}_2-adrenoceptor$ subtypes were measured by real time polymerase chain reaction and this was then compared with the control groups. The antiallodynic effect of intrathecal clonidine (3, 10, $30{\mu}g$) was evaluated and compared in the 4-methylcatechol treated rats and the control rats. Results: The expression of the ${\alpha}_{2A}$ and ${\alpha}_{2C}$ adrenoceptor subtypes did not change after 4-methylcatechol treatment. Intrathecal clonidine showed an earlier and better effect at the highest dose ($30{\mu}g$ intrathecal), but not with any other doses. Conclusions: Chronic intraperitoneal administration of 4-methylcatechol may improve the effect of intrathecal clonidine, but we could not prove the increase of ${\alpha}_{2A}$ and ${\alpha}_{2C}$ adrenoceptors in the spinal cord of 4-methylcatechol treated rats.

• 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 Life Science
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• v.10 no.6
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• pp.584-590
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• 2000

Natural products are one of the useful source of cardiovascular drugs, in particular, when they have antioxidant activity. Gagaminine, an alkaloid isolated from the roots of Cynanchum wilfordi Hemsley, has been reported to potently inhibit the aldehyde oxidase activity ({TEX}$IC_{50}${/TEX}=0.8$\mu$M) and reduce lipid peroxidation. However, the effect of gagaminine on vascular smooth muscle has not yet been investigated. In the present study, we examined whether gagaminine relaxes vascular smooth muscle by isometric tension study. In order to observe its relaxation effect on the arteries, conductivel vessel (rat thoracic aorta) and resistance vessel (pig coronary artery) were purposely used. Results indicated that gagaminine relaxed in a concentration-dependent manner $\alpha$-adrenoceptor agonist, phenylephrine (PE)-induced contraction of rat aorta. Pretreatment with gagaminine inhibited PE-induced contraction, noncompetitively. {TEX}$Ca^{2+}${/TEX}-induced contraction was significantly diminished by gagaminine. In pig coronary artery, gagaminine relaxed thromboxane receptor (U 46619)-mediated contraction in dose-dependent manner. Pretreatment with gagaminine also reduced the maximum contraction induced by KCl. These observations strongly suggest that agagminnine relaxes vascular smooth muscle, irrespective of both resistance and conductive artery. We demonstrate that gagaminine, a potent natural antioxidant, has a significant vasodilatory effect and its action mechanism van be ascribed at least in part to {TEX}$Ca^{2+}${/TEX} antagonistic action as evidenced by inhibition {TEX}$Ca^{2+}${/TEX}-induced contraction (rat aorta) and KCl-induced contraction (porcine artery). Furthermore, neither $\alpha$ -adrenoceptor nor thromboxane receptor seems responsible for the relaxation of gagaminine.

• Archives of Pharmacal Research
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• v.19 no.6
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• pp.456-461
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• 1996

Vascular relaxation action of crude extracts of two kinds of Coptidis rhizoma (Coptis chinensis and Coptis japonica, Ranunculaceae) was investigated and compared with that of berberine and palmatine, active alkaloid components of these plants. The results show that total extracts, berberine, and palmatine induced a concentration-dependent vasodilatation of rat thoracic aorta contracted with phenylephrine (PE). Palmatine, unlike to berberine, did not inhibit contraction induced by KCI. In calcium-free media, not only berberine but also crude extracts inhibited calcium-induced contraction. Furthermore, pretreatment of crude extracts inhibited contraction induced by PE noncompetitively. In PE-induced contraction, berberine was 2.5 times more potent than Coptis chinensis in the relaxation of rat aorta in terms of $IC_{50}$ values. Analysis of the effects of crude extracts on the Emax and $IC_{50}(PE)IC_{50}(KCI)$ ratios provides information on selectivity and indicates that extracts exhibit greater inhibition of the contrac tile response induced by PE than by KCI. We concluded that crude extracts have .alpha.-adrenoceptor blocking action and possesses inhibitory effect on calcium influx, which may be at least in part responsible for the antihypertensive action.

• The Journal of Korean Medicine
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• v.25 no.3
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• pp.67-77
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• 2004

Objectives : Many studies have reported that acupuncture analgesia was mediated through the activation of peripheral and central opioid receptors. However, there has been little electrophysiological study on the adrenergic mechanism of acupuncture analgesia in chronic inflammatory and neuropathic pain. The present study was undertaken to elucidate the role of adrenoceptors in the production of acupuncture analgesia in the chronic pain model. Methods : In the rat with chronic inflammation and nerve injury, dorsal horn cell (DHC) responses to afferent C fiber stimulation were used as a pain index and changes in electroacupuncture (EA) analgesia were recorded before and after intravenous administration of selective adrenoceptor antagonists. EA stimulations (2Hz, 0.5msec, 3mA) were applied to the contralateral Zusanli point for 30 min. Results : EA stimulation induced long-lasting inhibition of DHC responses in the rat with chronic inflammation and nerve injury. In both models of inflammation and neuropathic pain, α-adrenoceptor antagonist (phentolamine) significantly attenuated an inhibitory effect of EA on DHC responses. Selective α2-adrenoceptor antagonist (yohimbine) also had a similar suppressive action on DHC responses to that of phentolamine. However, β-adrenoceptor antagonist (propranolol) did not have any inhibitory effect on DHC responses in either model of chronic pain. Conclusions : These experimental findings suggest that in rats with chronic pain, EA stimulation with low frequency and high intensity produced an analgesic effect which was mediated through an activation of α2-adrenoceptors.

• YAKHAK HOEJI
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• v.32 no.4
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• pp.258-273
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• 1988

In this study attempts were made to observe the effects of guanabenz on renal function in dog, which manifests the antihypertensive action by inhibition of sympathetic tone through stimulating the presynaptic adrenoceptor (${\alpha}_2-adrenoceptor$). Guanabenz, when injected at a dose of $30.0{\mu}g/kg$, or infused at a dose of $3.0{\mu}g/kg/min$ intravenously, produced diuretic action with increased amounts of $Na^+\;and\;K^+$ in urine, and with decreased reabsorption rates of $Na^+\;and\;K^+$ in renal tubules. It was also observed that the rates of osmolar and free water clearances were increased, but the glomerular filtration rate and renal plasma flow were not changed. Guanabenz injected at a dose of $3.0{\mu}g/kg$ into a carotid artery or infused intravenously at a dose of $3.0{\mu}g/kg/min$ in a state of water diuresis elicited the diuretic action of the similar aspect as a case of guanabenz given intravenously. The diuretic action produced by guanabenz was completly blocked by pretreatment of i.v. prazosin, ${\alpha}_1-adrenoblocking$ agent, or of i.v. yohimbine, ${\alpha}_2-adrenergic$ blocking agent. Prazosin, when given into a renal artery, inhibited the diuretic action by i.v. guanabenz in only injected kidney, whereas in case of yohimbine the action was inhibited in both kidney. Guanabenz infused at a dose of $1.0{\mu}g/kg/min$ into a renal artery exhibited no significant changes of renal function in both kidney. In denervation experiments, guanabenz given intravenously produced typical diuretic action in innervated kidney, whereas in denervated kidney, it did not affect the action at initial period but exhibited the action with increase of only free water clearance at later period. These results suggest that guanabenz produced diuretic action in dog by inhibition of electrolyte reabsorption rates in renal tabules, mainly proximal tubule and of ADH release, which is mediated by stimulating of central sympathetic ${\alpha}_2-receptor$.

• The Korean Journal of Pharmacology
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• v.22 no.2
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• pp.115-122
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• 1986

To delineate the relationship between subtypes of central alpha-adrenoceptor and central calcium channel, influences of intracerebroventricular (icv) diltiazem and nifedipine on the changes of blood pressure and heart rate by icv methoxamine and clonidine were investigated in urethane-anesthetized rabbits. 1) Methoxamine (1mg, icv) produced pressor and bradycardiac effect and clonidine $(30\;{\mu}g,\;icv)$ produced hypotension and bradycardia. 2) Icv diltiazem and nifedipine elicited dose-dependent deprcssor and bradycardiac responses. The depressor response to nifedipine was more prominent than that to diltiazem but the bradycardiac effect of nifedipine was smaller than that of diltiazem. The depressor responses to icy nifedipine $(35{\mu}g)$ and icv diltiazem $(400{\mu}g)$ were persistent but those to intravenous (iv) nifedipine $(35{\mu}g/kg)$ and diltiazem $(200{\mu}g/kg)$ were transient. 3) The pressor response to methoxamine was little affected by pretreatment with in diltiazem $(400{\mu}g)$ or icv nifedipine $(35,\;350{\mu}g)$ but the bradycardiac response to methoxamine was significantly attenuated by the same pretreatment. 4) The depressor response to clonidine was markedly attenuated by pretreatment with icv diltiazem $(400{\mu}g)$ or icv nifedipine $(35,\;350{\mu}g)$ but not affected by pretreatment with iv diltiazem $(200{\mu}g/kg)$ or iv nifedipine $(20{\mu}g/kg)$. Pretreatment with icv and iv diltiazem or nifedipine reduced the bradycardiac effect of clonidine. 5) Pretreatment with icv clonidine had no effect on the depressor and bradycardiac responses to in diltiazcm or icv nifedipine. These results indicate that diltiazem and nifedipine have no effect on icv methoxamine-induced pressor response elicited by the activation of central alpha-l adrenoceptors whereas the icv clonidine-induccd depressor and bradycardiac effects which result from the activation of central alpha-2 adrenoceptors are inhibited by the calcium antagonists.

• The Korean Journal of Pharmacology
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• v.32 no.2
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• pp.189-199
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• 1996

Myocardial ${\alpha}_1-adrenoceptors$ have been shown to mediate a biphaslc inotropic response that was characterized by a transient decline followed by a sustained increasing phase in guinea pig ventricular muscle. Recently one group reported that an ${\alpha}_1-adrenoceptors-induced$ intracellular $Na^+$ decrease is linked to fast $Na^+$ channel inhibition and another group reported that it is linked to $Na^+$-$K^+$ pump activation by ${\alpha}_{1b}-adrenoceptors$. But until now, its mechanism is not clear. Therefore, to see whether the $Na^+$channel or $Na^+-K^+$ pump is related to a decrease in intracellular $Na^+$ activity and/or the negative inotropic response, and which ${\alpha}_1-adrenoceptor$ subtype was involved in the decrease in intracellular $Na^+$activity by phenylephrine, we used conventional and sodium selective microelectrodes, and tension transducer to determine the effects of ${\alpha}_1-adrenergic$ stimulation on membrane potential, intracellular $Na^+$ activity, and twitch force in guinea pig ventricular muscles. $10^{-5}$ M Phenylephrine produced a slight hyperpolarization of the diastolic membrane potential, a decrease or increase in $a_N^i_a$, and a biphasic inotropic response. The negative inotropic response accompanied by a decrease in intracellular $Na^+$activity, whereas in muscles showing a remarkable positive inotropic response without initial negative inotropic effect was accompanied by an increase in intracellular $Na^+$ activity. The decrease in intracellular $Na^+$ activity was apparently inhibited by WB4101, an antagonist of the ${\alpha}_{1a}-adrenoceptors$. The decrease in intracellular $Na^+$ activity caused by phenylephrine was not abolished or reduced by a block of the fast $Na^+$ channels. $V_{max}$ also was not affected by phenylephrine. Phenylephrine produced an increase in intracellular $Na^+$ activity in the presence of a high concentration of extracellular $Ca^{2+}$ (in quiescent muscle) or phorbol dibutyrate, a protein kinase C activator(in beating muscle). These suggest that the ${\alpha}_{1a}-adrenoceptors-mediated$ decrease in intracellular $Na^+$ activity may be related to the protein kinase C.

• Korean Journal of Acupuncture
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• v.35 no.1
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• pp.27-35
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• 2018

Objectives : The purpose of this study was to investigate the analgesic effect of electroacupuncture(EA) and radio-frequency warm needling(RFWN) stimulation in acupoint combination on ankle sprained pain in rats. Methods : The lateral ligaments of the Sprague-Dawley rats ankle were injured surgically resulting in sprain, of which was divided into EA, RFWN treatment groups and control group without treatment. The level of pain was measured through foot weight bearing force ratio followed by calculating pain relief. To stimulate proximal or distal area in ankle sprain, combination of proximal acupoints(GB34-GB39) and distal acupoints(GB39-GB42) from sprain area were applied, respectively, to either EA or RFWN stimulation. In addition, naltrexone or phentolamine was injected intraperitoneally before the stimulation to observe the pathway of analgesic effects. Results : In the proximal combination of GB34-GB39, EA and RFWN significantly increased pain relief compared to the control group (p<0.05). However, in distal combination with GB39-GB42, both EA and RFWN stimulation did not relieve pain due to ankle sprains. In the combination of GB34-GB39, the analgesia of EA was inhibited by blockade of the ${\alpha}$-adrenoceptor receptor. The analgesia of RFWN was inhibited by blockade of the ${\alpha}$-adrenoceptor receptor as well as ${\mu}$-opioid receptor. Conclusions : We observed that the proximal combination was effective in relieving pain when the treatment by acupoint combination was applied to the ankle sprain pain. Also, it was confirmed that this analgesia was also related to the pathways of ${\mu}$-opioid receptors and/or ${\alpha}$-adrenoceptors.

• The Korean Journal of Pharmacology
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• v.19 no.1
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• pp.123-131
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• 1983

1) To delineate the role of central ${\alpha}_2-adrenoceptors$ in the pressor response to raised intracranial pressure(ICP), the influence of yohimbine, an ${alpha}_2-adrenoceptor$ antagonist, on the pressor response to raised ICP was investigated in urethane-anesthetized rabbits. 2) The ICP was raised by infusing saline into a balloon placed in the epidural space. The rise of ICP was slow in the beginning of the infusion but it became sharp as the infusion proceeded. 3) In response to raised ICP, blood pressure(BP) tended to decrease slightly in the beginning and then increased sharply. BP, however, fell abruptly and markedly if ICP was raised further. The maximal pressor response to raised ICP was the increase of $49{\pm}2.4%$ of the original $BP(mean{\pm}SE\;in\;32\;experiments)$, and at this point the volume of saline infused into the balloon was $1.22{\pm}0.15\;ml$, and the ICP $165{\pm}6.4\;mmHg$. 4) Intraventricular yohimbine $(50{\mu}g)$ by itself did not affect BP. After the administration of this dose of yohimbine the increase of both ICP and BP was observed after the infusion of much smaller volume of saline than in the control animals, i.e., after the infusion of $0.83{\pm}0.02\;ml$ of saline the maximal increase of preesor response$(57{\pm}4.5%\;in\;6\;experiments)$ appeared and at this state the ICP was $164{\pm}9.6\;mmHg$. 5) Intraventricular $clonidine(30{\mu}g)$ markedly decreased BP by itself, and in the clonidine-treated rabbits the increase of ICP induced by the infusion was much less than in the control group and the pressor response to raised ICP was hardly seen. 6) The hypotensive effect of intraventricular clonidine was reversed by a susequent intraventricular $yohimbine(500\;{\mu}g)$. At this state the pressor response to raised ICP appeared as in the control animals. 7) These results show that the pressor response to raised ICP was facilitated when ${\alpha}_2-adrenoceptors$ in the rabbit brain was blocked by yohimbine and that yohimbine antagonized the inhibitory effect of clonidine on the pressor response to raised ICP.