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Dextromethorphan and its metabolite dextrorphan block α3β4 neuronal nicotinic receptors

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期293卷 962-967页

作者： Hernandez, SC Bertolino, M Xiao, YX Pringle, KE Caruso, FS Kellar, KJ Georgetown Univ Sch Med Dept Pharmacol Washington DC 20007 USA Algos Pharmaceut Corp Neptune NJ USA

Dextromethorphan (DM), a structural analog of morphine and codeine, has been widely used as a cough suppressant for more than 40 years. DM is not itself a potent analgesic, but it has been reported to enhance analgesia produced by morphine and nonsteroidal anti-inflammatory drugs. Although DM is considered to be nonaddictive, it has been reported to reduce morphine tolerance in rats and to be useful in helping addicted subjects to withdraw from heroin. Here we studied the effects of DM on neuronal nicotinic receptors stably expressed in human embryonic kidney cells. Studies were carried out to examine the effects of DM on nicotine-stimulated whole cell currents and nicotine-stimulated Rb-86(+) efflux. We found that both DM and its metabolite dextrorphan block nicotinic receptor function in a noncompetitive but reversible manner, suggesting that both drugs block the receptor channel. Consistent with blockade of the receptor channel, neither drug competed for the nicotinic agonist binding sites labeled by [H-3]epibatidine. Although DM is approximately 9-fold less potent than the widely used noncompetitive nicotinic antagonist mecamylamine in blocking nicotinic receptor function, the block by DM appears to reverse more slowly than that by mecamylamine. These data indicate that DM is a useful antagonist for studying nicotinic receptor function and suggest that it might prove to be a clinically useful neuronal nicotinic receptor antagonist, possibly helpful as an aid for helping people addicted to nicotine to refrain from smoking, as well as in other conditions where blockade of neuronal nicotinic receptors would be helpful.

关键词：镇咳药/药理学细胞培养的右美沙芬/药理学右啡烷/药理学烟碱拮抗剂/药理学受体 N-甲基-D-天冬氨酸/拮抗剂和抑制剂铷放射性同位素/代谢动物人类大鼠

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Mechanisms of use-dependent plasticity in the human motor cortex

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第7期97卷 3661-3665页

作者： Bütefisch, CM Davis, BC Wise, SP Sawaki, L Kopylev, L Classen, J Cohen, LG NINDS Human Cort Physiol Sect NIH Bethesda MD 20892 USA NIMH Lab Syst Neurosci NIH Bethesda MD 20892 USA NINDS Biometry & Field Studies Branch NIH Bethesda MD 20892 USA Univ Rostock Neurol Klin D-18055 Rostock Germany

Practicing movements results in improvement in performance and in plasticity of the motor cortex. To identify the underlying mechanisms, we studied use-dependent plasticity in human subjects premedicated with drugs that influence synaptic plasticity. Use-dependent plasticity was reduced substantially by dextromethorphan (an N-methyl-D-aspartate receptor blocker) and by lorazepam [a gamma-aminobutyric acid (GABA) type A receptor-positive allosteric modulator]. These results identify N-methyl-D-aspartate receptor activation and GABAergic inhibition as mechanisms operating in use-dependent plasticity in intact human motor cortex and point to similarities in the mechanisms underlying this form of plasticity and long-term potentiation.

关键词：右美沙芬/药理学诱发电位/药物作用长时程增强/药物作用劳拉西泮/药理学运动皮质/药物作用运动皮质/生理学 N-甲基天冬氨酸/药理学三嗪类/药理学人类

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The antitussive activity of δ-opioid receptor stimulation in guinea pigs

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期292卷 803-809页

作者： Kotzer, CJ Hay, DWP Dondio, G Giardina, G Petrillo, P Underwood, DC SmithKline Beecham Pharmaceut Dept Pulm Pharmacol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Med Chem King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Biol King Of Prussia PA 19406 USA

In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED50 values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the anti-tussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine ( mu-receptor antagonist;20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist;20 mg/kg, s.c.), at doses that inhibited the antitussive activity of m-and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor.

关键词： CHO细胞卡唑类/药理学细胞系克隆生物可待因/药理学咳嗽/预防和控制仓鼠亚科右美沙芬/药理学疾病模型动物剂量效应关系药物药物相互作用氢可酮/药理学左洛啡烷/类似物和衍生物左洛啡烷/治疗应用纳洛酮/药理学麻醉品拮抗药/药理学蛋白质结合吡啶类/药理学吡咯类/治疗应用吡咯烷类/药理学受体阿片样 δ/激动剂受体阿片样 δ/药物作用受体阿片样 δ/生理学受体阿片样 κ/激动剂受体阿片样 κ/药物作用受体阿片样 κ/生理学受体阿片样 μ/激动剂受体阿片样 μ/药物作用受体阿片样 μ/生理学动物豚鼠人类男(雄)性

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IP₃-independent release of Ca²⁺ from intracellular stores:: A novel mechanism for transduction of bitter stimuli

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JOURNAL OF NEUROPHYSIOLOGY 1999年第5期82卷 2657-2666页

作者： Ogura, T Kinnamon, SC Colorado State Univ Dept Anat & Neurobiol Ft Collins CO 80523 USA Univ Colorado Hlth Sci Ctr Rocky Mt Taste & Smell Ctr Denver CO 80262 USA

A variety of substances with different chemical structures elicits a bitter taste. Several different transduction mechanisms underlie detection of bitter tastants;however, these have been described in detail for only a few compounds. In addition, most studies have focused on mammalian taste cells, of which only a small subset is responsive to any particular bitter compound. In contrast, similar to 80% of the taste cells in the mudpuppy, Necturus maculosus, are bitter-responsive. In this study, we used Ca2+ imaging and giga-seal whole cell recording to compare the transduction of dextromethorphan (DEX), a bitter antitussive, with transduction of the well-studied bitter compound denatonium. Bath perfusion of DEX (2.5 mM) increased the intracellular Ca2+ level in most taste cells. The DEX-induced Ca2+ increase was inhibited by thapsigargin, an inhibitor of Ca2+ transport into intracellular stores, but not by U73122, an inhibitor of phospholipase C, or by ryanodine, an inhibitor of ryanodine-sensitive Ca2+ stores. Increasing intracellular cAMP levels with a cell-permeant cAMP analogue and a phosphodiesterase inhibitor enhanced the DEX-induced Ca2+ increase, which was inhibited partially by H89, a protein kinase A inhibitor. Electrophysiological measurements showed that DEX depolarized the membrane potential and inhibited voltage-gated Na+ and K+ currents in the presence of GDP-P-S, a blocker of G-protein activation. DEX also inhibited voltage-gated Ca2+ channels. We suggest that DEX, like quinine, depolarizes taste cells by block of voltage-gated K channels, which are localized to the apical membrane in mudpuppy. In addition, DEX causes release of Ca2+ from intracellular stores by a phospholipase C-independent mechanism. We speculate that the membrane-permeant DEX may enter taste cells and interact directly with Ca2+ stores. Comparing transduction of DEX with that of denatonium, both compounds release Ca2+ from intracellular stores. However, denatonium requires activati

关键词： 1-甲基-3-异丁基黄嘌呤/药理学钙/代谢环AMP/类似物和衍生物环AMP/药理学环AMP依赖性蛋白激酶类/拮抗剂和抑制剂右美沙芬/药理学酶抑制剂/药理学雌烯类/药理学肌醇1 4 5-三磷酸/生理学异喹啉类/药理学模型神经学泥螈属吡咯烷酮类/药理学兰尼碱/药理学信号传导/药物作用信号传导/生理学磺胺类味觉/生理学味蕾/药物作用味蕾/生理学毒胡萝卜内酯/药理学硫代核苷酸类/药理学 C型磷脂酶类/拮抗剂和抑制剂动物

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Neuroprotection (focal ischemia) and neurotoxicity (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity N-methyl-D-aspartate antagonist

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期291卷 399-408页

作者： Tortella, FC Britton, P Williams, A Lu, XCM Newman, AH Walter Reed Army Inst Res Dept Neuropharmacol & Mol Biol Div Neurosci Washington DC 20307 USA NIDA Addict Res Ctr Drug Dev Grp Baltimore MD 21224 USA

AHN649, an analog of dextromethorphan (DM) and a relatively selective low-affinity N-methyl-D-aspartate antagonist, was evaluated for neuroprotective effects using the rat intraluminal filament model of temporary middle cerebral artery occlusion. Rats were subjected to 2 h of focal ischemia followed by 72 h of reperfusion. In vehicle-treated rats, middle cerebral artery occlusion resulted in neurological deficits and severe infarction measuring 232 +/- 25 mm(3), representing approximately 25% contralateral hemispheric infarction. Post-treatment with AHN649 (0.156-20 mg/kg i.v.) or DM (0.156-10 mg/kg i.v.) significantly reduced cortical infarct volume by 40 to 60% compared with vehicle-control treatments. AHN649 neuroprotection was linear and dose dependent (ED50 = 0.80 mg/kg), whereas DM neuroprotection (ED50 = 1.25 mg/kg) was nonlinear and less effective at the higher doses (2.5-10 mg/kg). Although impaired neurological function scores improved in all groups by 24 to 72 h, the most dramatic improvement was associated with AHN649 treatments. In a rat electroencephalographic model of brain function, separate neurotoxicity experiments revealed that acute i.v. doses of DM caused seizures (ED50 = 19 mg/kg) and death (LD50 = 27 mg/kg). In contrast, AHN649 failed to induce seizure activity at doses up to 100 mg/kg (LD50 = 79 mg/kg). Collectively, AHN649 is described as a potent, efficacious neuroprotective agent devoid of serious central nervous system neurotoxicity and possessing potential therapeutic value as antistroke treatment. Furthermore, the feasibility of targeting low-affinity N-methyl-D-aspartate-site ligands as postinjury therapy for ischemic brain injury has been confirmed.

关键词：脑缺血/预防和控制脑动脉右美沙芬/类似物和衍生物右美沙芬/药理学右美沙芬/治疗应用剂量效应关系药物脑电描记术/药物作用兴奋性氨基酸拮抗剂/药理学兴奋性氨基酸拮抗剂/治疗应用兴奋性氨基酸类神经保护药/药理学神经保护药/治疗应用神经毒素类/药理学大鼠 Sprague-Dawley 受体 N-甲基-D-天冬氨酸/拮抗剂和抑制剂再灌注动物男(雄)性大鼠

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