European journal of pharmacology
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The reflex tracheal response induced by bronchoconstriction was investigated using a newly devised tracheo-bronchi preparation in anesthetized guinea pigs. Tracheal constriction and subsequent dilatation were observed in response to bronchoconstriction induced by the inhalation of 0.001-0.01% histamine and 0.003-0.03% acetylcholine. These tracheal responses were abolished by cervical vagotomy or treatment of the tracheal site with 1% tetrodotoxin. ⋯ These results demonstrate that a vagally mediated reflex tracheal response (constriction followed by dilatation) is induced by bronchoconstriction in anesthetized guinea pigs. Cholinergic nerves may mediate the constriction, and adrenergic and nonadrenergic noncholinergic (NANC) inhibitory nerves may mediate the dilatation. Furthermore, NO may be involved in the NANC reflex tracheal dilatation.
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The P2 purinoceptor antagonist suramin reverses skeletal muscle paralysis evoked by non-depolarizing neuromuscular blocking agents in vitro and in vivo. To further study the action of suramin on neuromuscular transmission, (miniature) endplate potentials ((m.)e.p.ps), motor nerve terminal currents and the release of radiolabeled acetylcholine was measured in isolated nerve-muscle preparations. In preparations paralysed by low Ca2+/high Mg2+ conditions, suramin (10 microM-1 mM) induced a concentration-dependent decrease in quantal content of the e.p.ps without affecting m.e.p.ps. ⋯ Suramin-induced inhibition of Ca2+ currents was not antagonized by ATP gamma S. Suramin (300 microM) reduced [14C]acetylcholine outflow in non-paralysed rat phrenic nerve-hemidiaphragm preparations by 32%. As suramin did not chelate Ca2+, these results indicate that suramin inhibits neuromuscular transmission by blocking prejunctional Ca2+ channels, thereby decreasing acetylcholine release upon nerve stimulation.
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Past studies have shown antagonists of excitatory amino acid receptors, both N-methyl-D-aspartate (NMDA) and non-NMDA, to produce an antinociceptive effect in vitro and in vivo. Additionally, NMDA receptor antagonists have been demonstrated to prevent morphine tolerance. We had found that one NMDA receptor antagonist, ketamine, potentiates morphine's analgesic effect in post-operative patients. ⋯ However, high-affinity sites in rats treated with D-AP5 and morphine displayed a higher affinity (KD = 0.45 +/- 0.09 nM) than those of control animals (KD = 0.95 +/- 0.08 nM). Results of this study indicate that competitive as well as non-competitive NMDA receptor antagonists enhance morphine's antinociceptive effect, and prevent the development of morphine tolerance. Thus, in our opinion, there opens a new frontier in clinical pain management, especially for those patients who require long-term opioid treatment for pain relief.
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5 beta-Methyl-7,8-dihydromorphinone (metopon), an isomer [6aS-(6a alpha,9a alpha, 10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9,10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]isoquinoline- 7-(9aH)-one (compound 1) derived from a photochemical rearrangement of 5 beta-methylmorphinone, and [6aS-(6a alpha,9a alpha,10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9, 10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]-14 beta- (p-nitrocinnamoylamino) isoquinoline-7-(9aH)-one (compound 2) were characterized for opioid receptor affinity, selectivity and analgesic properties. In competition binding assays using bovine striatal membranes, the three compounds inhibited the binding of 0.25 nM [3H][D-Ala2,(Me)-Phe4,Gly(ol)5]enkephalin (DAMGO), a mu-selective peptide, with IC50 values less than 5 nM. All three compounds exhibited lower affinity for delta- and kappa-opioid receptors. ⋯ Morphine sulfate, metopon and compound 1 produced 50% antinociception with i.c.v. doses of 0.83, 2.0 and 4.0 nmol, respectively. The mu-selective, irreversible opioid receptor antagonist beta-funaltrexamine blocked antinociception induced by metopon and compound 1, while delta- and kappa-opioid receptor selective antagonists did not effect antinociception. These findings demonstrate metopon and its isomer bound with high affinity to the mu-opioid receptor and produced antinociception through this receptor.
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The effects of intravenous administration of fenoldopam (0.3-10 micrograms.kg-1.min-1), dopamine (1-10 micrograms.kg-1.min-1) and noradrenaline (0.1-1 micrograms.kg-1.min-1) on systemic and splanchnic haemodynamics and oxygen supply-demand relationship were studied in 12 chronically instrumented, sedated sheep. Fenoldopam produced dose-dependent peripheral and splanchnic vasodilatation without change in arterial blood pressure. The coeliac trunk and portal vein blood flows were particularly sensitive to fenoldopam, whereas dopamine vasodilated these vascular beds only at high doses. ⋯ Both noradrenaline and fenoldopam, but not dopamine, were accompanied by increased portal lactataemia. We conclude that in sheep fenoldopam is a potent and selective splanchnic vasodilator but without vasodilatator effect on the renal circulation. The portal lactataemia associated with a decreased splanchnic oxygen extraction may present a significant limitation for some clinical applications of this drug.