European journal of pharmacology
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The ATP-gated K(+) channel openers diazoxide, levcromakalim and morphine induce cell hyperpolarization by opening the K(+) channels and enhancing K(+) efflux. This hyperpolarization decreases intracellular Ca(2+) levels, lessening neurotransmitter release thus leading to antinociception. ⋯ Antisense to all three opioid receptors attenuated the effect of diazoxide, suggesting that diazoxide is inducing the release of endogenous opioids activating the mu(MOR-1)-, delta(DOR-1)-, and kappa(KOR-1)-opioid receptors. Antisense to the mu-opioid receptor clone and delta-opioid receptor clone attenuated levcromakalim-induced antinociception, indicating that endogenous opioids acting at the mu- and delta-opioid receptors are potential candidates for the mediation of the antinociceptive effects of levcromakalim.
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Comparative Study
Cardiac inotropic vs. chronotropic selectivity of isradipine, nifedipine and clevidipine, a new ultrashort-acting dihydropyridine.
Cardiac effects of clevidipine, a new ultrashort-acting dihydropyridine Ca2+ channel antagonist were investigated in Langendorff-perfused rat hearts and compared to those of nifedipine and isradipine. The aim was to determine and compare the negative inotropic vs. chronotropic potency of these drugs. The hearts were perfused with oxygenated Krebs-Henseleit buffer at a perfusion pressure of 90 cm H2O. ⋯ When clevidipine or nifedipine was given, at a given concentration, the proportionate reduction in left ventricular dP/dt max was greater than that in heart rate, resulting in a high inotropic vs. chronotropic selectivity. It is concluded that in contrast to nifedipine and isradipine, clevidipine does not impair atrio-ventricular conduction. Like nifedipine, clevidipine is selective for inotropic vs. chronotropic cardiac effects.
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The effects of the antiglutamatergic agent, riluzole, were examined on the antinociceptive action of morphine, on the induction of physical dependence, and on the expression of the abstinence syndrome to the opiate in mice. Morphine was administered as a single dose (200 mg/kg) of a slow-release preparation. Acute and chronic administration of riluzole decreased the analgesic response to morphine, the intensity of abstinence behavior (administered 30 min before a dose of naloxone), and the development of physical dependence (repeatedly administered during the period of chronic morphine treatment).
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The effects of pretreatment with protein kinase C and protein kinase A inhibitors on the intraventricular insulin-induced attenuation of the antinociceptive effect of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO) were studied in mice. Intracerebroventricular (i.c.v.) pretreatment with insulin dose- and time-dependently attenuated the antinociceptive effect of i.c.v. DAMGO (5.6 ng) in mice. ⋯ Furthermore, i.c.v. pretreatment with serine/threonin kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H7), at doses of 3-30 nmol for 60 min, dose-dependently reversed the attenuation of the antinociceptive effect of DAMGO (5.6 ng, i.c.v.) caused by insulin. Intracerebroventricular pretreatment with selective protein kinase C inhibitor, calphostin C, at doses of 1 and 3 pmol for 60 min, but not with a highly protein kinase A inhibitor, (8R, 9S, 11S)-(-)-9-hydroxy-9-n-hexyloxy-carbonyl-8-methyl-2, 3, 9, 20-tetrahydro-8, 11-epoxy-1H, 8H, 11H-2, 7b, 11a-triaqzadibenzo[a, g]cycloocta[c, d, e]-trinden-1-one (KT5720), at dose of 10 pmol for 60 min, reversed the attenuation of the antinociceptive effect of DAMGO (5.6 ng, i.c.v.) caused by insulin. These results suggest that the reduction of DAMGO-induced antinociception by insulin in mice may be, in part, due to the activation of protein kinase C followed by the activation of tyrosine kinase.
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The gamma-aminobutyric acid type A receptor (GABA(A) receptor) sites involved in the direct and modulatory actions of general anesthetics remain to be elucidated. The mutation of tyrosine at position 157 in the beta2 GABA(A) receptor subunit was reported to reduce sensitivity to activation by GABA, but not pentobarbital. We examined whether this mutation of the beta2 subunit (Tyr157-->Phe) affects the direct and modulatory actions of other general anesthetics such as propofol and etomidate. ⋯ The mutation of the beta2 subunit reduced the apparent affinity for propofol. However, the mutation had no effect on both the direct actions of pentobarbital and etomidate or on the modulatory actions of pentobarbital, propofol and etomidate. These results suggest that unique loci may exist for the direct action of propofol and that the GABA binding site may not mediate the modulatory actions of general anesthetics at GABA(A) receptors.