The Journal of pharmacology and experimental therapeutics
-
J. Pharmacol. Exp. Ther. · Oct 1995
Comparative StudySpinal opioid receptors and adenosine release: neurochemical and behavioral characterization of opioid subtypes.
Release of adenosine from the spinal cord contributes to spinal antinociception by morphine. Morphine induces a Ca(++)-dependent release of adenosine from dorsal spinal cord synaptosomes, which is augmented under partially depolarizing conditions. The present study examined the opioid receptor subtypes involved in this release, and determined whether adenosine is an important mediator of antinociception induced by the spinal administration of selective opioid agonists in rats. ⋯ Caffeine did not block the antinociceptive response to delta agonists, but in fact augmented antinociception when combined with DPDPE and DELT. This augmentation was dose-dependent. This study demonstrates that activation of the mu receptor subtype is responsible for the opioid-induced release of adenosine from the spinal cord, that such release contributes to the spinal antinociception by mu agonists and that only release evoked by low doses of opioids is behaviorally relevant.
-
J. Pharmacol. Exp. Ther. · Oct 1995
Effects of cholinesterase inhibitors and clonidine coadministration on rat cortex neurotransmitters in vivo.
In previous investigations, we have demonstrated that cholinesterase inhibitors such as physostigmine (PHY) and heptylphysostigmine (HEP) elicit a significant and simultaneous increase in acetylcholine (ACh) and norepinephrine (NE) levels in the rat cortex. This effect is enhanced by idazoxan, a selective alpha-2 antagonist. These data suggest that a combination of cholinergic and adrenergic drug may improve the pharmacological effect of the cholinesterase inhibitor on cortical neurotransmitters such as ACh-NE. ⋯ Comparison between the two treatment combinations shows that, although CLO coadministration reduces the effect of PHY on ACh levels, HEP administered to animals pretreated with CLO produces a stronger effect than HEP alone. A possible explanation for this difference is the variation in duration of the two drugs on ACh elevation and muscarinic receptor desensitization. As a result of the alpha-2 agonist cholinesterase inhibitor coadministration, our data suggest that such a combination does not represent an advantage as a therapeutical alternative for treatment of cognitive impairment in Alzheimer disease patients.
-
J. Pharmacol. Exp. Ther. · Oct 1995
Peptide structural requirements for antagonism differ between the two mammalian bombesin receptor subtypes.
Recently it has been established that both a gastrin-releasing peptide (GRP) receptor and a neuromedin B (NMB) receptor mediate the actions of bombesin-related peptides in mammals. Five different classes of peptides that function as GRP receptor antagonists have been identified; however, it is unknown whether similar strategies will yield antagonists for the closely related NMB receptor. In the present study we have used either native cells possessing only one bombesin (Bn) receptor subtype or cells stably transfected with one subtype to determine whether using the strategies that were used successfully for GRP receptors would allow NMB receptor antagonists to be identified. [DPhe12]Bn analogs; des Met14 amides, esters and alkylamides; psi 13-14 Bn pseudopeptides; and D-amino acid-substituted analogs of substance P (SP) or SP(4-11) were all synthesized and each functioned as a GRP receptor antagonist. ⋯ These results demonstrate that none of the known strategies used to prepare peptide GRP receptor antagonists are successful at the NMB receptor, suggesting that a different strategy will be needed for this peptide, such as the formation of somatostatin octapeptide or D-amino acid-substituted substance P analogs. These results suggest that even though there is a close homology between GRP and NMB and their receptors, their structure-function relations are markedly different. These results indicate that the development of receptor subtype-specific peptide agonists or peptide antagonists for newly discovered receptor subtypes of gastrointestinal hormones/neurotransmitters may be difficult because the strategies developed for one well-studied subtype may not apply to the other even though it is structurally closely related.
-
J. Pharmacol. Exp. Ther. · Sep 1995
Saralasin suppresses arrhythmias in an isolated guinea pig ventricular free wall model of simulated ischemia and reperfusion.
The effects of saralasin on electrophysiological changes and arrhythmias induced by simulated ischemia and reperfusion were examined in an isolated tissue model. Segments of guinea pig right ventricles, stimulated regularly, were exposed to simulated ischemia for 15 min and then were reperfused with normal Tyrode's solution for 30 min. Transmembrane electrical activity and a high-gain electrogram were recorded. ⋯ Prolongation of transmural conduction time during ischemia and early reperfusion was significantly inhibited by both concentrations of saralasin. However, only 1 microM saralasin reduced the ratio of transmural conduction time to ERP enough to prevent arrhythmias. Our observations demonstrate that saralasin exerts antiarrhythmic effects in myocardial reperfusion by a mechanism independent of circulatory and central actions.
-
J. Pharmacol. Exp. Ther. · Aug 1995
Modulation of the GABAA receptor by propofol is independent of the gamma subunit.
Many anxiolytics, anticonvulsants and general anesthetics modulate gamma-aminobutyric acid type A (GABAA) receptors. The anxiolytic benzodiazepines potentiate the actions of GABA, and this only at GABAA receptors with gamma subunits. The general anesthetics both potentiate GABA and activate GABAA receptors directly, but their binding sites on the receptor are poorly defined. ⋯ In addition to activating currents directly, propofol potentiated currents elicited by GABA recorded from cells expressing either subunit combination. We conclude that the gamma 2 subunit is not a prerequisite for activation of GABAA receptors by propofol or for its potentiation of GABA-activated currents. However, the subunit may contribute to the efficacy of propofol as a GABAA receptor activator.