The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Dec 1999
Interactive role for neurosteroids in ethanol enhancement of gamma-aminobutyric acid-gated currents from dissociated substantia nigra reticulata neurons.
Although previous in vivo electrophysiological studies demonstrated a consistent ethanol enhancement of gamma-aminobutyric acid (GABA) responsiveness from substantia nigra reticulata (SNR) neurons, ethanol applied in vitro to dissociated neurons from the SNR had an inconsistent effect on GABA function. One source for the disparity between these contrasting in vivo and in vitro results could be an endogenous factor (acting on an auxiliary site on GABA(A) receptors) that was not available to the isolated SNR neurons. Because neurosteroids are present in vivo and act on an auxiliary site, it was hypothesized that the presence of a neurosteroid was important for a consistent effect of ethanol on GABA responsiveness from neurons studied in vitro. ⋯ At a concentration of alphaxalone as low as 30 nM, ethanol produced a robust concentration-related increase in GABA-gated currents from this cell type. The neurosteroid 3alpha, 5alpha-tetrahydrodeoxycorticosterone (100 nM) also permitted a reliable concentration-dependent ethanol enhancement of responses to GABA from SNR cells, indicative that the effects of alphaxalone were not unique. This consistent neurosteroid-induced ethanol enhancement of GABA responsiveness from dissociated SNR neurons supports the view that neurosteroids may play a key role in the action of ethanol on postsynaptic GABA(A) receptor function.
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J. Pharmacol. Exp. Ther. · Dec 1999
Modifications of blood volume alter the disposition of markers of blood volume, extracellular fluid, and total body water.
Recirculatory pharmacokinetic models for indocyanine green (ICG), inulin, and antipyrine describe intravascular mixing and tissue distribution after i.v. administration. These models characterized physiologic marker disposition in four awake, splenectomized dogs while they were normovolemic, volume loaded (15% of estimated blood volume added as a starch solution), and mildly and moderately hypovolemic (15 and 30% of estimated blood volume removed). ICG-determined blood volumes increased 20% during volume loading and decreased 9 and 22% during mild and moderate hypovolemia. ⋯ The fraction of CO not involved in drug distribution had a significant effect on the area under the antipyrine concentration-versus-time relationships (AUC) in the first minutes after drug administration. Hypovolemia increased the fraction of CO represented by nondistributive blood flow and increased the antipyrine AUC up to 60% because nondistributive blood flow did not change, despite decreased CO. Volume loading resulted in a smaller (less than 20%) antipyrine AUC decrease despite increased fast tissue distributive flow because nondistributive flow also increased with increased CO.
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J. Pharmacol. Exp. Ther. · Dec 1999
Ring-constrained orvinols as analogs of buprenorphine: differences in opioid activity related to configuration of C(20) hydroxyl group.
The relative positions of the C(20) substituents in buprenorphine, particularly the hydroxyl group, have been implicated in its actions as a partial mu-agonist and a kappa-antagonist. This hypothesis has been examined by the synthesis and pharmacological characterization of five orvinols in which the C(20) carbon atom of buprenorphine is constrained in a five-membered ring, fixing the hydroxyl group above (beta) or below (alpha) the plane of the ring. All five compounds were nonselective in binding assays with similar, low nanomolar affinities. ⋯ BU46 was a full agonist in the mouse writhing assay and antinociception was prevented by norbinaltorphimine, showing a kappa-mechanism of action. In contrast, BU47 acted as an antagonist of mu-, delta-, and kappa-mediated antinociception in the writhing assay. The results show that the configuration of the hydroxyl group is not important in binding affinity at mu-, delta-, or kappa-receptors but does influence kappa-potency and kappa-efficacy, particularly in vivo.
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J. Pharmacol. Exp. Ther. · Dec 1999
Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy.
Fenfluramine is an indirect agonist of 5-hydroxytryptamine (5-HT) receptors that acts by evoking 5-HT release and blocking 5-HT reuptake in neuronal cells. The current study compared the antinociceptive properties of fenfluramine with those of the tricyclic antidepressants amitriptyline and desipramine in rat models of acute, persistent, and neuropathic pain. In a rat model of neuropathic pain produced by tight ligation of the L(5)/L(6) spinal nerves, i.v. bolus injection of fenfluramine resulted in a dose-dependent and long-lasting (>4 h) blockade of mechanical allodynia (ED(50) = 3.5 mg/kg; 95% confidence interval, 2.2-5.4 mg/kg) and cold allodynia (ED(50) = 2.4 mg/kg; 95% confidence range, 1.2-4.6 mg/kg). ⋯ Intracerebroventricular bolus injection of 240 microg of fenfluramine significantly increased mechanical allodynia thresholds; however, the same dose administered spinally by intrathecal bolus injection was ineffective. The inhibitory effects of fenfluramine on mechanical allodynia (and tonic pain behavior in the formaldehyde solution test) were prevented by pretreatment with 10 mg/kg metergoline, a selective antagonist of 5-HT receptors, but not with the mu-opioid receptor antagonist naloxone. These results suggest that fenfluramine produces analgesia in the formaldehyde solution test and the spinal nerve ligation model of neuropathic pain by potentiating, at least in part, supraspinal 5-HT mediated processes.