Information de reference pour ce titreAccession Number: | 00002401-201202010-00013.
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Author: | Baptista-Hon, Daniel T 1; Deeb, Tarek Z 2; Othman, Nidaa A 2; Sharp, Douglas 3; Hales, Tim G 1,2
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Institution: | (1)The Institute of Academic Anaesthesia, Centre for Neuroscience, University of Dundee, Dundee, UK, (2)Department of Pharmacology & Physiology, The George Washington University, Washington DC, USA, (3)Department of Anesthesiology and Critical Care Medicine, The George Washington University, Washington DC, USA
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Source: | British Journal of Pharmacology. 165(3):693-704, February 2012.
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Abstract: | BACKGROUND AND PURPOSE: Morphine is an antagonist at 5-HT3A receptors. 5-HT3 and opioid receptors are expressed in many of the same neuronal pathways where they modulate gut motility, pain and reinforcement. There is increasing interest in the 5-HT3B subunit, which confers altered pharmacology to 5-HT3 receptors. We investigated the mechanisms of inhibition by morphine of 5-HT3 receptors and the influence of the 5-HT3B subunit.
EXPERIMENTAL APPROACH: 5-HT-evoked currents were recorded from voltage-clamped HEK293 cells expressing human 5-HT3A subunits alone or in combination with 5-HT3B subunits. The affinity of morphine for the orthosteric site of 5-HT3A or 5-HT3AB receptors was assessed using radioligand binding with the antagonist [3H]GR65630.
KEY RESULTS: When pre-applied, morphine potently inhibited 5-HT-evoked currents mediated by 5-HT3A receptors. The 5-HT3B subunit reduced the potency of morphine fourfold and increased the rates of inhibition and recovery. Inhibition by pre-applied morphine was insurmountable by 5-HT, was voltage-independent and occurred through a site outside the second membrane-spanning domain. When applied simultaneously with 5-HT, morphine caused a lower potency, surmountable inhibition of 5-HT3A and 5-HT3AB receptors. Morphine also fully displaced [3H]GR65630 from 5-HT3A and 5-HT3AB receptors with similar potency.
CONCLUSIONS AND IMPLICATIONS: These findings suggest that morphine has two sites of action, a low-affinity, competitive site and a high-affinity, non-competitive site that is not available when the channel is activated. The affinity of morphine for the latter is reduced by the 5-HT3B subunit. Our results reveal that morphine causes a high-affinity, insurmountable and subunit-dependent inhibition of human 5-HT3 receptors.
Copyright (C) 2012 John Wiley & Sons, Inc.
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Author Keywords: | alkaloids; Cys-loop receptors; electrophysiology; drug dependence; opiates.
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Language: | English.
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Document Type: | RESEARCH PAPERS.
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ISSN: | 0007-1188
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NLM Journal Code: | b00, 7502536
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DOI Number: | https://dx.doi.org/10.1111/j.147...- ouverture dans une nouvelle fenêtre
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