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Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone

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Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone. / Deeb, Tarek Z.; Sharp, Douglas; Hales, Tim G. (Lead / Corresponding author).

In: Molecular Pharmacology, Vol. 75, No. 4, 04.2009, p. 908-917.

Research output: Contribution to journalArticle

Harvard

Deeb, TZ, Sharp, D & Hales, TG 2009, 'Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone' Molecular Pharmacology, vol 75, no. 4, pp. 908-917.

APA

Deeb, T. Z., Sharp, D., & Hales, T. G. (2009). Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone. Molecular Pharmacology, 75(4), 908-917doi: 10.1124/mol.108.053322

Vancouver

Deeb TZ, Sharp D, Hales TG. Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone. Molecular Pharmacology. 2009 Apr;75(4):908-917.

Author

Deeb, Tarek Z.; Sharp, Douglas; Hales, Tim G. (Lead / Corresponding author) / Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone.

In: Molecular Pharmacology, Vol. 75, No. 4, 04.2009, p. 908-917.

Research output: Contribution to journalArticle

Bibtex - Download

@article{124b2b6831124e9ea901900dfaeaab81,
title = "Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone",
author = "Deeb, {Tarek Z.} and Douglas Sharp and Hales, {Tim G.}",
year = "2009",
volume = "75",
number = "4",
pages = "908--917",
journal = "Molecular Pharmacology",
issn = "0026-895X",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone

A1 - Deeb,Tarek Z.

A1 - Sharp,Douglas

A1 - Hales,Tim G.

AU - Deeb,Tarek Z.

AU - Sharp,Douglas

AU - Hales,Tim G.

PY - 2009/4

Y1 - 2009/4

N2 - <p>Homomeric 5-hydroxytryptamine (5-HT)(3A) and heteromeric 5-HT3AB receptors mediate rapid excitatory responses to serotonin in the central and peripheral nervous systems. The alkaloid morphine, in addition to being a mu-opioid receptor agonist, is a potent competitive inhibitor of 5-HT3 receptors. We examined whether methadone, an opioid often used to treat morphine dependence, also exhibited 5-HT3 receptor antagonist properties. Racemic (R/S)-methadone inhibited currents mediated by human homomeric 5-HT3A receptors (IC50 = 14.1 +/- 2.5 mu M). Incorporation of the 5-HT3B subunit into heteromeric 5-HT3AB receptors reduced the potency of inhibition by (R/S)methadone (IC50 = 41.1 +/- 0.9 mu M). (R/S)-Methadone also increased apparent desensitization of both 5-HT3 receptor subtypes. The inhibition of the 5-HT3A receptor was competitive; however, incorporation of the 5-HT3B subunit caused the appearance of inhibition that was insurmountable by 5-HT. In the absence of rapid desensitization, when dopamine was used as an agonist of 5-HT3AB receptors, the inhibition by (R/S)-methadone was voltage-dependent. The antagonist and desensitization-enhancing effects of (R/S)-methadone were shared by pure (R)- and (S)-methadone enantiomers, which had similar actions on 5-HT-evoked currents mediated by 5-HT3 receptors. However, (R)-methadone exhibited a larger voltage-dependent inhibition of dopamine-evoked currents mediated by 5-HT3AB receptors than did (S)-methadone. Inhibition of 5-HT3A receptors by (R/S)-methadone was not influenced by voltage. Thus, methadone displays multimodal subunit-dependent antagonism of 5-HT3 receptors.</p>

AB - <p>Homomeric 5-hydroxytryptamine (5-HT)(3A) and heteromeric 5-HT3AB receptors mediate rapid excitatory responses to serotonin in the central and peripheral nervous systems. The alkaloid morphine, in addition to being a mu-opioid receptor agonist, is a potent competitive inhibitor of 5-HT3 receptors. We examined whether methadone, an opioid often used to treat morphine dependence, also exhibited 5-HT3 receptor antagonist properties. Racemic (R/S)-methadone inhibited currents mediated by human homomeric 5-HT3A receptors (IC50 = 14.1 +/- 2.5 mu M). Incorporation of the 5-HT3B subunit into heteromeric 5-HT3AB receptors reduced the potency of inhibition by (R/S)methadone (IC50 = 41.1 +/- 0.9 mu M). (R/S)-Methadone also increased apparent desensitization of both 5-HT3 receptor subtypes. The inhibition of the 5-HT3A receptor was competitive; however, incorporation of the 5-HT3B subunit caused the appearance of inhibition that was insurmountable by 5-HT. In the absence of rapid desensitization, when dopamine was used as an agonist of 5-HT3AB receptors, the inhibition by (R/S)-methadone was voltage-dependent. The antagonist and desensitization-enhancing effects of (R/S)-methadone were shared by pure (R)- and (S)-methadone enantiomers, which had similar actions on 5-HT-evoked currents mediated by 5-HT3 receptors. However, (R)-methadone exhibited a larger voltage-dependent inhibition of dopamine-evoked currents mediated by 5-HT3AB receptors than did (S)-methadone. Inhibition of 5-HT3A receptors by (R/S)-methadone was not influenced by voltage. Thus, methadone displays multimodal subunit-dependent antagonism of 5-HT3 receptors.</p>

KW - N1E-115 NEUROBLASTOMA-CELLS

KW - HUMAN 5-HT3A RECEPTORS

KW - TYPE-3 RECEPTORS

KW - MOLECULAR DETERMINANTS

KW - ONDANSETRON

KW - INHIBITION

KW - CHANNEL

KW - CNS

KW - ACTIVATION

KW - BLOCKADE

U2 - 10.1124/mol.108.053322

DO - 10.1124/mol.108.053322

M1 - Article

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 4

VL - 75

SP - 908

EP - 917

ER -

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