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The 5‐HT3B subunit affects high‐potency inhibition of 5‐HT 3 receptors by morphine
Author(s) -
BaptistaHon Daniel T,
Deeb Tarek Z,
Othman Nidaa A,
Sharp Douglas,
Hales Tim G
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01582.x
Subject(s) - morphine , receptor , pharmacology , potency , chemistry , opioid , 5 ht receptor , competitive antagonist , antagonist , μ opioid receptor , serotonin , biology , biochemistry , in vitro
BACKGROUND AND PURPOSE Morphine is an antagonist at 5‐HT 3 A receptors. 5‐HT 3 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‐HT 3 receptors. We investigated the mechanisms of inhibition by morphine of 5‐HT 3 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‐HT 3 A or 5‐HT 3 AB receptors was assessed using radioligand binding with the antagonist [ 3 H]GR65630. KEY RESULTS When pre‐applied, morphine potently inhibited 5‐HT‐evoked currents mediated by 5‐HT 3 A 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‐HT 3 A and 5‐HT 3 AB receptors. Morphine also fully displaced [ 3 H]GR65630 from 5‐HT 3 A and 5‐HT 3 AB 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‐HT 3 receptors.