The 5-HT3B subunit affects high-potency inhibition of 5-HT3 receptors by morphine

Br J Pharmacol. 2012 Feb;165(3):693-704. doi: 10.1111/j.1476-5381.2011.01582.x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • HEK293 Cells
  • Humans
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Morphine / pharmacology*
  • Protein Subunits / physiology*
  • Radioligand Assay
  • Receptors, Serotonin, 5-HT3 / physiology*
  • Serotonin / pharmacology
  • Serotonin 5-HT3 Receptor Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology


  • Imidazoles
  • Indoles
  • Protein Subunits
  • Receptors, Serotonin, 5-HT3
  • Serotonin 5-HT3 Receptor Antagonists
  • Serotonin Receptor Agonists
  • GR 65630
  • Serotonin
  • Morphine