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Background: The alkaloid morphine is historically the oldest opiate, yet still today it has clinically important uses in analgesic therapies. The main analgesic effect of opioids, including synthetic opioids belonging to the family of 4‐anilidopiperidines, is mediated via activation of opioid receptors spread throughout the peripheral and central nervous system. However, morphine acting as a ‘dirty’ drug also exhibits effects on other receptor systems, e.g., the serotonergic system and its 5‐HT3 receptor. Therefore, this study focuses on the interaction of morphine and fentanyl‐type opioids (alfentanil, remifentanil and sufentanil) with 5‐HT3A receptors. Methods: Excised outside‐out patches from human embryonic kidney‐293 cells, stably transfected with the human 5‐HT3A receptor cDNA, were used to determine the opioid effects using the patch‐clamp technique. Results: Within clinical concentrations, the effects of morphine are concentration‐dependent. Morphine reduced current amplitudes, as well as activation and decay time constants. These effects were not competitive. Contrary to these results, all fentanyl‐type opioids only exerted effects far above their clinical concentration ranges. These effects were not homogenous but varying. Conclusions: Morphine is an opioid compound exhibiting special antagonistic interaction with 5‐HT3A receptors. This interaction is not shared by the newer synthetic derivatives of the fentanyl‐type opioids in the clinical relevant concentration range. [ABSTRACT FROM AUTHOR]