The effects of fentanyl-like Opioids and hydromorphone on human 5-HT3A receptors

BACKGROUND: 5-HT3 receptors are involved in various physiologic functions, including the modulation of emesis. 5-HT3 antagonists are clinically widely used as potent antiemetics. Emesis is also a side effect of opioid analgesics. Intriguingly, the natural opioid morphine shows specific interactions with human 5-HT3 receptors at clinically relevant concentrations. In the present study, we investigated whether this is a general effect of opioids, even when they are structurally diverse. Therefore, another morphine (phenanthrene-type) derivative, hydromorphone, and fentanyl including its (4-anilinopiperidine-type) derivatives were tested. METHODS: Whole-cell patches from human embryonic kidney-293 cells, stably transfected with the human 5-HT3A receptor cDNA, were used to determine the opioid effects on the 5-HT (3 mu M)-induced currents using the patch clamp technique (voltage-clamp). RESULTS: None of the fentanyl derivatives affected currents through the 5-HT3A receptor (3 mu M 5-HT) significantly in the clinically relevant nanomolar concentration range (IC50 values >30 mu M). In contrast, hydromorphone was considerably more potent (IC50 = 5.3 mu M), slowing the current activation- and desensitization-kinetics significantly (at 3 mu M by a factor of 1.9 and 2.4, respectively), similar to morphine. At concentrations much higher than clinically relevant, but within the range predicted,from Meyer-Overton correlations for nonspecific interactions, the fentanyl derivatives all showed at least a tendency to suppress current amplitudes, but they had diverse, effects on the activation- and desensitization-kinetics of 5-HT3A receptors. CONCLUSIONS: Only morphine and hydromorphone, but not the fentanyl derivatives, reduced 5-HT-induced current amplitudes and slowed current kinetics near clinically relevant concentrations'. The high potencies of morphine and hydromorphone, when compared to their lipophilicities, suggest a specific interaction with 5-HT3A receptors. In contrast, the effects of fentanyl-type opioids appear to be of unspecific nature. Because the rank order of opioid potencies for human 5-HT3A receptors is opposite of that for opioid receptors, the site involved is structurally different from opioid receptor binding sites. In agreement with recent data on different phenols, a phenolic OH-group (which morphine and hydromorphone possess) may contribute to specific interactions of morphine and hydromorphone with the 5-HT3A receptor. Future clinical studies could test whether corresponding differences in emetogenicity between different classes of opioids will be found.