The Effects of Fentanyl-Like Opioids and Hydromorphone on Human 5-HT3A Receptors

Maria Wittmann, MD, Thomas Schaaf, MD, Ineke Peters, MD, Stefan Wirz, MD, Bernd W. Urban, PhD, and Martin Barann, PhD
From the Klinik und Poliklinik fr An酲thesiologie und Operative Intensivmedizin, Universit酹skliniken Bonn, Bonn, Germany.

Address correspondence and reprint requests to Dr. Martin Barann, Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud Str. 25, 53127 Bonn, Germany. Address e-mail to martin.barann@ukb.uni-bonn.de.

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 然)-induced currents using the patch clamp technique (voltage-clamp).

RESULTS: None of the fentanyl derivatives affected currents through the 5-HT3A receptor (3 然 5-HT) significantly in the clinically relevant nanomolar concentration range (IC50 values >30 然). In contrast, hydromorphone was considerably more potent (IC50 = 5.3 然), slowing the current activation- and desensitization-kinetics significantly (at 3 然 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.