The effects of fentanyl-like opioids and hydromorphone on human 5-HT3A receptors.
BACKGROUND
5-HT(3) receptors are involved in various physiologic functions, including the modulation of emesis. 5-HT(3) 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-HT(3) 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-HT(3A) receptor cDNA, were used to determine the opioid effects on the 5-HT (3 microM)-induced currents using the patch clamp technique (voltage-clamp).


RESULTS
None of the fentanyl derivatives affected currents through the 5-HT(3A) receptor (3 microM 5-HT) significantly in the clinically relevant nanomolar concentration range (IC(50) values >30 microM). In contrast, hydromorphone was considerably more potent (IC(50) = 5.3 microM), slowing the current activation- and desensitization-kinetics significantly (at 3 microM 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-HT(3A) 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-HT(3A) 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-HT(3A) 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-HT(3A) receptor. Future clinical studies could test whether corresponding differences in emetogenicity between different classes of opioids will be found.
Wittmann
Maria
M
Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Universitätskliniken Bonn, Bonn, Germany.
Schaaf
Thomas
T
Peters
Ineke
I
Wirz
Stefan
S
Urban
Bernd W
BW
Barann
Martin
M
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000932:Antiemetics / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology*; D006801:Humans; D004091:Hydromorphone / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects* / Q000502:physiology; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology
D000701:Analgesics, Opioid; D000932:Antiemetics; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D009020:Morphine; D004091:Hydromorphone; D005283:Fentanyl