The effects of morphine on human 5-HT3A receptors.
5-HT3 receptors are ligand-gated ion channels that are involved in the modulation of emesis and pain. In this study, we investigated whether the opioid analgesic, morphine, exerts specific effects on human 5-HT3 receptors. Whole-cell patches from HEK-293 cells stably transfected with the human 5-HT3A receptor cDNA were used to determine the effects of morphine on the 5-HT-induced currents using the patch clamp technique. At negative membrane potentials, 5-HT induced inward currents in a concentration-dependent manner. The 5-HT3 receptor antagonist, ondansetron, (0.3 nM) reversibly inhibited the 5-HT-induced signals. Morphine reversibly suppressed 5-HT-induced peak currents as a function of concentration (IC50 = 1.1 microM, Hill coefficient = 1.2). The block by morphine decreased with increasing 5-HT concentrations, suggesting a competitive effect. In addition, the activation, as well as the inactivation, kinetics of the currents were significantly slowed in the presence of morphine. The morphine antagonist, naloxone, also inhibited 5-HT-induced currents (e.g., at 3 microM by 17%). The effects of morphine and naloxone were not additive. The potency of morphine and the competitivity of the blocking effect points to a specific mechanism at a receptor site rather than an unspecific membrane effect.
Wittmann
Maria
M
Klink und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Universitätskliniken Bonn, Bonn, Germany. maria.wittmann@gmx.de
Peters
I
I
Schaaf
T
T
Wartenberg
H C
HC
Wirz
S
S
Nadstawek
J
J
Urban
B W
BW
Barann
M
M
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D013045:Species Specificity
D009292:Narcotic Antagonists; D044406:Receptors, Serotonin, 5-HT3; D009270:Naloxone; D009020:Morphine