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ANALGESIA

The Effects of Morphine on Human 5-HT_3A Receptors

From the Klink und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Universitätskliniken Bonn, Bonn, Germany.

Address correspondence and reprint requests to Dr. med. Maria Wittmann, Universitätskliniken Bonn, Sigmund-Freud-Straße-Str. 25 D-53105, Bonn, Germany. Address e-mail to maria.wittmann{at}gmx.de.

Abstract

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-HT_3A 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 µM, 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 µM 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.

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