Karl J Föhr1, Kathrin Zeller2, Michael Georgieff3, Sarah Köster4, Oliver Adolph5. 1. University Hospital of Ulm, Department of Anesthesiology, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. Electronic address: karl.foehr@uniklinik-ulm.de. 2. University Hospital of Ulm, Department of Anesthesiology, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. 3. University Hospital of Ulm, Department of Anesthesiology, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. Electronic address: michael.georgieff@uniklinik-ulm.de. 4. Georg-August-Universität Göttingen, Institute for X-Ray Physics, Friedrich-Hund-Platz 1, D-37077 Göttingen, Germany. Electronic address: sarah.koester@phys.uni-goettingen.de. 5. University Hospital of Ulm, Department of Anesthesiology, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. Electronic address: oliver.adolph@uniklinik-ulm.de.
Abstract
BACKGROUND AND PURPOSE: Diphenhydramine is a well known H1-receptor antagonist that plays a major role in clinical practice. Nowadays, diphenhydramine is primarily applied to prevent nausea but also its sedative and analgesic effects are of clinical importance. As other drugs mediating sedative and analgesic properties partly operate via the inhibition of glutamate receptors, we tested the hypothesis that diphenhydramine, as well interacts with excitatory ionotropic glutamate receptors. EXPERIMENTAL APPROACH: Electrophysiological patch-clamp experiments were performed on glutamate receptors which were heterologously expressed in human TsA cells. KEY RESULTS: Diphenhydramine inhibits NMDA-mediated membrane currents in a reversible and concentration-dependent manner at clinically relevant concentrations. The inhibition occurred in a noncompetitive manner. Diphenhydramine did not compete with NMDA or glycine for their binding sites and half-maximal inhibition was obtained around 25 μM diphenhydramine, independent of the subunit composition. The inhibition was caused by a classical open channel blocking mechanism and varied strongly with the membrane potential. Our results suggest that diphenhydramine most probably interacts with the Mg2+ binding site or a very closely related area of the channel pore. CONCLUSION AND IMPLICATIONS: The data presented here provide evidence that the NMDA receptor antagonism of diphenhydramine contribute to its sedative and potentially LTP-related effects like analgesia and amnesia.
BACKGROUND AND PURPOSE:Diphenhydramine is a well known H1-receptor antagonist that plays a major role in clinical practice. Nowadays, diphenhydramine is primarily applied to prevent nausea but also its sedative and analgesic effects are of clinical importance. As other drugs mediating sedative and analgesic properties partly operate via the inhibition of glutamate receptors, we tested the hypothesis that diphenhydramine, as well interacts with excitatory ionotropic glutamate receptors. EXPERIMENTAL APPROACH: Electrophysiological patch-clamp experiments were performed on glutamate receptors which were heterologously expressed in human TsA cells. KEY RESULTS:Diphenhydramine inhibits NMDA-mediated membrane currents in a reversible and concentration-dependent manner at clinically relevant concentrations. The inhibition occurred in a noncompetitive manner. Diphenhydramine did not compete with NMDA or glycine for their binding sites and half-maximal inhibition was obtained around 25 μM diphenhydramine, independent of the subunit composition. The inhibition was caused by a classical open channel blocking mechanism and varied strongly with the membrane potential. Our results suggest that diphenhydramine most probably interacts with the Mg2+ binding site or a very closely related area of the channel pore. CONCLUSION AND IMPLICATIONS: The data presented here provide evidence that the NMDA receptor antagonism of diphenhydramine contribute to its sedative and potentially LTP-related effects like analgesia and amnesia.