Open channel block of NMDA receptors by diphenhydramine.
OBJECTIVE
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.


METHODS
Electrophysiological patch-clamp experiments were performed on glutamate receptors which were heterologously expressed in human TsA cells.


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.


CONCLUSIONS
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.
University Hospital of Ulm, Department of Anesthesiology, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. Electronic address: karl.foehr@uniklinik-ulm.de.
Karl J
KJ
Föhr
University Hospital of Ulm, Department of Anesthesiology, Albert-Einstein-Allee 23, D-89081 Ulm, Germany.
Kathrin
K
Zeller
University Hospital of Ulm, Department of Anesthesiology, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. Electronic address: michael.georgieff@uniklinik-ulm.de.
Michael
M
Georgieff
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.
Sarah
S
Köster
University Hospital of Ulm, Department of Anesthesiology, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. Electronic address: oliver.adolph@uniklinik-ulm.de.
Oliver
O
Adolph
D001665:Binding Sites; D002413:Cations, Divalent / Q000378:metabolism; D004155:Diphenhydramine / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002413:Cations, Divalent; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D004155:Diphenhydramine; D008274:Magnesium
Amnesia; Analgesia; Diphenhydramine; LTP; Learning and memory; NMDA receptor; Patch clamp; Sedation