Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in xenopus laevis oocytes

Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and postoperative analgesic requirements, but mechanisms remain unclear. N-methyl-D-aspartate (NMDA) receptors...

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Published in:	Anesthesiology (Philadelphia) Vol. 100; no. 6; pp. 1531 - 1537
Main Authors:	HAHNENKAMP, Klaus, NOLLET, Joke, HOENEMANN, Christian W, VAN AKEN, Hugo K, BUERKLE, Hartmut, HALENE, Tobias, SCHAUERTE, Svenja, HAHNENKAMP, Anke, HOLLMANN, Markus W, STRÜMPER, Danja, DURIEUX, Marcel E
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott 01-06-2004
Subjects:	Anesthesia Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Biological and medical sciences Dose-Response Relationship, Drug Female Gene Expression Regulation - drug effects Gene Expression Regulation - physiology Humans Medical sciences Microinjections Oocytes - drug effects Oocytes - metabolism Piperidines - pharmacology Receptors, N-Methyl-D-Aspartate - biosynthesis Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism Recombinant Proteins - biosynthesis Recombinant Proteins - genetics Recombinant Proteins - metabolism Remifentanil Xenopus laevis Human Vertebrata Xenopus laevis Amphibia NMDA Anesthesia Salientia Germinal cell Narcotic analgesic Oocyte Remifentanil
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Summary:	Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and postoperative analgesic requirements, but mechanisms remain unclear. N-methyl-D-aspartate (NMDA) receptors are thought to play a major role in development of postoperative pain and opiate tolerance. The authors hypothesized that Ultiva directly stimulates human NMDA receptors. To test this hypothesis, the authors expressed human NR1A/NR2A and NR1A/NR2B NMDA receptors in Xenopus laevis oocytes by injection of messenger RNA prepared in vitro. After protein expression, they used a two-electrode voltage clamp to measure currents induced by NMDA receptor agonists and opioids. Noninjected cells were unresponsive to all compounds tested. Glutamate/glycine (1 nM-1 mM each) or Ultiva (0.01 pM-0.1 mM) stimulated NMDA receptors concentration dependently. NR1A/2A EC50 values were 8.0 microM/12 microM for glutamate/glycine and 3.5 nM for Ultiva, and NR1A/2B EC50 values were 3.9 microM/1.9 microM for glutamate/glycine and 0.82 microM for Ultiva. Glycine in combination with Ultiva showed no additive effect compared with Ultiva alone. Ultiva-induced currents were inhibited by MK-801 (pore blocker) but not by 7-CK (glycine antagonist), D-AP5 (glutamate antagonist), or naloxone. Fentanyl (10 microM) did not stimulate NMDA receptors. These data indicate that Ultiva but not fentanyl stimulates NMDA receptors of different subunit combinations (NR1A/2A, NR1A/2B). The mechanism seems to be allosteric activation of the NMDA receptor.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0003-3022 1528-1175
DOI:	10.1097/00000542-200406000-00028