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BJA Advance Access published online on August 19, 2005
British Journal of Anaesthesia, doi:10.1093/bja/aei215
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: journal.permissions@oupjournals.org
Accepted June 27, 2005

Laboratory Investigation

Low dose of S(+)-ketamine prevents long-term potentiation in pain pathways under strong opioid analgesia in the rat spinal cord in vivo

J. Benrath 1 {dagger}, C. Brechtel 2 {dagger}, J. Stark 3, and J. Sandkühler 3*

1 Klinische Abteilung für Anästhesie und Allgemeine Intensivmedizin B, Medizinische Universität Wien, Währinger Gürtel 18-20, AKH, A-1090 Wien, Austria; Zentrum für Hirnforschung, Abteilung für Neurophysiologie, Medizinische Universität Wien, Spitalgasse 4, A-1090 Wien, Austria
2 Institut für Physiologie und Pathophysiologie, Universität Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany
3 Zentrum für Hirnforschung, Abteilung für Neurophysiologie, Medizinische Universität Wien, Spitalgasse 4, A-1090 Wien, Austria

* To whom correspondence should be addressed.
J. Sandkühler, E-mail: juergen.sandkuehler{at}meduniwien.ac.at


  Abstract

Background. µ-Opioid receptor (MOR) agonists are strong antinociceptive drugs. Low, but not high doses of the MOR agonist fentanyl prevent synaptic long-term potentiation (LTP) in pain pathways. Block of spinal N-methyl-D-aspartate (NMDA) receptors prevent central sensitization. Here we tested whether the NMDA receptor antagonist S(+)-ketamine reduces C-fibre-evoked potentials and prevents induction of LTP despite high doses of fentanyl.

Methods. C-fibre-evoked field potentials were recorded in the superficial laminae I/II of the rat lumbar spinal cord. High-frequency stimulation (HFS) was applied to the sciatic nerve at C-fibre strength to induce LTP. S(+)-ketamine 5 mg kg-1 was given 1 h before or after HFS. S(+)-ketamine 5 mg kg-1 and fentanyl as a bolus (40 µg kg-1) followed by an infusion (96 µg kg-1 h-1) were given before HFS to test the action of the combination of these drugs.

Results. HFS potentiated C-fibre-evoked field potentials to mean 173 (SEM 15)% of control (n=7) for at least 1 h. Low-dose S(+)-ketamine given before HFS blocked the induction of LTP. S(+)-ketamine given after HFS had no effect on the maintenance of LTP. Low-dose S(+)-ketamine prevented induction of LTP under fentanyl-infusion.

Conclusions. Low-dose S(+)-ketamine does not affect C-fibre-evoked potentials alone but blocks LTP induction in pain pathways. In contrast, high doses of opioids strongly reduce C-fibre-evoked potentials, but do not fully prevent LTP induction. In this animal study the combination of S(+)-ketamine with fentanyl reveals both a reduction of C-fibre-evoked potentials and prevention of LTP and seem therefore a better choice for perioperative pain management compared with the sole administration.

Keywords: anaesthetics i.v., ketamine; analgesia, pre-emptive; analgesics, opioid, fentanyl; model, rat; spinal cord, c-fibres.
{dagger}Both authors contributed equally to the manuscript.
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