Low dose of S+-ketamine prevents long-term potentiation in pain pathways under strong opioid analgesia in the rat spinal cord in vivo.
BACKGROUND
micro-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 microg kg(-1)) followed by an infusion (96 microg 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.
Benrath
J
J
Klinische Abteilung für Anäthesie und Allgemeine Intensivmedizin B. Medizinische Universität Wien, Austria.
Brechtel
C
C
Stark
J
J
Sandkühler
J
J
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D004558:Electric Stimulation / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D005283:Fentanyl