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

Background. mu-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 mg kg(-1)) followed by an infusion (96 mu g 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.