Studies with ketamine and alfentanil following Freund's complete adjuvant-induced inflammation in rats

1. N-Methyl-D-aspartate (NMDA) receptor antagonists suppress inflammatory hyperalgesia and the development of acute opioid tolerance. They may also enhance opioid-induced antinociception, while suppressing postopioid-induced hyperalgesia and opioid-enhanced inflammatory hyperalgesia. 2. The non-competitive NMDA receptor antagonist, ketamine, is a racemic chiral drug; its individual enantiomers have differing affinities for the NMDA receptor. The anaesthetic and antinociceptive potencies of (S)-ketamine are 1.5- and threefold higher, respectively, than those of (R)-ketamine in laboratory rodents. 3. The present study investigated the effects of racemic ketamine and enantiopure (S)-ketamine on inflammatory hyperalgesia in rats, 5 days after intraplantar injection of Freund's complete adjuvant (FCA) into one hind paw. First, racemic or (S)-ketamine was administered alone; second, racemic or (S)-ketamine was administered 30 min after initiation of i.v. infusions of the mu-opioid agonist, alfentanil. 4. Area under the curve (AUC) values for Von Frey paw withdrawal threshold (PWT) versus time curves were significantly increased (P < 0.05) for both inflamed and non-inflamed hind paws by racemic and (S)-ketamine (5 & 10 mg/kg, s.c.). Similarly, AUC values for reduction of hind paw volume versus time were significantly increased (P < 0.05) by racemic and (S)-ketamine (10 mg/kg, s.c.). 5. Alfentanil infusions significantly increased PWT in both hind paws, but neither racemic nor (S)-ketamine (5 mg/kg, s.c.) administered 30 min after initiation of alfentanil infusion produced further increases in PWT. 6. Racemic and (S)-ketamine produced antinociceptive effects in both hind paws, but an antihyperalgesic effect per se was not apparent. Additionally, there was a possible anti-inflammatory effect of both drugs in the inflamed hind paw. These findings complement previous studies in which non-competitive NMDA receptor antagonists suppressed behavioural hyperalgesia. 7. However, racemic and (S)-ketamine did not further enhance alfentanil's antinociceptive effects, although they appeared to prolong alfentanil's antinociceptive effects in the non-inflamed hind paw. These findings suggest that factors such as time-course, frequency and the mode of administration of NMDA receptor antagonists, in addition to the type of antinociceptive model (i.e. inflammatory compared with acute) and the nociceptive testing procedure (i.e. noxious mechanical compared with low threshold stimuli) may influence their effects on opioid-induced antinociception.