NMDA receptor antagonist MK-801 blocks non-opioid stress-induced analgesia in the formalin test

The analgesic effect of a 3-min swim stress was assessed using the formalin test. Male Swiss mice were injected i.p. with naloxone (0.1 or 1.0 mg/kg), MK-801 (0.075 mg/kg) or saline 15 min prior to swimming in water maintained at 20 degrees C or 32 degrees C. The mice were then injected with 20 microliters of 5% formalin into the plantar surface of 1 hind paw and pain behaviour (time spent licking the injected paw) was continuously monitored during the subsequent 10 min. Swim stress produced a significant reduction in pain behaviour at both 20 degrees C and 32 degrees C. MK-801 completely blocked the analgesia produced by both the 20 degrees C and 32 degrees C swim. At a dose of 0.1 mg/kg, naloxone partially antagonized the analgesia produced by the 32 degrees C swim but did not affect the analgesia produced by the 20 degrees C swim. Naloxone at a dose of 1.0 mg/kg had no effect on swim stress-induced analgesia. Neither MK-801 nor 0.1 mg/kg naloxone altered baseline pain behaviour, although 1.0 mg/kg naloxone did significantly reduce it. It is unlikely that the effect of MK-801 on swim stress-induced analgesia is due to an interaction with an opioid mechanism, as MK-801 had no effect on morphine analgesia. These results suggest that the analgesia produced by the 20 degrees C swim stress in the formalin test is non-opioid in nature and mediated via the NMDA receptor, whereas the 32 degrees C swim stress-induced analgesia has both an opioid and non-opioid component.