There are suggestions of sex differences in N-methyl-D-aspartate (NMDA) receptor system involvement in the mediation of analgesia. The present study examined the effects of the specific, competitive NMDA antagonist, NPC 12626, on the nociceptive (50 degrees C hot plate) responses of reproductive male and female laboratory mice exposed to (i) an ethologically relevant aversive stimulus, the odor of a predator and (ii) administration of the kappa opiate agonist, U69,593. A 30-s exposure to 2-propylithietane, the major component of weasel odor, elicited a 'non-opioid' analgesia that was in both sexes insensitive to naloxone and the kappa opiate antagonist nor-binaltorphimine. In male mice this non-opioid analgesia was antagonized by NPC 1262, while in reproductive females the predator-induced analgesia was insensitive to NPC 12626. Similarly, NPC 12626 attenuated the analgesic effects of the kappa opiate agonist, U69,593, in male mice while having no significant effects on the equivalent levels of kappa opiate analgesia in females. These results show that there are sex differences in NMDA involvement in the expression and, or mediation of both non-opioid stress-induced and kappa opiate-mediated analgesia.