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The anesthetic agent, ketamine, has the potential to recruit spinopetal noradrenergic and serotonergic neuronal pathways for its antinociceptive effect. Neurochemically, ketamine has been shown to interact with opiate receptors and thus may increase neuronal activity in the spinopetal monoaminergic (norepinephrine and serotonin) systems in a manner similar to morphine. In addition, ketamine should facilitate the antinociceptive effect of the monoamines at the level of the spinal cord by an action of the drug to prevent the neuronal reuptake of the monoamines. In this study, the analgesic action of both ketamine and morphine, as measured by the tail-flick test in rats, was inhibited by norepinephrine, serotonin and opiate receptor antagonists. Monoaminergic receptor inhibitors were more potent as antagonists of ketamine's analgesia while the opiate receptor antagonist naloxone was more effective against morphine analgesia. The greater sensitivity of the antinociceptive effect of ketamine to monoaminergic antagonist may reflect the importance of the inhibition of norepinephrine and serotonin reuptake in the analgesic action of the drug. Transecting the spinal cord of rats at T4-6 revealed distinct differences between the analgesic mechanisms of ketamine and morphine. For example, the potency of ketamine was increased nearly 9-fold in spinal rats whereas morphine's potency was decreased. This observation suggests that ketamine may activate both analgesic and antanalgesic systems supraspinally, and that its antinociceptive effect in intact animals is a summation of these opposing actions. Partial evidence that supraspinal noradrenergic neurons might be involved in the antanalgesic component of ketamine's action was provided by experiments demonstrating enhanced analgesia in intact animals after depletion of norepinephrine with FLA-63. In spinal animals a significant difference was also observed in the neuronal processes mediating the residual analgesic effects of morphine and ketamine. The analgesic effect of morphine remained primarily sensitive to naloxone but seemed to use a local serotonergic process (sensitive to the serotonergic antagonist methysergide) at higher doses of the opiate. Ketamine's analgesia, on the other hand, was only inhibited by methysergide. In conclusion, although it appears that morphine and ketamine may both activate spinopetal monoaminergic processes through an opiate mechanism, the two drugs differ significantly with regard to some of the components of their antinociceptive actions. The differences may be related to ketamine's ability to alter the metabolism of monoaminergic neurotransmitters involved in pain processing.