The effects of s.c. doses of naloxone, methysergide and phentolamine on ketamine-induced spinal analgesia were assessed to determine the involvement of opiate, serotonergic and noradrenergic components mediating ketamine's antinociceptive action. Ketamine administered intrathecally (i.t.) produced a significant elevation in tail-flick latency in rats. The spinal antinociceptive effects of ketamine were dose dependently reversed by methysergide (ID50 = 0.008 mg/kg s.c.), phentolamine (ID50 = 0.88 mg/kg s.c.) and naloxone (ID50 = 3.0 mg/kg s.c.). Unlike morphine, which remains analgesic and dependent on opiate interactions following bilateral lesions of the dorsolateral funiculus (DLF), ketamine analgesia was absent following DLF lesions. Thus, ketamine appears to produce an antinociceptive response which is dependent upon the neuronal activity of the descending pain-inhibitory pathways. The monoaminergic components comprising the descending pathways appear to be more prominent in the action of ketamine than they are in the spinal action of morphine. Furthermore, the spinal opioid receptors involved in ketamine's effect may be different from the mu subtype preferred by morphine.