Trycyclic antidepressants are often effective in the management of neuropathic pains. To elucidate the mechanism of tricyclic-induced analgesia, amitriptyline and other drugs were injected into lightly anesthetized rats either systemically or via lumbar intrathecal cannulas. Analgesia was assessed by measuring the latency of the tail flick reflex. Using this model, intrathecal amitriptyline (30 micrograms) significantly enhanced the analgesic effect of an intraperitoneal dose of morphine (0.5 mg/kg) that by itself produced no measurable effect. Given systemically, amitriptyline (30 or 100 micrograms intraperitoneally) was ineffective. Cocaine (30 micrograms) also potentiated morphine analgesia, but iprindole, a tricyclic antidepressant with a very weak inhibitory effect on monoamine uptake, was ineffective. This enhancement of analgesia by intrathecal amitriptyline was prevented by pretreating the rats with p-chlorophenylalanine (300 mg/kg). These results are consistent with the hypothesis that amitriptyline produces analgesia by blocking serotonin uptake and therefore enhancing the action of serotonin at the spinal terminals of an opioid-mediated intrinsic analgesia system.