The effects of acute and chronic treatment with tricyclic antidepressants (TCA) upon antinociception induced by intrathecally administered serotonin (5-HT), norepinephrine (NE), and morphine were assessed at weekly intervals by the tail-flick method in the rat. Acute pretreatment with either clomipramine (28.5 mumol/kg, s.c.) or desipramine (85.5 mumol/kg, s.c.) enhanced the analgesia induced by both intrathecally-administered morphine (7.5 nmol) and 5-HT (241 nmol), compared to saline (1 ml/kg) but only desipramine facilitated the effects of intrathecally administered NE (0.49 nmol). The chronic (22 day) administration of both tricyclic antidepressants resulted in loss of the enhancement of the effects of morphine (day 22) and 5-HT (day 15); only desipramine (day 15) abolished the facilitation of NE. In a similar study, acute pretreatment with the non-tricyclic antidepressant inhibitor of the reuptake of NE, nisoxetine, (97.5 mumol/kg, s.c.), amplified the effects of intrathecally administered NE and morphine but not 5-HT-induced analgesia. Although chronic (22 day) treatment with nisoxetine caused a loss of the effects of enhancement of morphine (day 8), there was no effect upon the action of NE and antinociception induced by 5-HT was facilitated (day 22). Receptor binding studies indicated that chronic (22 day) treatment with clomipramine, desipramine or nisoxetine reduced the affinity of opiate [3H]naloxone) receptors in the spinal cord. These results demonstrate that (1) acute treatment with trycyclic antidepressants enhanced analgesia induced by intrathecally injected morphine, and (2) the chronic administration of trycyclic antidepressants resulted in a loss of enhancement of the effects of morphine, given intrathecally, which appeared to be independent of alterations in the activity of NE or 5-HT but may be associated with the development of subsensitive opiate receptors.