Antinociceptive activities of heterocyclic antidepressants (HCAs) were studied after intrathecal (i.t.) administration in mice. HCAs with selective norepinephrine reuptake blocking properties (noradrenergic HCAs), such as desipramine and protriptyline, produced different antinociceptive profiles from HCAs with selective serotonin reuptake blocking properties (serotonergic HCAs), such as fluoxetine and citalopram. Noradrenergic HCAs were antinociceptive in all of the three nociceptive tests employed in the present study, i.e., tail-flick (TF) test, i.t. substance P-induced behavioral (SPB) test and intradermal hypertonic saline-induced behavioral (HSB) test. Intrathecal noradrenergic HCAs potentiated systemic or i.t. morphine-induced antinociception in the TF test. Serotonergic HCAs were partially antinociceptive in the SPB and HSB test, but inactive in the TF test. Furthermore, serotonergic HCAs did not enhance the antinociception produced by systemic or intrathecal morphine. The present data suggest that the efficacy of HCAs in the control of chronic pain stems, at least partially, from their action in the spinal cord, their analgesic activities probably involve blockade of monoamine reuptake. and the spinal serotonergic system probably possesses a dual action in regard to spinal nociception, while the noradrenergic system does not.