Clonidine and morphine depress nociceptive reflex responses when given alone; when given in combination, the effect of each is potentiated by the other. The present study was designed to test if activity in ascending axons evoked by electrical stimulation of afferent C-fibers in the sural nerve of the rat also exhibits potentiation of the depressant effects of clonidine and morphine when both drugs are administered in combination by intrathecal (i.t.) injection to the lumbar spinal cord. For comparison, experiments were also carried out on the tail-flick response in rats. The results show that (1) clonidine produced a dose-dependent inhibition of the tail-flick response (Ed₅₀ 20 μg); (2) a combination of ineffective doses of clonidine (0.3 μg) and morphine (2 μg) significantly inhibited the tail-flick response; (3) clonidine (35 μg) reduced spontaneous, C-fiber-evoked and, due to co-activation, Aδ-fibre-evoked activity in ascending axons; and (4) clonidine at a threshold (0.3 μg) or higher (3 μg) dose administered together with morphine at a dose (2 μg) that caused only a moderate inhibition produced a supra-additive effect in significantly depressing spontaneous, Aδ-and C-fiber-evoked ascending activity. The dose-response curve of depression by morphine alone of C-fiber-evoked activity (ED₅₀ 8 μg) is significantly shifted by clonidine to the left (ED₅₀ 0.9 μg). Naloxone (0.2mg/kg) injected intravenously did not affect the inhibition of ascending activity caused by clonidine at the highest dose (35 μg), but it reduced the depressant effect of combined i.t. administration of clonidine and morphine. The potentiation of the antinociceptive effects of clonidine and morphine given in combination are possibly due to actions of the two drugs at different sites between the nociceptive afferents and the neurons sending their axons to the brain.