The activity of clonidine and its interaction with morphine was assessed in the mouse tail flick assay. In this assay, clonidine was found to be 10 times more potent than morphine. Clonidine potentiated morphine antinociceptive activity approximately five-fold and morphine potentiated clonidine activity four-fold. Clonidine's agonstic activity was not reversed by naloxone hydrochloride (10 mg/kg) while the potentiating effect of clonidine by morphine was. Tolerance to the antinociceptive effect of morphine was observed in morphine pellet-implanted mice but no cross tolerance was observed for clonidine. These data indicate that clonidine-induced analgesia is not a result of an interaction at morphine receptors; but rather, common pathway(s) are present which appear to complement the agonistic interaction of each.