Intrathecal delivery of alpha(2)-adrenergic agonists produces an analgesic effect. However, hemodynamic side effects limit their clinical usage. To more fully characterize the effects on heart rate and arterial blood pressure of alpha(2)-adrenergic agonists, clonidine and tizanidine were injected intrathecally in conscious dogs. Both compounds produced a potent inhibition of thermal foot-withdrawal latencies at 1000 micrograms, which was blocked by the alpha(2)-adrenergic antagonist yohimbine. Tizanidine (250-500 micrograms) did not change heart rate. Clonidine (500 -2000 micrograms) and tizanidine (1000-2000 micrograms) decreased heart rate. The tizanidine effect was inhibited by yohimbine and the alpha(2)/imidazoline antagonist idazoxan, as well as the parasympathetic blocker glycopyrrolate. No drug completely inhibited the clonidine-induced bradycardia. Clonidine had a biphasic effect on arterial blood pressure, a decrease at 500 micrograms and an increase at 2000 micrograms. Tizanidine decreased arterial blood pressure at all doses. The results indicate that, while the analgesic effects of both drugs are similar, the hemodynamic responses differ. While the decrease in heart rate with tizanidine is consistent with alpha(2)-adrenergic binding and vagal action, the bradycardia induced by clonidine is more complex. In addition, the increased arterial blood pressure with high doses of clonidine, which is suggestive of a peripheral vasoconstrictive effect, does not occur with tizanidine.